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Science and art of Clinical Research:Role of clinical


Science and art of Clinical Research: â?”Role of clinical

Researcher & Monitor
Kranti Sikha Tripathy


ABSTRACT : Clinical research, though essentially a subset of applied science in so far as the involved aspects of the science of medicine and relevant aspects of life sciences in general are concerned, the design, conduct, interpretation and inferences are intimately associated with human elements like value judgment, ethical considerations, human rights,trust,sympathy,pain scores, feeling of wellbeing and social performance etc.Hence the science of medicine which is the mother of clinical research though traditionally considered to be based on experimental evidence, the art of clinical research is more inclined towards modern quality of life assessment, addressing general feeling of wellbeing, physical activity domain tempered with milk of human kindness, human right considerations and humane discretion. In this context, the role of a clinical researcher and the monitor becomes rather onerous who in their roles of pursuing the essentiality of scientific ends have to balance scientific efficiency with human considerations like subject protection. Successful discharge of their duties does not lie only being text book-driven and rule & regulations-oriented but on value judgment and ethically sound discretion. These difficult roles are to be enacted right from the inception starting from designing the clinical trial protocol through the conduct of the actual trial involving human volunteers and finally ending in inferences and final presentation of the clinical trial results for approval of the regulatory authorities. It is proposed to revisit clinical trial in all its aspects indicating the subtle scientific and art elements involved in each stage and the actions of the researcher and the monitor desired there on based on value judgment and ethical considerations.




Debate still continues as to whether â?oClinical Researchâ?ť is an exact science or an art form .In real practical terms this can be termed a hybrid between, applied science and art. This duality makes the job of a clinical researcher extremely challenging balancing the scientific activities with more demanding aspects of social engineering ,human rights, human kindness, sympathy and value judgements.Clinical research is the very backbone of modern medicines and health care making them the mother of medical innovation and scientific breakthroughs. Clinical research brings the latest therapies and pharmaceuticals from the laboratory to the bed side of human patients. It blends the two worlds, the lab and the clinic and translates basic discoveries into treatment for human disease. Since it begins with participation of human volunteers and the ultimate beneficiaries are human beings, human aspects play a vital role in everything connected with the process. We shall revisit different stages of clinical research and bring out the subtleties of science and art involved in each stage with the onerous responsibilities thrust on clinical researchers and monitors to address them effectively.




Although â?oClinical trialsâ?ť was reportedly first introduced in 1025 A.D ,the first clinical trial was infact documented in 1753 A.D for treatment of the then dreaded disease â?oscurvyâ?ť. It begins with the innovator or clinical trial sponsor and ends with research participants which are volunteering humans. Along the continuum are CROs, site management organization, clinical trial sites, investigators, clinical research coordinators and CRAs.



Before the actual human clinical trail begins, it is imperative morally and legally to zero in on an, â?oactive lead compoundâ?ť selected out of several â?opotential candidate drugsâ?ť perhaps through an elaborate mechanism involving,â?ť lead compound committeeâ?ť and â?oproduct development representativeâ?ť. These trials involve in-vitro( test tube or lab) studies and in-vivo ( trials on animals ) studies so that chances of precious human lives at risk are minimized and required preliminary efficacy, toxicity and pharmacokinetic data merits to go in for human trials.Pre-clinical testing from initial synthesis to animal testing takes from 1 to 3 years. Documentation of the experimental data is required to obtain the IND number (Investigational new drug number) from FDA (USA) to go in for human trials which starts from Phase-0 and ends in Phase-IV( Five phases, the last one being post-marketing surveillance test).




Developing a new drug product or device takes a very long time and also involves huge lot of money. It has been estimated that the average time between submission of application for new drug approval (ANDA) to obtaining approval from FDA is 8.5 years and involves an expense of $802 millions for a new prescription drug. Hence before committing such cost-intensive proposition, in-depth analysis need be made by sponsors prior to go in for human trials. Such analyses comprise the expected benefits, harms, cost of adopting and translating a clinical finding in to practice. One such method is called,â?ťCost-effective analysis (CEA)â?ť and the methodology is depicted here below:



C1-C2 Net Costs

CEA =????? or ??????

O1- O2 Net health outcomes



â?oCâ?ť, stands for cost associated with an intervention and suffixes 1 and 2 are alternatives

â?oOâ?ť, stands for outcome of the interventions (1 and 2 are two alternatives)


Net costs is the sum of cost of the intervention and cost of treating the side effects minus the costs averted because of the intervention (i.e. costs of care for the prevented disease condition)


Outcomes in case of CEAs are measured in different ways. One such method is measured in terms of â?oLife years saved (LYS)â?ť.This method accounts for how an intervention strategy affects mortality. However it does not take into account â?othe quality of lifeâ?ť associated with different health outcomes. To capture both the effects of life years saved and QOL (quality of life ),the number of years with illness or injury can be multiplied by a weightage factor varying from 0 ( death ) to 1 ( full health ) to generate, â?oquality adjusted life years (QALYS )â?ť.CEA that uses QALYS in the denominator of their cost effectiveness ratios are often referred as â?ocost utility analyses ( CUAs )â?ťbecause they incorporate peopleâ?Ts preferences or utilities for different status of health, illness and injury ( CUAs are subset of CEA ).Economic analyses other than CEAs serve as cost-minimization analyses and â?o cost-benefit analyses(CBAs)â?ť also provide information about potential value of the intended clinical research/trial.



This theory which stipulates that rightness or goodness of the action in taking up the clinical research work is based on the potential consequences. The most ethically praiseworthy action according to this theory are those that maximize the good for the greatest number amongst humanity. It is essentially a balancing act between scientific efficiency and protection of research subjects and forms the rationale for taking up the study through clinical research.




The next step is to formulate an action plan of the impending trials which is popularly known as â?oClinical trial protocolâ?ť. The plan describes, what will be done in the study, how will it be conducted and why each part of the study is necessary and each study has its own rules about who can participate. This document should be a well thought of and scientifically based coming out of theâ?ť thinking hatâ?ť which needs to be innovative and need-based although standard templates are available for overall guidance. The most common elements include background and significance, specific aims or endpoints, inclusion and exclusion criteria, study procedure and statistical designs with an overall sound rationale for a clinical trial. Here science and art are judiciously integrated to make it scientifically attractive and innovative.




This is perhaps the first field action taken in the pursuit where ethical and scientific considerations are interwined.There are networks of regulations in different countries but the common thread arose in response to abuse of human research participants. There are several international guidelines and codifications ,the main guidelines being, The Nuremburg code, The Declaration of Helsinki, The Belmont Report (USA), International Conference on Harmonization Guidelines for good clinical practice(ICH GCP) setting standards at the international level for the rights, fairness ,respect,beneficence,justice and privacy of human trial subjects.Traditionally,the science aspect of the clinical trial is considered to be based on experimental evidence while art aspect of the trial is based on trust,sympathy,the threatened patient and other human aspects like pain scores, feeling of wellbeing and social performance that transcend mere statistics. The art of medicine is more and more turned into science i.e. with modern quality of life assessments addressing general feelings of wellbeing; physical activity domain etc.Each study component has an ethical aspect. These ethical aspects can not be separated from the scientific objectives as ethical and scientific aspects jointly make a successful clinical trial. The researcher should focus on,â?ť what ought to be doneâ?ť in research involving human subjects. At this stage, the aspect of,â?ť informed and voluntary consentâ?ť of the human subject coupled with inclusion and exclusion criteria occupies center stage in respect of subject selection without any bias. The statement,â?ť Bad science is bad ethicsâ?ť is true here and the intersections of scientific goals and ethical concerns should be properly addressed by the clinical investigator and his/her team together with the monitor and coordinator. The clinical researcher should ask some very valid questions to himself/herself and should proceed ahead only on the basis of appropriate answers:


? How much risk of harming a study volunteer is too much risk?

? What protection ought to be built into a protocol that involves cognitively or socio-economically vulnerable research subjects?

? How should it be determined whether the benefits of the new knowledge to be gained through the instant research for the society is sufficiently important to place research subjects at risk of harm or even at risk of more inconvenience?

? If a study does not promise potential direct benefits for subjects, will the studyâ?Ts result be significant or important enough for society to counterbalance the risks or inconvenience a subject may experience during the trial?

? While designing consent forms, how much information is the â?oright amountâ?ť?


Understandably, the ethical tension inherent in the relationship between the goals of a clinical medicine or device and those of clinical research is necessary to develop excellence in research involving human participation. The clinical investigator must understand the subtle distinction between clinical care in research and standard clinical care. Being a successful clinical researcher, means being a master at achieving two goals concurrently â?”the goal of achieving scientific advancement and due protection of human subjects.




These trials may be of five types namely,â?ť prevention trialsâ?ť,â?ť screening trialsâ?ť,â?ť diagnostic trialsâ?ť,â?ť treatment trialsâ?ť and â?oquality of life (QOL) trialsâ?ť. Conventionally, the different phases in sequence begins with Phase-0 and ends in Phase-III on successful completion of which drug approval for the new drug is accorded by FDA (USA).The subsequent phase is Phase-IV which is a post-marketing surveillance trial to collect comprehensive data on safety. efficacy, dosage requirements and adverse side effects after long use of the invented drug candidate. In all such human trials, the fundamental design rests on aspects of randomization, blind or double blind and placebo effect controlled trials in contrast to the usual purely evidence-based trials.

Randomization means that each subject is assigned a random number (based on statistical random numbers) so that each subject either receives the study treatment or a placebo treatment (fake treatment) but without his knowledge.

Blind means, the subject does not know which treatment he is receiving. Double-blind means both the investigator and the subject are not aware of which treatment is being given by him/her and which treatment is being received by him/her respectively. The main underlying principle is to isolate the effect of the drug being studied and to prevent human bias in study. The other important parameter is the number of subjects involved in the trial which has a large bearing on the degree of reliability of the research at hand. This is described as, â?opowerâ?ť of the trial.


3 .0 Roles of Researcher and Monitor:


Most monitors and investigators start their job in confusion as to whether they should treat the subject as pure science or a form of an art.Unfotunately,the job is difficult to clearly delineate since it is more art than science, more luck than skill and more experience-driven than textbook-driven. For example, a monitorâ?Ts responsibility is toâ?ť monitor the conduct of a research trialâ?ť and this is what we observe while looking to the code of Federal Rules (CFR).There are no guidelines or rules that outlines the tasks appropriate for a site visit and there are no rules to specify the frequency of such visits. Hence to monitor trials effectively value judgment more than specified rules are necessary. It is also important that monitors and researchers anticipate study-related hurdles and necessary regulatory filings to enable the research team to meet the challenges both at the qualitative and quantitative front. Proper â?obenchmarkingâ?ť should be incorporated: (a) to increase credibility of research studies (b) to identify key opinion leaders and investigators for protocol design input and clinical trials (c) to evaluate commitment, skill and qualification of the research team particularly the investigator (d) to create effective structures for both internal and external accountabilities (e) partner to leverage CRO expertise amongst other things. Beyond reviewing patient records, a good monitor needs to take a global â?osnapshotâ?ť of how each patient is progressing during the trial. This snap shot is useful for confirming that a patient is receiving adequate care, the collected data is coherent and the trial is progressing satisfactorily. If any of the elements of a snap shot seem questionable, it becomes the responsibility of the monitor to discuss those concerns threadbare with investigator, coordinator and even the sponsors. In those circumstances, it is difficult to know whether the treatment is having a favorable effect, no effect or even adverse effect. The best way to answer the real- life scenario is to meticulously scrutinize whether the subject(s) have really gone through random, double-blind controlled clinical trial procedures. Being a good monitor means being a good manager also, leading from the front, fostering team spirit and building up synergy in the organization. The ethical and scientific aspects of the trial must be in sync and no compartmentalization should be allowed. Ethically sound clinical research understands the implications of how, when, why and where there are conflicts between meeting scientific research goals and protecting research participants. The goals of science also conflict with the goals of clinical care when a physician recruits his/her own patient into a trial in which the physician happens to be an investigator.Here.at risk is a physicianâ?Ts objectivity in decision making since the difference between the goals of a clinical medicine and the goals of a clinical research is not the same thing. Although separation of the roles of an investigator and a clinician may neither be practical nor desirable, the clinical researcher should be alert to these differences and the potential conflicts. The other aspect that comes to my mind is the â?oquality managementâ?ť of research. This should mean both quality assurance and quality improvement.

While submitting the final report of the clinical research, it is necessary to take a dispassionate view of the entire pursuit rather than finding out alibis to be able to project an attractive and rosy picture to satisfy both tangible (may be economic gains) and intangible benefits ( may be ego or image considerations).




1 .www.pubs.acs.org/subscribe/journals/mdd/v04/i03 clinical.html


3 .www.books.google.co.in (Introduction to the Art and Science of Clinical research)

4 .www.books.google.co.in (Statistics applied to Clinical Research)

5 .www.mh.bmj.cm

6 .www.ahrq.gov/clinic (American journal of preventive medicine)

7 .www.books.google.co.in (Clinical Research-What it is and How it works?)

8 .www.nlm.nih.gov/medline plus/clinical trials.html

9 .en.wikipedia.org/wiki/clinical_trial

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Role of ICH GCP and Recruitment Strategies Training of Clinical Sites Staff in Successful Patient Recruitment Rates


Role of ICH GCP and Recruitment Strategies Training of Clinical Sites Staff in Successful Patient Recruitment Rates

By Marithea Goberville, Ph.D. [email protected]



Clinical development of any drug relies on successfully recruiting patients within the project time frames to meet development and regulatory milestones. Poor patient recruitment is the number one reason clinical trials fail or experience costly delays. This article examines how successful subject enrollment is affected by ethical and regulatory standards, and recruitment strategies training of clinical sites staff. The analysis herein synthesizes the literature in key areas related to patient recruitment, such as regulatory and ethical issues, incentives, protocol assessment, investigator obligations and training of clinical sites staff. Based on a review of the literature, it is clear that higher patient recruitment rates can be accomplished through a renewed commitment of clinical site staff and investigators to the application of high ethical and regulatory standards. This is essential to consummate in order to guarantee that societal trust in research is not eroded, therefore assuring subjects that risks are minimized, there are safeguards to protect them, and provisions exist to protect their privacy. It is also evident that all staff members involved in subject recruitment must receive the necessary education and training to equip them with the information they need to ensure that every potential participant is motivated, has a clear understanding of the protocol, and has as much knowledge as possible to make an informed decision.



One of the most critical success factors in clinical development is to motivate patients to participate in the clinical trials that eventually lead to new drugs. In 2001, over 85 percent of all completed medical research studies experienced recruitment delays, and 34 percent were delayed for more than one month.1, 2 â?oTime to marketâ?ť is one of the most important phrases in clinical research. The faster a company can get a product approved, the more financial value it will have for the company. Delays in getting a drug to market can be very costly to pharmaceutical companies: as much as $1 million per day for a drug destined to make half a billion dollars in annual sales.3 Given this information, it is easy to understand why patient recruitment has been called â?othe most difficult and challenging aspect of clinical trials,â?ť with flaws in recruitment identified as one of the weakest links in the new drug development chain and thus one of the main reasons for the failure of clinical studies.4, 5, 6, 7

Contributing to the increased pressure for effective patient recruitment are the rising demands of regulatory bodies for an increase in the number of trials per new drug application (NDA) filed and a rise in the number of patients required per trial. This creates a challenge for both sponsors and clinical research organizations (CROs), because more than 5,300 patients are needed per NDA, a figure that has jumped 32 percent since the early 1990s (Figure 1).8 Some conclude that this increased number of subjects required for NDA clinical trials could reduce post-marketing adverse events, therefore making recruitment strategy crucial to the success of a trial.3, 9 On the contrary, it can also be argued that the nature of the drugs being tested affects the number of subjects needed for a trial. 3, 9


Figure 1: Average number of eligible patients per NDA (Source: Tufts Center for the Study of Drug Development, 2002).8


Low patient enrollment rates typically have several negative implications, such as a more expensive clinical trial in which extra resources may be dedicated to the recruitment effort, longer duration of clinical trial which lowers morale of staff and participants, and less statistical power for the study and validity of the results.10 In addition, poor clinical trial recruitment and retention will not only impede the successful evaluation of new and existing interventions, but it will also prevent greater efficiency in clinical development.11 Based on this information, the subject recruitment period is considered a key phase in which the industry is believed to have the least control. Current enrollment strategies do not respond to the need for consistent, on-time recruitment; a broader strategy is required. If the patient enrollment period in clinical trials could consistently be reduced, it would cause a major advancement in optimizing the drug development process and preserving economic health. Unfortunately, human beings are very good at routinely pushing back deadlines, believing that we are successful at meeting timelines, while project schedules, if left unchanged, are almost never met. This deadline push back can also be applied to investigators who have seriously overestimated the patient recruitment potential. Based on this phenomenon, â?oLasagnaâ?Ts Lawâ?ť was coined in 1970s to describe this methodological error in enrollment estimates and has become the most popular rationale for clinical trial delays. Given that the current enrollment period represents about 50 percent of the duration of a clinical trial, the overall development program would take 25 percent less time if the recruitment phase shrunk by half. Faster and more successful enrollment, when achieved, would accelerate the drug development process to speeds not yet seen globally and restore the competitive edge to the industry.12

Patients today want more from their experience as trial subjects. They have less trust and more knowledge than ever before. As a result, they do not simply want to be trial subjects, but often want to participate in N=1 trials.13 Optimizing patient recruitment is a topic that has received much attention in the medical literature14 and this article will be no exception. The current article will address the practical matters of primary importance to successful patient recruitment: the impact of relevant ethical and regulatory issues, and the roles of the clinical investigator and sites staff.
More than just Standards
Regulations and ethical standards of practice are indispensable for maintaining scientific quality, whether a trial is conducted within a single institution or across multiple centers. All of us want the drugs that are prescribed for us to be safe and effective to treat our ailments. Therefore, it is the role of regulatory authorities to ensure that pharmaceutical companies comply with specific guidelines. One of these guidelines is the International Conference on Harmonizationâ?Ts (ICH) Good Clinical Practice (GCP). GCP is â?oan international ethical and scientific quality standard for designing, conducting, recording and reporting clinical trials that involve human subjectsâ?ť.15 Compliance with GCP provides assurance that data and reported results are credible and accurate, and that the rights, safety, confidentiality, and well-being of trial subjects are protected. GCP is not just one set of safety standards, issued by one regulatory agency, or found in one document. Instead, the GCP standard evolved over time, is recognized by regulatory agencies around the world, and includes the procedures by which drugs and devices are approved for human use. The ICH brought together regulatory agencies and industry representatives from the United States (US), Europe and Japan â?” and observers from all over the world â?” to agree to a single set of technical requirements for the registration of pharmaceuticals for human use. The ICH GCP Guideline is a joint initiative between government regulators and industry manufacturers.16 Government and industry representatives work together closely to ensure a smooth development of ICH guidelines that address industry concerns while maintaining the most prudent standards for consumer safety.

Given the regulations and guidelines that exist, how do pharmaceutical companies ensure that regulatory standards are implemented and followed? Several regulatory bodies in the US, such as the Office for Human Research Protection (OHRP), along with the Department of Health and Human Services (HHS), Food and Drug Administration (FDA), National Institutes of Health (NIH), Institute of Medicine (IOM), National Bio-Ethics Advisory Commission (NBAC), and the Institutional Review Boards (IRBs) ensure that the clinical trial process, which includes the very important aspect of patient recruitment, is conducted in full compliance with the ICH GCP guidelines. The IRBs consist of committees of experts and lay persons who review the research as it proceeds. Watching the IRBs are the FDA and other federal agencies such as the National Institutes of Health (NIH), whose rules are designed to protect subjects taking part in medical research.

The primary responsibility of the IRBs is to assure that all ethical issues have been fully addressed in the protection of human subjects who volunteer to participate in clinical trials. To fulfill this responsibility, the IRBs are guided by three main principles: i) subjects must be informed about the nature of the study â?” details of participation must be voluntary, ii) benefits of the research must outweigh the risks, and iii) promoting fair procedures in the selection of subjects. The IRBs meet to review the protocol, or research plan, for the proposed project and may approve or disapprove it or make changes before granting approval. It must also review, approve or disapprove the informed consent form that is presented to potential trial subjects. The IRBs also conduct annual continuing reviews while the project is under way. These reviews ensure that: i) risks to subjects are minimized, ii) selection of subjects is fair and equitable, iii) there are safeguards to protect subjects, iv) informed consent is employed and documented from each subject, and v) provisions exist to protect the privacy of subjects and maintain confidentiality of the data.

Clinical study subjects, who may or may not even benefit from the trial, and who accept some degree of risk in participating, deserve the assurance that their protection is top priority. Subjects taking part in clinical trials are not always patients in hospitals and institutions. Many are patients of private practitioners involved in clinical research. Few are not patients at all, but are healthy individuals who have been recruited for a study through a newspaper ad, poster, or other source. FDAâ?Ts IRB and informed consent regulations ensure that research subjects are informed and willing participants, who understand all the risks and benefits of the study, and that their health and safety are not unnecessarily endangered. According to these regulations investigators/researchers must i) provide subjects with adequate information about the study, ii) discuss in full detail questions subjects might have about the study, iii) be sure all the risks and responsibilities of participation are understood, iv) ensure that the subject is aware of other options (if receiving treatment) and what the advantages and disadvantages are, v) obtain the subjectâ?Ts voluntary consent to enroll in the study and, vi) ensure subjects that their privacy is protected. Written consent must be obtained from study participants before any study-related activities are performed. The informed consent process can be a serious â?~mental blockâ?T for potential study participants and there are several factors that might influence the subject recruitment outcome: i) qualifications of those administering consent, ii) conflicts of those administering consent, iii) how well the information in the consent form is understood, iv) where the subject can obtain more information on the study or his/her rights, and v) to what extent subjects should know about investigator and institutional conflicts of interest. Another aspect of the informed consent process is that of privacy authorization. Due to increasing public concern about loss of privacy and the fear of discrimination based on abuse of sensitive health information, the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule was created.17 This Privacy Rule ensures national standards and establishes appropriate safeguards to protect patientsâ?T medical records and other personal health information. It gives patients the right to examine and obtain a copy of their own health records, and it empowers them to control certain uses and disclosures of their health information. Privacy authorization must be obtained from each participant, as part of the informed consent process, granting permission to disclose his or her protected health information (PHI). With this privacy safeguard in place, increased subject recruitment might be encouraged because potential participants will have assurances that private information will remain private. Therefore, it is important that investigators and their staff are educated and trained to present the information contained in the informed consent and privacy authorization documents in a way that facilitates potential subjectsâ?T true understanding about a trialâ?Ts risks, benefits, safety and privacy measures. Educating participants in the clinical trial process as well as the measures in place to protect them will make them more likely to participate in a clinical research study. A European survey indicated that 71 percent of individuals were not aware of patient protections such as the Declaration of Helsinki, ethics committees, and the informed consent process.18 These responses were consistent with another survey in which 40 percent of Americans said they would be more likely to participate if they were informed of the protective measures and 85 percent felt that more public education is needed.19 Therefore, improving the communication involved in informed consent should increase study participant enrollment. Such communication imparted at an early stage of the patientâ?Ts participation in the trial would mitigate the premature termination of patients from withdrawal of consent due to perceived lack of protective measures.


Offering Incentives to Participants
Despite the tension between the need to recruit subjects and the obligation to offer them certain types of protection, a different but equally crucial issue concerns the types of inducement investigators can offer recruit subjects. Payment to research subjects is reportedly a common practice in the US, although no empirical data have been published documenting the nature and extent of this practice.20, 21 Therefore, not much is known about the amount, method, and timing of payment to subjects who agree to enroll in clinical research. However, the FDA information sheets for the IRBs state that financial or other forms of incentive should be based on the time involved, the inconvenience of the subject, reimbursement for expenses while participating, and should not be so large to constitute a form of coercion. Compensation to trial participants is not considered a benefit, but merely a recruitment incentive.22 Financial incentives are often used when health benefits to subjects are remote or non-existent, for example: Phase I healthy volunteers who are not taking part to benefit from the drug itself. The trial sponsor and investigator will jointly make the decision about how much subjects are paid. The amount and schedule of all payments are presented to the IRBs at the time of initial review. IRBs will then review the level of payment to ensure it is appropriate, and if compensation is too excessive it will not be approved. Lump sums paid upon completion of an entire study are generally not acceptable to the IRBs. In most cases, pro-rated reimbursement is more acceptable, providing that such incentive is not coercive. The IRBs also requires all information concerning payment, including the amount and schedule of compensation, be outlined in the informed consent document and discussed with the subjects prior to enrollment.

Payment levels can be a very complex issue, because if the financial carrot is too big, it can become so enticing that it impair peopleâ?Ts judgment, make them accept risks and do things that they would not or should not otherwise do. According to the IRBs, an overly attractive offer might cause potential subjects to misrepresent themselves since they want to be eligible for the study. This can be a problem both for the safety and well being of the subject as well as the validity of the data. On the other hand, it should not be overlooked that too little compensation can have a negative influence on patient recruitment rates in the more educated developed countries. The reason is simply because subjects recruited in the western world are more clued in about clinical trials, they have higher expectations, are more inquisitive and are more demanding than patients recruited in developing countries.

The circumstances under which potential trial subjects make decisions should be as free of influence as possible, recognizing that the influence of circumstances is hard to separate. We are all influenced by a myriad of different things, including our health and social conditions. Therefore, before participating in a clinical trial, it is necessary that both investigator and subject discuss the study and the subjectâ?Ts role in it until both are satisfied that the subject can make an informed decision about whether to participate. It is the responsibility of IRBs, investigators and clinical sites staff to help ensure that any potential conflict of interest stemming from financial relationships are identified and eliminated or managed with the subjectâ?Ts best interests in mind.


Study Protocol Assessment and Considerations

A clinical trial starts with developing a study protocol that is feasible without being too restrictive in its inclusion/exclusion criteria.23 It can also be argued that patient recruitment strategy/efficacy starts at this point. Study designs that are conceptually simple, and that address questions of clinical relevance where genuine uncertainty exists, are likely to facilitate the recruitment of participants. Sometimes, it is so easy to design a protocol that is scientifically thorough, but is not practically possible to execute. There exists an understandable desire to maximize treatment differences and avoid analytical bias through â?~cleanâ?T protocols; but on the other hand, the clinical reality is full of â?~greysâ?T, and so a naturalistic approach is also important.23 According to the literature, several aspects of study protocols contribute to poor patient recruitment, such as protocol designs with eligibility criteria that are so tight that potential study subjects do not qualify for entry and protocols that are too difficult for investigators to follow due to overly complex study designs.24, 25, 26 Furthermore, protocols that require substantial efforts on the part of investigators can leave them with a lack of enthusiasm and full support for the design and aims of the study protocol, resulting in low recruitment rates.27 There is very little evidence in the literature on the importance of thorough review of clinical trial protocols to identify potential problems prior to their initiation.28 The process of systematic appraisal of the protocol should be a main concern to the investigator prior to agreeing to participate, since it will allow for identification of problems, and ensure that the site staff knows what is expected from them and has made an informed decision to participate. This is a crucial step because overall it can improve not only patient recruitment rates but also the clinical research process through trial sites taking a proactive role in the design and conduct of clinical trials. Following protocol appraisal, clinical sites staff and investigators should take the necessary measures to guarantee that everyone on the team is well-trained and educated in the investigative study protocol. These competencies will result in consistent adherence to study schedules, significantly fewer protocol deviations, and lower screen failure and dropout rates. However, the easiest way to ensure feasible study designs from initiation is for sponsors, CROs and anyone involved in planning trials and writing protocols to take subjectsâ?T lives into consideration. The needs of participants should be anticipated and accommodated early enough in the protocol design and development period, thereby designing systems and protocols that are not just good on paper, but will work for the subjects. Therefore, creating study protocols with patient perspectives in mind, the likelihood of successful enrollment can be increased.


Recruitment and the Placebo Orthodoxy

A critical aspect of study design is the choice of an appropriate control arm, which can enhance investigator interest and comfort, particularly if the control arm reflects good clinical practice. In the development of new drugs, trials are designed with a control capable of allowing investigators to discern the effects of the drug under investigation. One of the best means to fulfill this requirement is to compare an investigative therapy with a placebo, which can be double or triple-blind.29, 30 Implicit in a placebo trial is the idea that the choice is between â?~thisâ?T treatment and â?~noâ?T treatment. Blinded placebo-controlled trials have sometimes been the source of anxiety on the part of the prospective participants and public, usually because an element of deception seems to be involved, or because patients who are allocated to the control group may seem to be at an unfair disadvantage.31, 32, 33 Some people with serious and life-threatening diseases are concerned about the impact of being randomized to a placebo treatment and how this might affect their illness.34 Consequently, subjects are reluctant to participate, making it very hard to recruit patients for such studies. This phenomenon was also evidenced by Welton et al. who concluded that, for preventative trials, the inclusion of a placebo arm may reduce a patientâ?Ts willingness to participate.35 When a placebo is used in a controlled study there is always a question of what to do for the subjects that have been randomized to the non-active treatment arm of the study. In such cases, critics argue that patients in the control arm of the study should receive an accepted therapy rather than the placebo. By using an active and effective drug, control patients would not be placed at risk for deterioration of their disease. Therefore, the key question is not whether a new therapy is better than nothing but whether it is better than the current standard of care.36, 37 On the contrary, critical information cannot always be obtained by giving control patients an existing therapy. For some effective therapies, the drug may perform no better than placebo in a particular trial even though other trials demonstrate the drugâ?Ts superiority to placebo. Also, drug companies are often reluctant to compare their new discoveries against a proven therapy, especially against a therapy that may soon go generic, because they may not ultimately establish an â?oefficacyâ?ť or â?ocostâ?ť advantage. Due to the controversy surrounding placebos, the FDA has allowed some accommodations in the clinical study design that do not sacrifice the critically important information that investigators gain from use of placebos. For example, the FDA allows â?ocrossoverâ?ť studies in which each subject serves as his or her own control and therefore, no one is denied the active compound. In crossover studies, patients will take a placebo for a certain period of time, and then crossover to the investigative drug for an equal amount of time. On the contrary, patients might begin with the active treatment, and several weeks later crossover to the placebo. This study design not only allows for groups of patients to be compared, but individual patient results can be measured when on each â?otreatment arm.â?ť In certain cases, patients might be willing to participate only if they receive a particular treatment. The crossover insures that each subject will receive both treatments. Although the crossover study design is not flawless, it is certainly at present the best alternative to placebos. Based on the concerns about placebo-controlled study designs, patient education can play a vital role to ensure that the subjects understand that they may not derive any benefit from the compound under investigation. In placebo-controlled studies, treatment should only be conducted after the patient has given informed consent to participate and has been enrolled. Prior to making a decision about whether to participate or not, patients should be informed of the alternative forms of treatment under study. Also, study sponsors and investigators need to improve their understanding of the extent to which placebo controls have a role in clinical trials.


Investigator Obligations
A successful clinical trial depends upon the clinical investigator doing his or her job. As the number of new medical products that are brought to the market grows, the number of clinical investigators involved in clinical trials is expected to increase. According to an article in CenterWatch, there are more clinical investigators than ever before carrying out industry clinical trials (33,000 in 2000). By 2005, clinical research, which includes pharmaceutical research, will need 56,000 clinical investigators for industry-sponsored drug development alone.38 The tremendous growth in the clinical research market has attracted a significant amount of inexperienced clinical investigators, evidenced by the fact that only one quarter of investigators have more than five years experience and 63 percent are new to the field.38 This proliferation of inexperienced investigators is also due, in part, to sponsorsâ?T increasing acceptance of non-academic investigators. The acceleration of competitive forces in the investigator marketplace is partly driven by narrowing profit margins. Therefore, more and more physicians have turned to clinical trials to compensate for managed care-driven reductions in patient-care revenue or simply as something of interest to become involved with.39, 40 Consequently, we have an industry filled with first-timers who are learning from their own mistakes as they go along, and in the process using valuable time developing their own procedures instead of using what is already â?otried and testedâ?ť by others.41 Moreover, it is evident that the potential impact of the number of relatively inexperienced investigators is magnified by a medical education system that has not been designed to teach research practices or research ethics.

Timely enrollment of subjects into approved clinical trials is desirable, but care must be taken to ensure that the interests of patients are not jeopardized during the recruitment process. Many ethical and legal concerns exist regarding incentive payments to investigators for increasing or expediting subject recruitment. Incentives can include monetary payments, reimbursements for travel, or other expenses that may not be study related such as finderâ?Ts fees and payments for enhanced enrollment. Financial incentives to physician-investigators as well as private physicians for accelerated patient enrollment, is commonplace. These incentives may cause physicians and physician-investigators to stretch inclusion and exclusion criteria for the trial in order to enroll as many subjects as possible, thereby compromising the validity of the trial. As a result, it is not surprising that the inability of physicians to integrate their roles as caregivers and that of scientists often confuses patients as to the nature of clinical research.42, 43 Patients are an important source of subjects in both academic and independent research settings. Unfortunately, financial incentives often stand in the way of the true intent for subject recruitment; for example, physicians have been reported to enroll patients who do not even have the disease being studied. Such participation of ineligible subjects is a major concern that can affect human-subject safety and data validity.44 Also, physicians with no knowledge of the disease being studied are participating in trials, resulting in data not always being accurately collected.45, 46 A recent survey reviewed the widespread financial relationships among industry, investigators, and academic institutions and how the conflicts of interests arising from these ties, can influence biomedical research in important ways.47 Conflicts of interest, whether financial or non-financial in origin, may at times, if not examined and addressed, adversely affect participantsâ?T understanding of research, or the voluntariness of their participation. Potential subjects as well as the public are increasingly aware of and concerned about possible conflicts of interest and should be provided appropriate information about possible conflicts prior to enrollment. Moreover, investigators should attempt to eliminate, reduce, or properly manage such conflicts wherever possible.


Clinical Sites Staff: The Need for Training
According to an analysis in CenterWatch, 40 percent of all pre-qualified volunteers fail to enroll due to lack of responsiveness from study site personnel.48 Medical professionals and funding agencies do not seem to recognize the importance of a trained, experienced, multidisciplinary team in setting up and coordinating a clinical trial.49 An educated and well-trained clinical sites staff is key to the successful implementation of Phase I-III clinical trials. According to Gennery, training is one of the most critical areas in the process of GCP.50 The European Forum reported that many of the research staff are not fully educated about the principles of GCP rules.51 Therefore, it is important that the clinical sites staff is well trained in GCP guidelines to ensure patient safety and the accuracy of reported data. A staff that is well trained in the prospective investigative treatment will ensure that during the informed consent process, patients i) have a clear understanding of the study protocol, ii) are motivated and iii) that they have a complete comprehension of that what is expected of them. As a result, removing all these possible communication gaps will prevent subjects from having unrealistic expectations of the clinical trial.10, 52 Also, in most instances, in order to enroll enough participants, multiple approaches will have to be used by the staff – the siteâ?Ts recruiting practices may vary according to the type of study. The recruiting strategies used for a study involving the elderly should be different from that used in recruiting younger patients. Therefore, developing recruiting strategies specific to every study that is undertaken, will have a very positive effect on the participants and should increase recruitment rates significantly.
Follow-up must become a key responsibility of the clinical sites staff to improve subject recruitment and retention rates. Many published clinical trials have less than adequate follow-up. When conducting clinical trials, investigators attempt to minimize data loss; however, some data may not be collected, particularly when subjects are lost to follow-up. Thus, the completeness of follow-up has a profound effect on the quality of the results, so every effort should be made to maximize it. Follow-up rates of less than 80 percent seriously affect the validity of the results and reduce the chances of their publication by good quality journals.53 Also, real differences in outcome between control and treatment groups may be diluted by poor follow-up rates. Where clinical visits are an important element of the trial protocol, clinical sites staff can improve attendance rates by the following strategies: make a reminder phone call before a visit, make a reminder phone call as soon as possible following a missed visit, make the experience at the clinical site as pleasant and simple as possible, providing clinical hours that are convenient for participants, and consider home visits for those who are unable to attend assessment visits. These follow-up strategies can provide support and motivation for subjects and significantly improve retention.


Importance of Clinical Research SOPs

In order to assure ethical and informed enrollment practices, it is essential that investigative sites impose standards for subject recruitment. One of the best ways to ensure that these standards are met is to formulate and follow standard operating procedures (SOPs). These procedures can transform the actions of every clinical sites staff member into coordinated clockwork that will ensure operational efficiencies and regulatory compliance vital to the success of patient recruitment. SOPs are defined by the ICH as â?odetailed, written instructions to achieve uniformity of the performance of a specific function.â?ť These documents are necessary to achieve maximum safety and efficiency of the performed clinical research operations. Besides the efficiency benefit, a clinical site developing SOPs profits from the fact that it enforces and facilitates the difficult and most critical phase of interpreting and implementing GCP regulations and guidelines to its own clinical research practice. For example, applying and explaining GCP regulations and guidelines with examples of the investigatorâ?Ts clinical research specific-SOPs helps to ensure a more practical and meaningful interpretation of GCP documents and enhances learning for the investigator and his or her team. It is important to note that SOP is not the same as GCP and vice versa. However, when GCP trainers integrate and reference well-written and comprehensive clinical research-specific SOPs into GCP training, they will emphasize the importance and relevance of SOPs and they will help enhance GCP compliance.54 Consequently, it is safe to say that clinical sites that do have SOPs for patient recruitment procedures have a higher probability of being GCP compliant and having better productivity, resulting in higher enrollment rates, subjects that feel secure about their safety and credible data collected.


Outsource patient recruitment training
Several options exists to ensure that clinical sites staff is well-trained and knowledgeable about recruiting subjects for clinical research. For example, recruitment strategies training can be outsourced to training companies such as BBK Healthcare and Kriger Research Group International (KRGI). KRGI is an international CRO that also provides professional training services. Their training is geared towards the whole spectra of issues critical to the successful operation within the pharmaceutical industry and clinical trials. KRGIâ?Ts training program for clinical sites staff and employees is very flexible in that the training can be provided virtually or on-site, and training modules can be customized based on the siteâ?Ts specific SOPs. BBK Healthcare is a consulting firm that offers strategic training for developing and fine-tuning a clinical siteâ?Ts ability to support enrollment efforts. With the help of an advisory board, BBK Healthcare has established an initiative called Good Recruitment Practices (GRP), a set of principles for improving the recruitment of study participants by combining the best practices of clinical research (including GCP) with the marketing science of health care communications.55 The ultimate goal of GRP is to improve the benefits afforded to subjects who participate in clinical research studies through education and guidance provided to sponsors, investigators and clinical sites staff.

Another possible option for clinical sites staff to receive training is for pharmaceutical companies to sponsor trial-site education, such as courses offered by the National Institutes of Healthâ?Ts (NIH) Human Participants Protection Education for Research Teams.56 These courses will teach clinical sites staff how to: i) maximize recruiting efforts cost effectively, ii) clarify FDA policies and considerations regarding review of patient recruitment materials for clinical trials, iii) emphasize GCP compliance, iv) utilize proven methods that sponsors have used to increase patient enrollment, and v) enhance communication strategies for clinical trial recruitment. These courses will result in a clinical sites staff that better understands the regulations involved in clinical research of human subjects and that has a better comprehension of their own responsibilities in planning and conducting clinical trials. Training will ensure proper clinical trial conduct by investigative sites staff, and will guarantee protection of the rights and safety of human subjects in research.

Apart from outsourcing the training of clinical sites staff, training can also be provided within the sites by staff members such as Research Subject Advocates (RSAs).57 The RSA is trained in ethics, compliance and regulatory affairs, and also assists investigators with the design and conduct of clinical trials. Moreover, the RSA serves as a go-to person for research subjects when subjects have questions or concerns about the study, their safety and welfare, or their rights as volunteers in the research process. Another important role that the RSA plays is that of educator. RSAs teach research ethics to clinical investigators and the site staff and conduct routine seminars. Therefore, having an RSA as a member of a clinical sites staff is beneficial for ensuring a highly educated and well-trained staff that is vital to the successful enrollment of study participants. Unfortunately, most of the clinical sites hardly have enough staff to conduct all other aspects of a clinical trial, having an RSA on staff might not be within the budget of many sites.


There is a compelling national need to recruit human subjects to participate in clinical research â?” a need vital to the continued progress and discovery of new, effective drugs. Based on the findings in the literature, patient recruitment rates can increase dramatically if investigators and clinical sites staff are motivated, well educated and supported with tools to discuss study participation with patients, since they are the ones who actually interact with potential subjects and most often lead recruiting efforts. Moreover, they should make potential subjects feel respected, safe, and fully informed about their decision to participate in clinical trials. The more potential participants understand the connection between the clinical research process and the ethical and regulatory standards in place to protect them, the more likely they will be to support and participate in clinical trials. Successful recruitment may also depend on how a patient is approached about participation, and the level of awareness the public or a patient has about clinical research prior to considering it as a treatment option. It is clear that in order to accomplish successful patient recruitment rates, a renewed commitment to the application of high ethical and regulatory standards is essential to guarantee that societal trust in research is not eroded. Therefore, assuring subjects that risks are minimized, there are safeguards to protect them, and provisions exist to protect their privacy. It is also necessary that all site staff members, including investigators, receive the necessary education and training to equip them with the information they need to ensure that every potential subject is motivated, has a clear understanding of the protocol, and has as much knowledge as possible to make an informed decision and give privacy authorization. Staff members can benefit from workshops and training to improve their communication skills in guiding patients through the informed consent stage, answering patient questions and expanding patient understanding; therefore, improving the costly and time-consuming process of patient recruitment.



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Drug Discovery and The People Behind The Scenes



“The number of people involved in getting a drug to the first patient is a small phonebook. It’s hundreds to even a thousand or two thousand, depending on the nature of the work. It requires people from a whole set of different disciplines, ranging from a geneticist who may be that person who makes the first link of a gene with a disease, to the chemist who tried to understand how to make a chemical that will interact with a protein, that a biochemist will have isolated, to a pharmacist who will figure out how to take that chemical and put it into some kind of delivery device, what we call a pill or injection, who work to try to predict how that drug is going to behave in a patient or in a large population, and so on. The set of disciplines is immense.”
                                                                                                                                             John Leonard, M.D., Abbott

Modern drug discovery is the product of cooperation. Many sectors contribute, particularly in building the basic science foundations. Both public and private organizations play unique but increasingly interdependent roles in translating basic research into medicine.


Understand the disease
Before any potential new medicine can be discovered, researchers work to understand the disease to be treated as well as possible, and to unravel the underlying cause of the condition. They try to understand how the genes are altered, how that affects the proteins they encode and how those proteins interact with each other in living cells, how those affected cells change the specific tissue they are in and finally how the disease affects the entire patient. This knowledge is the basis for treating the problem.

Target Identification
Choose a molecule to target with a drug
Once they have enough understanding of the underlying cause of a disease, pharmaceutical researchers select a “target” for a potential new medicine. A target is generally a single molecule, such as a gene or protein, which is involved in a particular disease. Even at this early stage in drug discovery it is critical that researchers pick a target that is “drugable,” i.e., one that can potentially interact with and be affected by a drug molecule.
Target Validation
Test the target and confirm its role in the disease
After choosing a potential target, scientists must show that it actually is involved in the disease and can be acted upon by a drug. Target validation is crucial to help scientists avoid research paths that look promising, but ultimately lead to dead ends. Researchers demonstrate that a particular target is relevant to the disease being studied through complicated experiments in both living cells and in animal models of disease.
Drug Discovery
Find a promising molecule (a “lead compound”) that could become a drug
Armed with their understanding of the disease, pharmacists are ready to begin looking for a drug. They search for a molecule, or “lead compound,” that may act on their target to alter the disease course. If successful over long odds and years of testing, the lead compound can ultimately become a new medicine.

Early Safety Tests
Perform initial tests on promising compounds
Lead compounds go through a series of tests to provide an early assessment of the safety of the lead compound. Pharmaceutical Researchers test Absorption, Distribution, Metabolism, Excretion and Toxicological (ADME/Tox) properties, or “pharmacokinetics,” of each lead. Successful drugs must be:
• absorbed into the bloodstream,
• distributed to the proper site of action in the body,
• metabolized efficiently and effectively,
• successfully excreted from the body and
• demonstrated to be not toxic.
These studies help researchers prioritize lead compounds early in the discovery process. ADME/Tox studies are performed in living cells, in animals and via computational models.

Lead Optimization
Alter the structure of lead candidates to improve properties
Lead compounds that survive the initial screening are then “optimized,” or altered to make them more effective and safer. By changing the structure of a compound, scientists can give it different properties. For example, they can make it less likely to interact with other chemical pathways in the body, thus reducing the potential for side effects.

Preclinical Testing
Lab and animal testing to determine if the drug is safe enough for human testing
With one or more optimized compounds in hand, researchers turn their attention to testing them extensively to determine if they should move on to testing in humans. Pharmacists carry out in vitro and in vivo tests. In vitro tests are experiments conducted in the lab, usually carried out in test tubes and beakers (“vitro” is “glass” in Latin) and in vivo studies are those in living cell cultures and animal models (“vivo” is “life” in Latin). Scientists try to understand how the drug works and what its safety profile looks like. The U.S. Food and Drug Administration (FDA) requires extremely thorough testing before the candidate drug can be studied in humans.
During this stage researchers also must work out how to make large enough quantities of the drug for clinical trials. Techniques for making a drug in the lab on a small scale do not translate easily to larger production. This is the first scale up. The drug will need to be scaled up even more if it is approved for use in the general patient population. At the end of several years of intensive work, the discovery phase concludes. After starting with approximately 5,000 to 10,000 compounds, scientists now have winnowed the group down to between one and five molecules, “candidate drugs,” which will be studied in clinical trials.


Investigational New Drug (IND) Application and Safety
File IND with the FDA before clinical testing can begin; ensure safety for clinical trial volunteers through an
Institutional Review Board Before any clinical trial can begin, the researchers must file an Investigational New Drug (IND) application with the FDA. The application includes the results of the preclinical work, the candidate drug’s chemical structure and how it is thought to work in the body, a listing of any side effects and manufacturing information. The IND also provides a detailed clinical trial plan that outlines how, where and by whom the studies will be performed. 

The FDA reviews the application to make sure people participating in the clinical trials will not be exposed to unreasonable risks. In addition to the IND application, all clinical trials must be reviewed and approved by the Institutional Review Board (IRB) at the institutions where the trials will take place. This process includes the development of appropriate informed consent, which will be required of all clinical trial participants.

Statisticians and others are constantly monitoring the data as it becomes available. The FDA or the sponsor company can stop the trial at any time if problems arise. In some cases a study may be stopped because the candidate drug is performing so well that it would be unethical to withhold it from the patients receiving a placebo or another drug. Finally, the company sponsoring the research must provide comprehensive regular reports to the FDA and the IRB on the progress of clinical trials.

Phase 1 Clinical Trial
Perform initial human testing in a small group of healthy volunteers
In Phase 1 trials the candidate drug is tested in people for the first time. These studies are usually conducted with about 20 to 100 healthy volunteers. The main goal of a Phase 1 trial is to discover if the drug is safe in humans. Researchers look at the pharmacokinetics of a drug: How is it absorbed? How is it metabolized and eliminated from the body? They also study the drug’s pharmacodynamics: Does it cause side effects? Does it produce desired effects? These closely monitored trials are designed to help researchers determine what the safe dosing range is and if it should move on to further development.
Phase 2 Clinical Trial
Test in a small group of patients
In Phase 2 trials researchers evaluate the candidate drug’s effectiveness in about 100 to 500 patients with the disease or condition under study, and examine the possible short-term side effects (adverse events) and risks associated with the drug. They also strive to answer these questions: Is the drug working by the expected mechanism? Does it improve the condition in question? Researchers also analyze optimal dose strength and schedules for using the drug. If the drug continues to show promise, they prepare for the much larger Phase 3 trials.
Phase 3 Clinical Trial
Test in a large group of patients to show safety and efficacy
In Phase 3 trials researchers study the drug candidate in a larger number (about 1,000-5,000) of patients to generate statistically significant data about safety, efficacy and the overall benefit-risk relationship of the drug. This phase of research is key in determining whether the drug is safe and effective. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines).
Phase 3 trials are both the costliest and longest trials. Hundreds of sites around the United States and the world participate in the study to get a large and diverse group of patients. Coordinating all the sites and the data coming from them is a monumental task. During the Phase 3 trial (and even in Phases 1 and 2), researchers are also conducting many other critical studies, including plans for fullscale production and preparation of the complex application required for FDA approval.

New Drug Application (NDA) and Approval
Submit application for approval to FDA
Once all three phases of the clinical trials are complete, the sponsoring company analyzes all of the data. If the findings demonstrate that the experimental medicine is both safe and effective, the company files a New Drug Application (NDA) — which can run 100,000 pages or more — with the FDA requesting approval to market the drug. The NDA includes all of the information from the previous years of work, as well as the proposals for manufacturing and labeling of the new medicine.

Going from small-scale to large-scale manufacturing is a major undertaking. In many cases, companies must build a new manufacturing facility or reconstruct an old one because the manufacturing process is different from drug to drug. Each facility must meet strict FDA guidelines for Good Manufacturing Practices (GMP).
Making a high-quality drug compound on a large scale takes great care. Imagine trying to make a cake, for example, on a large scale — making sure the ingredients are evenly distributed in the mix, ensuring that it heats evenly. The process to manufacture most drugs is even more complicated than this. There are few, if any, other businesses that require this level of skill in manufacturing.
Ongoing Studies and Phase 4 Trials
Research on a new medicine continues even after approval. As a much larger number of patients begin to use the drug, companies must continue to monitor it carefully and submit periodic reports, including cases of adverse events, to the FDA. In addition, the FDA sometimes requires a company to conduct additional studies on an approved drug in “Phase 4” studies. These trials can be set up to evaluate long-term safety or how the new medicine affects a specific subgroup of patients.

“My calling to the pharmaceutical industry has been a personal one. When I was a child, I had a disease called rheumatic fever that came from strep throat. It had an effect on my heart and, as a child — in third grade for me — I was unable to play with other children. In fact, I had to lie in a bed for months and be carried. It was a medicine that I took that allowed me to get up again, and it was a medicine that the company that I work for today made. That’s why I joined the pharmaceutical industry.

Andrew Dahlem, Ph.D.
Eli Lilly and Company


The whole drug discovery process takes an average of  10 – 15 years. There are people from many disciplines that are striving hard for discovery of single drug molecule. Pharmaceutical industry plays a major role in the process. The definition of a pharmacist is definitely not limited to “the one who dispenses a drug”. It is much more than that. BE PROUD TO BE A PHARMACIST

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Successful Monitoring of Clinical Trials: SOP Writing & Staff Training Aspects


Successful Monitoring of Clinical Trials: SOP Writing & Staff Training Aspects
Svitlana Belinska
[email protected]


An ideal situation for the pharmaceutical company regarding the conduct of a clinical trial is to assure safety of its participants and accuracy of its results. In addition, all necessary efforts should be taken to avoid any kind of delays with the completion of the trial. Successful and rapid completion of a clinical trial leads to rapid marketing of a new pharmaceutical product which in turn assures profit margins for the pharmaceutical companies.

All clinical trials conducted with the participation of human patients are to be monitored. The method and degree of monitoring depend on degree of risk involved in participation, as well as scope and complexity of the clinical trial. Regardless of the methods used, monitoring should be conducted on a regular basis. The main goals of monitoring are to assure adequate protection of the rights of human subjects and the safety of all subjects involved in clinical investigations and the quality and integrity of the resulting data. So while planning a clinical trial and designing the protocol, monitoring plan should be considered very carefully to assure adequate fulfillment of its tasks. This article will give the general idea about the nature of monitoring and its role on conduct of clinical trials.

The nature of clinical trials monitoring and its main requirements

Peopleā?Ts health is the most important thing in any time and in every society. So while developing drugs for people a lot of efforts should be done to avoid any mistakes and misconducts.

Sponsor or the designers monitor the progress of a clinical trial. A Sponsor selects different procedures for monitoring clinical trials and these procedures may be reviewed by Food and Drug Administration.

One or more individuals with appropriate qualification should be assigned to monitor the progress of a clinical trial. A monitor should have enough knowledge, training, and education; be able to travel, possess good communication skills.

While choosing a monitor for a clinical study the following is to be considered:
– the number of investigators participating in a study
– the number and location of the facilities
– the type of drug involved
– complexity of the study
– the disease or condition being studied

Before a clinical trial is initiated, the monitor should conduct a pre-study visit to check if investigator understands the nature of the study, its procedures, requirements, his/her obligations; able to enroll certain number of patients, has adequate facilities, accepts to follow protocol and regulatory requirements.

In the course of the study a monitor conducts periodic visits to sites to assure that the investigator fulfills his/her obligations and the facilities continue to be acceptable, study protocol is followed; to check patients safety, accuracy of the study data and records, regulatory requirements are met.

To assure the accuracy of the study data the individual patients records and other source documentation should be reviewed and compared with the reports prepared by the investigator. Thus, during a monitoring visit the monitor is to compare a number of patient records and other source documentation with the investigatorā?Ts reports and to determine that the recorded information is complete, accurate and legible, there are no omissions, missing visits or examinations, informed consents have been properly documented.

After each visit a monitor should prepare a monitoring visit report, which reflects the full situation at the site: findings, conclusions, any actions taken to correct any deficiencies noted during the visit.

Writing Standard Operation Procedures

Conduct of clinical trials is a very complicated activity. It is regulated by GCP-ICH requirements and other applicable laws; concern of protecting the safety and welfare of patients participating in a study. During the conduct of a clinical trial the principle investigator, project manager and a monitor must use a written policies and procedures describing the monitoring and reporting procedures.
Study investigators must follow a protocol exactly and meet other sponsor demands.
Standard Operation Procedures (SOP) is a document designed for the study conduct and used by certain Clinical Research Organizations or Sponsor companies while conduct of the procedures for clinical trials. Before a study is set up a Sponsor should consider which SOPs will be used for this study. SOPs describe all study related procedures and these procedures are to be performed in comply with the agreed with a Sponsor SOPs. It is requested that SOPs comply with the principles of ICH-GCP, FDA (if applicable) and any local regulatory requirements.
SOPs are critical tools in successful business operations for all those involved in doing clinical trials, including investigative sites, sponsors and IRBs. They are essential for standardizing processes, for ensuring that regulatory and organizational policy requirements are met, for training new personnel and for managing workload.

It is very important for SOP to be understood by all clinical trial staff. Thus, certain requirements as for its writing are met and the following considered:
– the title must be descriptive
– date when the SOP became operative is to be specified
– the edition number and a statement that this edition replaces an earlier edition from an earlier date
– the exact distribution of SOPs
– the signature of the person responsible for writing the SOP
– the signature of the person responsible for authorising the SOP
To make the SOPs clear for those who work with them, author should use easy language, detailed explanation of all steps, convenient format. The SOP must be located in a place with an easy access.

Staff training
Training is also very important part of any clinical trial. All members of a clinical trial should be aware of how to use SOPs, have some kind of medical training depending on the therapeutic area, of a tested drug, be instructed on logistic aspects, etc.
According to ICH Good Clinical Practice Guidelines, it is required that Investigators and other study staff working on a clinical trial are qualified by training and experience to undertake their relevant roles and responsibilities.

A record of the members of staff working on a clinical trial is kept within the Trial Master File, using the sponsor approved Staff Authorization and Responsibilities List.

A record of the relevant training for each member of staff undertaking work on a clinical trial must also be kept, in line with the Staff Training Record SOP.

Quality Assurance

Any clinical trial is to be audited by the Quality Assurance department to ensure the study is conducted properly, and all study related documents are recorded and maintained correctly. Quality Assurance department provides audit to evaluate clinical research activities for compliance with the study protocol, all applicable regulations, guidelines and standard operation procedures.

Clinical quality assurance department periodically reviews SOPs, oversees a distribution of the SOPs, all the staff is trained to use the SOPs.

Clinical quality assurance department conducts audits during which whole set of study documents are checked for any mistakes, discrepancies, omissions, frauds, if any, deviations from SOPs and a study protocol.

Adequate monitoring and appropriately composed SOPs are able to prevent timely any delays, occurring of serious problems, and any significant inconveniences, which may affect the whole process of the new drug development. Such a simple thing, as it is seen from the first sight, plays a very important role in this complicated structure of the drug development.


FDA Oversight of Clinical Investigators
Ethical Principles for Medical Research Involving Human Subjects

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How to Set Up a Successful Investigative Site


How to Set Up a Successful Investigative Site

Compiled By:
Sharon Free
Email: [email protected]
May 30, 2007



According to a recent Impact Report by Tufts Center for the Study of Drug Development, pharmaceutical companies now have an average total R&D cost of $802 million per new drug entity and $897 million, if both pre-and post approval phases are included. Pharmaceutical companies must initiate their clinical trials in an increasingly efficient manner to ensure thorough protocol development, prompt regulatory readiness, high quality, cost-effective study initiation training, accurate and efficient study supply delivery, steady enrollment, quality data collection, monitoring, reporting, timely issue resolution, data locks, and study closeout. All of these functions must be done within a set budget and timeline.
This is a difficult, multitask assignment that might become even more difficult as the medical industry braces for the aging baby boomers. Couple this with potential investigator shortfalls, stricter regulations, and tighter trial budgets as the industry tries to control drug development costs. What might be a potential option for accomplishing the challenge of developing drugs while lowering costs and decreasing development times? If an investigative site is to grow successfully, specific functions of the clinical trials process must first be solidly in place. A common pitfall in this industry is for the owner or Director of Business Development of a young site to promote itself before it can adequately perform more studies. This happens when site management has not yet recognized the critical importance of developing the appropriate infrastructure needed to support a site aiming to grow its clinical trials business carefully and thoughtfully. There are basic elements needed to build a firm foundation for growth with quality.
Site Evaluations
The site evaluation is a critical step for both the sponsor and the site. For the site, these visits determine whether or not they will be selected to participate in the research, while for the sponsor, they are the primary method of determining the best sites to conduct their studies.
When a sponsor or contract research organization (CRO) is looking for investigative sites for a protocol, the first contact is usually by telephone. If it appears that there is a high level of interest in the protocol on the part of the potential investigator, and if the sponsor feels there is good potential for placing a study at the site, it will arrange a time to visit the site in person. This will enable the sponsor to better evaluate the investigatorâ?Ts capability to do the project. Many companies require that a signed confidentiality agreement be signed before the protocol is discussed. In this case, they will fax or mail an agreement to the site and have it signed and returned before sending the materials. When a sponsor makes an evaluation visit to a potential investigative site, he or she will be evaluating the investigatorâ?Ts experience, expertise and interest in the trial, as well as the staff, facility and potential patient population available. The sponsor may have a checklist that will guide the CRA in making an assessment. The main attributes assessed in an evaluation visit are the investigatorâ?Ts experience, expertise and interest. The sponsor will want a copy of the investigatorâ?Ts curriculum vitae (CV) in order to make a general assessment of the investigatorâ?Ts experience and expertise. The sponsor will also want to know if the investigator has conducted similar trials to the one being proposed, or has worked with similar compounds. The sponsor will also want to evaluate whether the site has sufficient staff and an appropriate facility to do the study. Many sponsors will not place a study at an investigative site that does not have a clinical research coordinator (CRC). During the visit, the CRA will want to meet with the CRC and spend some time interviewing them. Not only must there be appropriate people available for a study, but they must have sufficient time to do the necessary work. There are several factors a CRA will want to discuss during an evaluation visit. One is whether or not the site is doing or planning to do within the same time period, any competing studies. Another factor is the timing for the study. If the site has too many active studies at the same time, a study may not get the attention it needs to be done well. The CRA will also want to check on the laboratory and pharmacy, if either will be used for the study, to ensure that laboratory accreditations are current and the facilities are adequate to perform the necessary study activities. The importance of the site evaluation visit cannot be overstated. It is this visit, more than any other factor that determines whether or not the site will be selected to participate in the research. Consequently, the investigator and CRC should be well prepared for the visit and ready to show their site at its best.
Budgeting, Grants and Contracts
Protocols have become more complex, calling for more procedures, on average. This means that sites must be careful about whether or not they can actually afford to do a study, without losing money, and that they will need to be very selective about the projects they decide to take on. There are many hidden costs that the investigative site has to beware of. Investigative sites are typically taking on clinical projects that require an estimated $4,000 to 6,000 in hidden cost per study that are not being reimbursed by sponsors and CROs. Some Sponsors will determine a range or a single per subject grant figure that they will pay and will not budge from this figure. Investigators either accept it or will not be able to do the study. Other sponsors will allow more flexibility, depending on experience with an investigator or geographical location. Costs do differ in different parts of the country, so it makes sense to allow some flexibility. CRCs often help investigators when it comes to figuring a budget and determining an appropriate grant amount for a study. A good way to come up with a grant figure is to look at each study activity, attach a cost to it, add an additional amount for overhead and other required activities, and total it up. The charge for each item should also include the cost of the time of the person performing it. An example of an Uncompensated PI costs for a hypothetical study is shown below.
Example of Top Uncompensated PI Costs 18 week, 10 subject trial
Study Supervision
Investigator Meeting Attendance
Case Report Form
Initiation Visit Attendance
Adverse Event Management
CRA Meetings and Interactions
An example of a grant worksheet for a hypothetical study is shown below.
Study Activity
Number of Visits
Expanded Charge
Phone pre-screen
Medical History
Physical Exam
Treadmill stress test
Office visit
Phone assessments
Subtotal for Procedures
Coordinator Time
Pharmacy Charge
Overhead- 15%
Grand Total per completed subject
In the example shown there are three visits that are more labor-intensive, the three that involve physical exams and stress testing. To determine the prorating dollar amount, each of these visits should count as two and the other five visits should be counted as one, for a total of eleven. If the cumulative amount of $5,152 is divided by 11, the cost per visit is $468.36. Based on this, the three more intensive visits should be prorated at $937, and the other five at $468 (with the extra dollar added to the cost of the last visit). Note that if a subject drops out after visit 3, the investigator would be paid $1,837. For a subject dropping out at Week 7, the payment would be $4,214, and so forth. This is a simple way of calculating grants and prorating visit cost, but it is quite effective if the initial amounts for each procedure and activity are realistic. It is easy to explain and should help the investigator and the CRC in negotiating a grant amount that is fair to both the sponsor and the site. If the CRC is involved in grants, he or she must have a good understanding of both the process and the specifics for each protocol in order to be able to discuss the grant with the investigator and the sponsor, and to track the figures to ensure that all sums are paid as appropriate. A contract between the Sponsor and the investigator will be signed before the trial starts at a site. This document usually contains the responsibilities of the investigator, including the number of subjects the site is expecting to enroll, timelines for enrollment, grant amounts and the regulatory requirements for the investigator. It also contains the responsibilities of the sponsor, including when and how the grants will be paid, monitoring of the study and sponsor regulatory requirements. The investigator should always request for an indemnification clause from the sponsor. It will be signed by the appropriate company representatives, and by the investigator. ( Note that in larger institutions contracts may be signed by someone in the contract office, rather than by the investigator.) Contracts are rarely written, negotiated or signed by the CRC, although he or she may have input into the contract when working on it with the investigator.

Study Initiation meetings
The study initiation visit, sometimes known as the start up visit, is held at the investigatorâ?Ts site just before the study begins. The CRA, and sometimes additional sponsor personnel, will meet with the investigator and the supporting staff. The purpose of the meeting is to review the study protocol, processes and procedures to ensure that all site personnel understand what is necessary to perform the study.
The study initiation should be held at the point when all regulatory paperwork is complete for the site and the study drug and other supplies have been shipped, but before any subjects have been enrolled. Many sponsors will not allow the site to begin enrollment until after this meeting is held. A good meeting may take half a day, or even longer for a very complicated study, so you may have to work with your sponsor to find a time when all your relevant staff is available for a meeting.
The CRA is almost always in charge of the initiation meeting, although the sponsor medical monitor and/or an in house associate monitor may also be present. It is important that all site personnel who will be involved in the study attend the meeting. The initiation meeting provides an opportunity for everyone at the site to become familiar with the study and to understand everyoneâ?Ts study role.
After the meeting, the CRA will complete a visit report detailing what was discussed and completed during the visit. Many companies have a special visit report for this meeting. ICH Guidelines call for a trial initiation monitoring report that documents the trial procedures were covered with the investigator and his or her staff; this report is to be kept in both the sponsor and investigator study files. The same purpose can be accomplished by the CRA sending the investigator a letter listing what was covered during the meeting. This meeting can go a long way in helping to ensure a successful study. It deserves the full attention of the CRC, the investigator and other involved staff.
Working with CRAs
For actual study conduct the study coordinator or CRC is the most important person at the site and the CRA is the most important sponsor representative. Since they will be spending a lot of time working on the study together, the CRC and the CRA must establish a good working relationship. Monitoring can be relatively easy and enjoyable or it can be a nightmare; the difference is often dependant upon the relationship between the CRC and the CRA. It takes time to develop a rapport with the CRA and to develop a monitoring visit routine that works well for both of you. Each person needs to understand how the other works. The CRA should determine the best times and methods for routine communications with the CRC and let the CRC know the sponsor expectations. Some CRCs, and some CRAs, simply have better interpersonal relationship skills than others do. Itâ?Ts amazing what a smile and good manners will do. Taking the CRA to lunch occasionally is a nice gesture. Remember, however, to always maintain a professional relationship. Itâ?Ts easy to develop a friendship over the course of a long study, but you still need to remember that it is a business relationship.
Some sponsors will hire a contract research organization (CRO) to do the study monitoring for a project. The dynamics of the working relationships among the CRC, the CRA, the sponsor and the CRO can be complex. If not clearly defined during the investigator meeting, the study initiation meeting is a good time to clarify the communication channels for the study. The CRC may be required to communicate regularly with the CRO for some things, such as enrollment updates, and the sponsor for other things, such as serious adverse event reporting. Whatever the situation, being clear on the correct reporting and communication procedures will help the study progress smoothly.
A good relationship with the sponsor throughout the study is one of the major factors in obtaining more studies from the same sponsor. Being able to maintain a good relationship with the CRA, whether a sponsor or CRO person and timely and correct communications about other issues is not only a good for the study, but is good public relations for your site.
Shipping of Biological Samples
The packaging and shipping of biological samples is often the responsibility of the CRC. These activities are highly regulated, and there are significant fines for not complying with the regulations. All North American airlines and FedEx, the largest shipper of infectious materials, use the IATA regulation as their standard. Meeting the conditions of this standard will ensure meeting the provisions of the other US regulations. Many sponsor companies require evidence of training in this area when it is relevant for their trial.
Quality Assurance
The growing site needs to establish a quality assurance (QA) department, even if that department starts with nothing more than a single full-time equivalent (FTE), or a partial FTE, depending upon workload. A number of site alliances and site management organizations (SMOs) share one quality assurance FTE who travels from site to site, to QA the charts prior to monitor visits. Sponsors, CROs, and monitors recognize and appreciate this investment in quality. The purpose of the QA department is to develop and implement programs designed to improve the quality of studies conducted at the site, starting from day one. This raises the bar for patient safety, and should enhance outcomes of monitoring visits. Quality Assurance, as defined by the International Organization for Standardization (ISO 9000), refers to a set of activities whose purpose is to demonstrate that an entity meets all quality requirements. QA activities are carried out to inspire the confidence of both customers and managers that all quality requirements are being met. Applying this definition to the clinical trials industry, QA serves to ensure that Good Clinical Practice (GCP) guidelines are adhered to, resulting in a quality product: clean, reliable data. According to FDA, GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials.3 Compliance with this standard provides public assurance that the rights, safety, and well being of trials subjects are protected, consistent with the principles originating with the Declaration of Helsinki; and that the clinical trial data are credible. Because of its importance, the QA team should report to the highest level of management, and maintain independence from the operations group.5 In addition, the QA team should be presented to the site as a positive, cooperative force, and not as adversarial to site operations.6 Using this approach, the QA team can audit studies at prescribed times, such as at study-up, and once a month thereafter. Findings of each audit are to be shared with the principal investigator, sub-investigators, study coordinators, and any other personnel involved with the study. The auditing exercise can serve to prepare the site for monitoring visits, FDA audits, and sponsor audits.
Standard operating procedures (SOPs)
To facilitate the operation of a GCP-compliant site, a good Quality Assurance department works with all levels of management to develop standard operating procedures (SOPs). These procedures are designed to bring consistency to common practices conducted at the site by providing a standard format, method, authorization trail, and implementation process. The goal of SOPs is to improve quality by preventing or limiting errors and non-compliance problems at the site level. The QA Department should review the SOPs annually to keep them current, and should be diligent about their being followed. SOPs address a wide range of clinical and administrative topics, ranging from obtaining informed consent to randomization procedures to collecting data to handling a code on a patient. Most procedural errors occur with the first three or four patients enrolled in a study, so it is a good idea to develop an SOP instructing the QA Department to review and approve all charts and source documents for the first four patients in all studies. Once enrollment extends beyond the first few patients, it is suggested to have all paperwork completed by the study coordinator, research assistant, or data entry staff within 24 hours of each patient visit. This process limits the number of missed procedures. For example, the study coordinator may have taken a blood pressure reading during the patient visit, and may have quickly jotted it down on a piece of paper instead of recording it in the case report form. Implementing this simple procedure can improve the quality of the paperwork completed at the site. Whether sites create their own SOPs, or customize templated SOPs, they include various elements such as title and objective. As company SOPs are generally considered to be confidential documents, it is recommended that anyone at the site who is given the SOP binder fill out a sign-out sign-in sheet to document this transaction. If SOPs appear on the company’s intranet, they should be password-protected. Further information about SOPs can be found in How to Grow Your Investigative Site.
Regulatory affairs
Growth at the site level is accompanied by a tremendous increase in regulatory paperwork generated in support of clinical studies. This workload becomes particularly noticeable once the site reaches a milestone of some seven to nine ongoing trials. As long as the site participates in a smaller number of trials, it is usually possible for regulatory responsibilities to be assumed by an administrative type or by the study coordinator. Once this milestone is reached, however, the site will probably need to hire a regulatory affairs person. Initially, this individual may assume other administrative duties if he or she is not fully consumed with regulatory paperwork, but eventually the position will expand into a full time job. Some of the responsibilities of the regulatory affairs person (or, eventually, the regulatory affairs director) include corresponding with local, central, and in-hospital Institutional Review Boards (IRBs); keeping abreast of HIPAA issues; maintaining all paperwork for the regulatory binder; and properly reporting adverse events (AEs) and serious adverse events (SAEs). Dedicating an FTE to regulatory activities will accomplish two major goals: it will free up the study coordinator to perform other study-related tasks; and it will improve the site’s turnaround time for submitting paperwork needed for study startup. Offering good turnaround times is an important marketing tool for the site. It shows efficiency, and complements the skill, knowledge and experience that a site can offer to sponsors.
The regulatory binder
The regulatory binder is the record of study documentation. Because all clinical studies tend to have many of the same components, the regulatory affairs department, with input from the site, should consider developing a format for the binder that standardizes needed documents for all studies. Although various sponsors and CROs may provide study binders, it is preferable that the site uses its own standard binder. This will regiment the site, and enhance quality by organizing paperwork needed for proper study conduct and for visits from monitors, FDA and sponsors.
The binder includes:
* IRB-approved signed informed consent forms
* Serious Adverse Event (SAE) reports
* FDA Statement of Investigator Form 1572
* Continuing and final review reports (CVs and medical licenses of the principal investigator(s) and sub-investigator(s))
* Letters of indemnification and confidentiality
* 21 CFR (Code of Federal Regulations) 54 Financial Disclosure by Clinical Investigators
* Clinical supplies: Proof of receipt of CRFs, lab kits, diaries, etc.
* Protocols, protocol amendments and signature pages
* Investigator brochures
* Drug accountability records
* Telephone logs
* IRB-approved materials, IRB correspondence and Continuing Review Reports
* Advertisements and approvals
* General correspondence with the CRO and/or sponsor (includes newsletters)
* Reorder forms
* Site signature and delegation logs (stating who is responsible for which study activity. The logs are signed and initialed).
* Follow-up forms
* Monitoring logs and reports
* Shipment records
* Screening logs (documenting who was screened for enrollment)
* Laboratory certificates and values
* Equipment logs
* IND safety reports
FDA audit
The real test of a site’s preparedness is how it fares during an audit by FDA. It’s not a question of if an FDA audit will happen, but when. According to the Center for Drug Evaluation and Research (CDER), divisions of FDA, there are approximately 300 onsite inspections annually of U.S. clinical investigators. Inspections can last anywhere from several days for routine inspections to a few weeks if serious problems are uncovered. Through its Bioresearch Monitoring (BIMO) Program, the FDA carries out three types of clinical investigator audits:
* Study-oriented Inspection
* Investigator-oriented Inspection
* Bioequivalence Study Inspection
Within the first five minutes of visiting a site, the FDA inspector usually develops a good sense as to whether a problem exists. If staff acts nervous and worried, the inspector will suspect that something is awry and will find deficiencies. If, however, the clinical staff is secure about the quality of the data, SOPs are properly followed, and the regulatory binder is carefully kept, this, too, will be obvious to the inspector.
The auditor’s job is to ensure that regulations designed to protect the rights and safety of human subjects are being followed along with aspects of good clinical practice leading to ethical development of investigational compounds and devices. With this in mind, it is best to go through the audit in the spirit in which it is intended. On the final day of the FDA audit, the inspector will conduct an exit interview. During this interview, the FDA inspector will discuss findings. For this reason, it is helpful if the site’s top management can sit in at this meeting. It is preferable if the CEO, DCO, principal investigator, and QA director are present. A site manager may have to request permission from the inspector to include these members of the management team. Sometimes, the inspector will not permit all of these people to be present, allowing only the primary investigator and the QA director.
There are necessary ingredients for growing a site into a larger, highly professional operation. This includes the creation of an infrastructure for the purpose of improving the quality of clinical trials conduct, leading to cleaner data, greater patient safety, and improved outcomes of visits from monitors, and auditors. To achieve this, there needs to be new staff positions, such as a Director of Clinical Operations, and head of Quality Assurance; SOPs have to be developed, and the regulatory binder has to be maintained. Using this type of professional approach, the site will grow in an organized, regulatory-compliant manner and you are sure to have a successful clinical trial that will run smoothly and cost efficient for all parties involved.
1.Tufts Center for the Study of Drug Development, “Impact Report: Post-Approval R&D Raises Total Drug Development Costs to $897 Million,” 5 (3) May/June 2003.
2.J. Carpenter, “21 CFR 11 Compliance at Investigator Sites,” Applied Clinical Trials, 12
(7) 35 (July 2003).
3. R.A. Koshore Nadkarni, S. Antel, and K. Sargent, “The Value of Site-Based Quality Assurance Systems for Clinical Testing Sites,” The Monitor, 14 (4), 29 (Winter 2000).
4. Definition of Quality Assurance, praxiom.com/ accessed September 25, 2003.
5. Food and Drug Administration, www.fda.gov/oc/gcp/default.htm accessed September 25, 2003.
6. “Guidance for Industry Good Clinical Practice: Consolidated Guidance,” Center for Drug Evaluation and Research, April 1996, p. 1, www.fda.gov/cder/guidance/959fnl.pdf accessed September 25, 2003.
7. R.A. Koshore Nadkarni, S. Antel, and K. Sargent, “The Value of Site-Based Quality Assurance Systems for Clinical Testing Sites,” The Monitor, 14 (4) 30 (Winter 2000).
8. Ibid., The Monitor, p. 30.
9. B.M. Miskin and A. Neuer, How to Grow Your Investigative Site (Boston, MA, CenterWatch, 2002), www.centerwatch.com/bookstore/pubs_profs_grwinv.html.
10. FDA Information Sheets, Guidance for Institutional Review Boards and Clinical Investigators, www.fda.gov/oc/ohrt/irbs/operations.html#inspections. accessed September 25, 2003.
11. Ibid., FDA Information Sheets, accessed September 25, 2003.
12. www.fda.gov/oc/ohrt/irbs/operations.html#inspections. accessed September 25, 2003.
13. The CRCâ?Ts Guide to Coordinating Clinical Research by Karen E. Woodin, PH.D.
14. Thomson Centerwatch
15. Clinical Trials.gov
16. Guide to Monitoring Clinical Research by Karen Woodin & John Schneider
17. Department of Health and Human Services
18. Centerwatch.com
19. Government Clinical Trial Website
20. http://nccam.nih.gov/clinicaltrials/factsheet/

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Results Reported From Clinical Trials on SARS, MRSA, the ACADEMIA Trial, and ARDS CME Disclosures


Results Reported From Clinical Trials on SARS, MRSA, the ACADEMIA Trial, and ARDS CME Disclosures

Antonios Liolios, MD


The results of several important and interesting studies were presented during this thematic session at the recent 16th Annual Congress of the European Society of Intensive Care Medicine in Amsterdam, The Netherlands. The first talk was an update on severe acute respiratory syndrome (SARS), the global threat that shook the world not too long ago. The human perspective was brought into focus as it was the most significant factor for the successful management of the epidemic. The results of the Antecedents to Cardiac Arrests, Deaths and EMergency Intensive Care Admissions (ACADEMIA) trial were then presented. In this study, it was found that an impressive percentage of patients who suffered cardiac arrests died or were admitted to the intensive care unit (ICU) after showing warning signs. More impressively, almost all of these patients (90%) were seen by a physician before the event. The necessity for isolating ICU patients with methicillin-resistant Staphylococcus aureus (MRSA) was examined in a 2-center prospective study in 2 mixed ICUs to assess the benefits of isolation compared with universal precautions. No significant effects on decreasing MRSA spread were seen in MRSA ICU patients by isolating them when universal precautions were followed. And finally, the saga of the ARDSNet, lung protective, low tidal volume ventilation for acute respiratory distress syndrome (ARDS) was settled as the final response from the Office of Human Research Protections became recently available.

Severe Acute Respiratory Syndrome Trial
Thomas E. Stewart, MD,[1] of Mount Sinai Hospital, Toronto, Ontario, Canada, presented the Toronto experience with SARS. By February 9, 2003, there were 305 cases reported to the World Health Organization (WHO) of a previously unknown severe respiratory syndrome. WHO released a Global Alert on March 12, 2003. One of the first victims of the disease was Dr. Carlo Urbani, a WHO infectious disease specialist who traveled to the Vietnam French Hospital of Hanoi on February 28, 2003. A patient had presented with an unusual influenza-like virus and an expert’s opinion was sought. The case in question was found to be SARS and Dr. Urbani died on March 29, 2003 in a Bangkok hospital. He contributed greatly to the early detection and containment of SARS.

In Toronto, the index patient was a 78-year-old female who had visited Hong Kong between February 13th and 23rd and died at home on March 5. Family members developed the syndrome and presented to local hospitals. By July 10, 2003, there were 438 Canadian SARS cases and approximately half of them were healthcare workers. The Toronto experience was presented in a study in which 38 adult patients with SARS-related critical illness admitted to 13 ICUs in the Toronto area were followed until April 15, 2003.[2] Of 196 patients with SARS, 38 (19%) became critically ill, 7 (18%) of whom were healthcare workers. The median age of these 38 patients was 57.4 years. The median duration between initial symptoms and admission to the ICU was 8 days. Twenty-nine (76%) required mechanical ventilation and 10 of these (34%) experienced barotrauma. Mortality at 28 days was 34% (13 of 38 patients), and for those requiring mechanical ventilation, mortality was even higher (13 of 29 patients, 45%). Patients who died were more often older, had pre-existing diabetes mellitus, and on admission to hospital were more likely to have bilateral radiographic infiltrates. In another study examining the impact of SARS on healthcare workers, 164 healthcare workers from 2 university ICUs were quarantined and, of them, 16 (10%) developed SARS. It appeared from this study that healthcare workers rarely become critically ill, and although certain practices may place them at higher risk, adequate infection control precautions were probably effective. Affected patients had primarily single-organ respiratory failure, and half of mechanically ventilated patients died.

Dr. Stewart underlined what an important factor fear was in the fight against SARS. Frontline workers were at the highest risk and, in order to saves lives, they had to deal with rapid change. In another study by Scales and colleagues,[3] it was shown that SARS acquisition is a threat to healthcare workers. SARS developed in 6 of 31 persons who entered a patient’s room, including 3 who were present in the room for more than 4 hours. SARS occurred in 3 of 5 persons present during the endotracheal intubation, including 1 who wore gloves, gown, and an N-95 mask. The syndrome also occurred in 1 person with no apparent direct exposure to the index patient. In most, but not all cases, developing SARS was associated with factors typical of droplet transmission. What is interesting in this study was that SARS developed in 1 healthcare worker despite the fact that the worker wore fully protective gear (N-95 mask, gown, and gloves). Additionally, SARS developed in a healthcare worker who had no identified contact with the index patient or with any other persons known to have SARS, which makes the containment of the infection even more difficult.

SARS significantly affected the ability of the Toronto hospitals to deliver healthcare. ICUs were closed and personnel had to be quarantined for more than 10 days. Additionally, personnel had to function while always taking extreme precautions, including wearing uncomfortable masks and gowns. Healthcare workers were separated from their families, risking the possibility that they would become infected and potentially die of the disease. Dealing with fear was the most important issue. Despite the considerable stress, healthcare providers chose to stay and work, thus placing the lives of their patients ahead their own.

Results of the ACADEMIA Trial
Juliane Kause, MD,[4] of Portsmouth, United Kingdom, presented data on the ACADEMIA trial. The aim of the ACADEMIA trial was to estimate the incidence of deaths, cardiac arrests, and unplanned ICU admissions. Another goal of the study was to describe the various physiologic characteristics and their relationships to these events and to assess the feasibility of a larger-scale study. ACADEMIA was a 3-day prevalence, multicentered, international (United Kingdom, Australia, and New Zealand), prospective, observational study, including patients aged 16 years or older. Exclusion criteria were visitors and relatives, patients who died on arrival to hospital, and out-of-hospital cardiac arrests. Important collected data per primary event were physiologic antecedents, if the patient was seen by a doctor prior to the primary event, and the “do not resuscitate” (DNR) status. All primary events were defined as in-hospital cardiac arrests, deaths, and unanticipated ICU admissions (ie, not elective surgery). The antecedents, which were recorded up to 24 hours before each event, were the presence of a threatened airway, abnormal respiratory rate (respiratory rate less than 5 or greater than 36 breaths/minute), bradycardia or tachycardia (pulse rate less than 40 or greater than 140 beats/minute), hypotension (systolic blood pressure < 90 mm Hg), mental status changes (Glasgow coma score [GCS] decrease of at least 2), and prolonged seizures. All these measurements and observations were timed and compared with the primary event. A total of 93 hospitals were enrolled, mostly in the United Kingdom (69), 2 in New Zealand, and 21 in Australia. A total of 1103 acute beds were enrolled in the study.

There were 683 events recorded, and the majority of these (383, 60%) were associated with an antecedent. A total of 1032 antecedents were recorded. The most common antecedents overall were a fall of the systolic blood pressure below 90 mm Hg, a fall in GCS, a threatened airway, bradypnea, and bradycardia. Most of the events happened within 15 minutes before the arrest, but a significant number of antecedents (290, 28%) took place more than 8 hours before the arrest. Most common antecedents occurring within 15 minutes before the event were a fall of the GCS, hypotension, threatened airway, bradycardia, and bradypnea. Most common antecedents recorded 15 minutes to 24 hours prior to the event were hypotension, GCS fall, threatened airway, and tachypnea. There were 168 deaths associated with antecedents, and 12% of these were not in DNR patients. In 9 of these patients, the physician was not aware of the event for more than 1 hour. In cardiac arrest patients with antecedents (112 of them were not DNR patients), 34 patients were not seen by a doctor for more than 1 hour. The antecedents to unanticipated ICU admissions were hypotension, GCS fall, threatened airway, and tachypnea. There were differences in the recorded primary events and antecedents profile between the United Kingdom and Australia-New Zealand. In summary, in this study, most patients with potentially salvageable serious events had recorded abnormalities in vital signs up to 24 hours before the event. Many severe pathophysiologic abnormalities were continuously present for up to 24 hours before serious outcomes; and nearly 90% of potentially salvageable patients with antecedents are seen by a doctor before a serious event. There are differences in primary events and antecedent profile between United Kingdom and Australia-New Zealand, which probably reflects structural differences in the organization of health services of these 2 regions.

Patient Isolation in MRSA
Geoffrey J. Bellingan, MD,[5] from the Bloomsbury Institute of Intensive Care Medicine, London, United Kingdom, presented a study on source isolation for MRSA patients. MRSA prevalence is increasing in the United Kingdom, and standard precautions require single-room patient isolation. This may require additional financial and nursing resources, while many hospitals may lack sufficient single rooms. There are no trials looking at isolation as a factor alone. Studies usually include isolation in the context of surveillance or contact precautions so the exact role of isolation in preventing the spread of MRSA is unclear. Additionally, many studies do not apply to the adult ICU because they are for neonates in whom isolation is easier and less costly. It is noteworthy that the baseline background level of MRSA prevalence in these studies is often low. Despite recommendations for screening and isolation of patients with MRSA, there has been little uniformity in ICUs in the United Kingdom on this matter.

In a study by Hails and coworkers,[6] questionnaires were sent out to ICUs in the United Kingdom, followed up by telephone interviews. In 217 (96%) ICUs that responded, there were marked variations in patient screening, staff screening, infection control procedures, isolation of colonized and infected patients, and ward discharge policy. In all, 16.2% of ICU patients were found to have been colonized or infected with MRSA. Based on this information, this study was performed. It was a 2-center, prospective study performed in 2 mixed ICUs to assess the benefits of source and cohort isolation over and above universal precautions. The study lasted for a year, and all patients admitted for more than 48 hours were studied. Patients were screened for MRSA colonization (nose/groin) on admission, and weekly thereafter. There were 3 study periods in the study. In the first and last 3-month periods (phase 1/3), MRSA-positive patients were moved to single rooms or cohort bays. In the middle 6 months (phase 2), patients were not moved if they became colonized. Universal standard precautions for infection control were always used independent of study phase. The patient population was similar in each phase. There was no significant difference between the 2 ICUs in compliance with handwashing/disinfection, regardless of patient dependency or presence or absence of MRSA.

There were 437 patients studied in phase 1/3 and 418 in phase 2. Of these patients, 68 (15.6%) had MRSA in phase 1/3 and 69 (16.5%) in phase 2. There were no differences between the 2 phases regarding percentage of patients becoming colonized with MRSA, infected with MRSA in the ICU, and outcome.

The rate of acquisition of, or infection with, MRSA and mortality were similar whether patients were moved or not, and this was confirmed by multivariate analysis of risk. Actually, there were fewer patients colonized or infected during the nonisolation period, although this difference did not reach statistical significance (65 vs 51 patients). It was concluded that when universal precautions are used, patient isolation does not affect MRSA transmission and may not be a policy requirement for such patients.

ARDSNet Trial Design and Patient Safety Questioned
Finally, Roy G. Brower, MD,[7] of Johns Hopkins University, Baltimore, Maryland, discussed the issue of “ARDSNet Controversy: Clinical Trial Design and Patient Safety.” The well-known trial received considerable publicity regarding its safety, and Dr. Brower presented the details and outcome of the controversy. A few words about the various departments involved in the evolution of the events: under the Department of Health and Human Services in the United States is the Office of Human Research Protections (OHRP) and the National Institutes of Health (NIH) research department of extramural research. Under the latter is the NIH ARDSNetwork. The OHRP monitors various institutional review boards (IRBs) and the NIH ARDSNetwork for patient safety and compliance with the pertinent regulations.

Before the study in question, there were concerns and data from experimental or small human studies that physicians were ventilating patients with ARDS using higher than optimal tidal volumes (Vt), thus contributing to further lung injury. A study was then designed and undertaken by the ARDSNet. In this study, the traditional high Vt used at the time was compared to a lower Vt derived from previous small human studies. The levels selected were 12 mL/kg vs 6 mL/kg of predicted body weight respectively. A significant decrease in mortality favoring the low Vt group was seen, and the study was stopped because a significant clinical benefit was demonstrated.[8] In 2001, the Fluids and Catheters Treatment Trial (FACTT) was initiated. Similarities to the Vt trial were the hemodynamic protocols (2 arms: fluid-conservative vs fluid-liberal) and that all patients were ventilated with a Vt of 6 mL/kg.

The controversy began in July 2002 when a complaint to the OHRP was filed by intramural investigators,[9] followed by the voluntary delay of the FACTT study by the NIH. The question was the selection of the optimal and the control Vt used to ventilate ARDS patients. There were concerns that the high Vt (12 mL/kg) used as control was higher than the “routine” Vt traditionally used by physicians caring for ARDS patients. Additionally, the lower Vt may also contribute to excess mortality as they suggested the existence of a “U” shaped mortality curve (higher mortality at either end) associated with various Vt as plateau pressure changes. Finally, there was no “routine care” study group that might have demonstrated a better outcome if included.

The ARDSNet researchers responded that the selected Vt was consistent with traditional recommendations, published surveys of clinical practice, and current practice. The lower Vt was set at 6 mL/kg based on 4 previous encouraging clinical studies,[10] one phase 2 randomized clinical trial (RCT), and on contemporary clinical recommendations. ARDSNet used the traditional design for process-of-care trials in which 2 differing approaches were compared. Requirements for this approach include sound physiologic rationale for both approaches, both approaches in clinical use by proponents, and equipoise or substantial uncertainty. When using this approach, “routine care” groups are not included. Several significant recent ICU trials have used this approach, including one by Rivers and colleagues.[11] The ARDSNet reply was that both studies were appropriately designed in relation to safety; and there is no evidence for a “U-shaped” relationship between mortality and plateau pressure. Additionally, there is no evidence to suggest a safe level of plateau pressure. Finally, the 6 mL/kg Vt strategy was already associated with low mortality in 2 large RCTs.

An independent review board was established by the NIH, and the report published in August 2002 suggested that there were methodologic problems with the Intramural Investigators’ analysis. It stated that both ARDSNet trials were appropriately designed in relation to patient safety. Additionally, the report said that the FACTT trial should be resumed. Despite the NIH review of the ARDSNet trial, OHRP requested that NHLBI continue to suspend the ARDSNet trial until OHRP had completed its own internal review. Finally, the OHRP reported that “risk to subjects participating in the ARMA trial were minimized and reasonable in relation to the anticipated benefits to the subjects and the importance of the knowledge that was expected to result.” It also stated that the FACTT trial could resume without changes to trial design or study procedures. The OHRP recommended improvement of the patient consent process and the IRB review process and further discussion on similar topics. Dr. Brower concluded that the traditional trial design can minimize risk and enlighten clinical practice, and there should be increasing expectations for rigor with IRB overview and informed consent.

The seriousness of the SARS epidemic reminds us how vulnerable we are against viral infectious agents with a respiratory/droplet mode of transmission. Patients without known exposure to the agent may become sick. Half of those who become intubated die. Healthcare workers are at particularly high risk; and it appears that in similar circumstances, full protection may not offer absolute safety. Although healthcare workers rarely become critically ill, high vigilance to the occurrence of suggestive symptoms, even in low-risk individuals, should always be exercised.

The Internet played a major role in the early recognition and containment of the disease. Shortly after the first unusual clusters of a mysterious respiratory illness started accumulating in Hong Kong, healthcare providers around the globe were alerted through emails sent to them via the International Critical Care Internet Discussion Group.[12] International health organizations and experts cooperated in a real-time fashion, exchanging ideas and information about the disease. It might have become a major worldwide disastrous epidemic, had SARS occurred before the Internet era. Events like the SARS epidemic in Western societies are uncommon. Despite its huge toll on morale, resources, and healthcare provision, the epidemic also demonstrated the heroic nature of critical care providers. Despite their fear and uncertainty, they remained at their posts voluntarily, isolating themselves from their loved ones and even giving their lives in their struggle against the disease. Maybe this is a modern application of an old saying: “No one has greater love than this, to lay down one’s life for a friend.”[13]

MRSA is an increasing global health problem, and patient isolation has been part of the management protocol in many hospitals. The efficacy of this approach has not been examined in a prospective study, despite the fact that isolation is a significant additional cost of care along with barrier precautions and decontamination.[14] In the study by Hails and colleagues,[6] a large variation was demonstrated in MRSA policies, procedures, and prevalence in English ICUs. The study presented by Dr. Bellingan[5] showed that if barrier precautions and strict hygienic measures are to be applied, patient isolation may not be necessary. It is an interesting concept, which could lead to significant savings and improved patient care. The findings question the current widespread (but also widely underapplied) dogma of MRSA patient isolation, so new studies are required before these findings may become standard medical practice.

The common knowledge that many urgent inhospital events are actually predictable was eloquently demonstrated by the ACADEMIA study, presented by Dr. Kause.[4] The majority of the patients, who died from a cardiac arrest or had to be transferred to the ICU, had easily recognizable warning signs of an imminent disaster, in some cases 24 hours earlier. Almost all of them had been seen by a doctor within the previous 15 minutes, so it is hard to understand why these events eventually occurred. One possible explanation is that these patients were already very sick, so the warning signs of hypotension, tachypnea/bradypnea, tachycardia/bradycardia, airway compromise, and mental status changes were not properly evaluated. On the other hand, these antecedents may have been present in many other patients who did not have an arrest. In any event, this study underlines the need to individualize care and to spend more time at the bedside. Simple, cheap, easily obtainable bedside clinical signs in the context of the particular patient may give invaluable information that may save a life. The only requirement this approach entails is more time spent with the patient.

Dr. Brower’s presentation[7] hopefully puts an end to a year-long ongoing saga. The ARDSNet study has been declared as safe, well designed, and applicable to everyday clinical practice by the OHRP; and the FACCT study should never have been stopped. There is room to improve the process of informed consent, but this does not decrease the validity of the findings. Was this turmoil necessary? One could argue that every measure protecting patients’ safety should be pursued in expense of time and additional financial costs. In December of 2002, the American Thoracic Society sent a letter to the OHRP expressing, among other things, the concern that OHRP’s investigation would convey the message to the public that “the process of clinical investigation cannot be trusted” and might be a “major impediment to future research in critical care and other disciplines.” This was actually the case, as these events received considerable publicity. Three months earlier, a letter questioning the trial’s safety was sent to the OHRP by the Alliance for Human Research Protection, reflecting the public concerns that enrolment into this study may have jeopardized the participants.[15]

Although the study now has been declared to be safe and well conducted, there is concern that what is left for the public is a feeling of suspicion and mistrust toward the scientific-medical community. It is noteworthy that after reviewing the analysis, which sparked the controversy, the independent panel concluded that there were “methodological problems with the intramural investigators’ analysis.” Should we be more careful next time?

The Review in a Nutshell
SARS is a very virulent agent that can affect persons without previous documented exposure to it.
Most patients who die from a cardiac arrest or are admitted to the ICU have shown warning signs.
Isolation may not be necessary for MRSA patients.
The ARDSNet low-Vt trial has been declared as safe and well conducted by the OHRP.
Stewart TE. Thematic session on hot topics. Results from the most recent clinical trials in intensive care medicine. SARS (severe acute respiratory syndrome). Program and abstracts of the 16th Annual Congress of the European Society of Intensive Care Medicine; October 5-8, 2003; Amsterdam, The Netherlands.
Fowler RA, Lapinsky SE, Hallett D, et al. Critically ill patients with severe acute respiratory syndrome. JAMA. 2003;290:367-373. Abstract
Scales DC, Green K, Chan AK, et al. Illness in intensive care staff after brief exposure to severe acute respiratory syndrome. Emerg Infect Dis. 2003;9:1205-1210. Abstract
Kause J. Thematic session on hot topics. Results from the most recent clinical trials in intensive care medicine. ACADEMIA (Antecedents to Cardiac Arrests, Deaths and EMergency Intensive care Admissions): predicting cardiac arrest. Program and abstracts of the 16th Annual Congress of the European Society of Intensive Care Medicine; October 5-8, 2003; Amsterdam, The Netherlands.
Bellingan GJ. Thematic session on hot topics. Results from the most recent clinical trials in intensive care medicine. Challenging the dogma: do we have to isolate patients with MRSA? Program and abstracts of the 16th Annual Congress of the European Society of Intensive Care Medicine; October 5-8, 2003; Amsterdam, The Netherlands.
Hails J, Kwaku F, Wilson AP, et al. Large variation in MRSA policies, procedures and prevalence in English intensive care units: a questionnaire analysis. Intensive Care Med. 2003;29:481-483. Abstract
Brower RG. Thematic session on hot topics. Results from the most recent clinical trials in intensive care medicine. ARDSNET: controversy regarding clinical trial design and patient safety. Program and abstracts of the 16th Annual Congress of the European Society of Intensive Care Medicine; October 5-8, 2003; Amsterdam, The Netherlands.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301-1308. Abstract
Eichacker PQ, Gerstenberger EP, Banks SM, et al. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med. 2002;166:1510-1514. Abstract
Amato MB, Barbas CS, Medeiros DM, et al. Beneficial effects of the “open lung approach” with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation. Am J Respir Crit Care Med. 1995;152:1835-1846. Abstract
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377. Abstract
International Critical Care Internet Discussion Group. Available at:
http://www.pitt.edu/~crippen. Accessed November 21, 2003.
St. John’s Gospel, 15:13.
Herr CE, Heckrodt TH, Hofmann FA, et al. Additional costs for preventing the spread of methicillin-resistant Staphylococcus aureus and a strategy for reducing these costs on a surgical ward. Infect Control Hosp Epidemiol. 2003;24:673-678. Abstract
Alliance for Human Research Protection. Letter to Office for Human Research Protections. Available at:
http://www.researchprotection.org/ethical/ARDSNet090402.html. Accessed November 21, 2003.

Here is some interesting background information on S.A.R.S.


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Selection and Evaluation of Clinical Investigators: What Really Counts?


Selection and Evaluation of Clinical Investigators: What Really Counts?

(Tami) Phuong Tran (B.SC.)
Student of KRC – Clinical Research Associate Training Program


Successful clinical studies will acknowledge the complexity of carrying out a scientific task involving human subjects. The principles involved as well as the respect for the rights of the subjects need to be recognized at all times. Therefore, the clinical investigator responsible for carrying out the study must possess a degree of knowledge, experience and practice. Not only is this an important requirement, but also involving minorities in the clinical study. The process of choosing a clinical investigator to run a clinical trial may be a daunting task. How can one know what to look for in a clinical investigator and what really counts? This article will examine the different areas on what to look for in a clinical investigator, provided with examples.


Clinical trials have become more complex in which standards and regulations that must be met are now more crucial then ever. Government officials such as the International Review Board (IRB) and Food and Drug Administration (FDA) are closely monitoring clinical trials. Regulations and guidelines must be followed in order for a clinical trial to be successful. It is highly important to protect the rights and welfare of all clinical trial subjects. Therefore, one of the utmost important factors involving the success of a clinical research trial lies amongst the selection and evaluation of a clinical investigator. Clinical investigators perform the actual research used to support applications for new drugs, biologics and medical devices. A clinical investigator may be a professional researcher operating out of a research institution such as a research hospital or university, or may be a practicing physician who also conducts clinical research. (1) A company in the process of developing new drugs, biologics or medical devices will therefore hire a clinical investigator to carry out the trial by recruiting subjects, conduct the research and report the results back to the company.

The individual(s) involved with the process of selecting and evaluating the clinical investigator must possess the skills and knowledge in the clinical research area in order to know what to look for. What really counts in the selection and evaluation of the clinical investigator? Looking into different key areas and qualities in which a successful investigator candidate should possess can make a clinical trial run more smoothly. Proper selection of clinical investigators is perhaps the single most important factor in the success of a clinical trial. (2). A highly desirable clinical investigator should have knowledge in the research area, possess positive research practices and ethics, will be unbiased to the trial and be involved with the minority society. A minority researcher may also be a desirable candidate as a clinical investigator due to the ties they may have with ethnic communities.

Company or Sponsor Responsibility

Before beginning a clinical research trial, who in the company is responsible for the selection of the clinical investigator? When pharmaceutical companies come up with a new drug or medical device it will need to go through research before the approval process can take place. Usually the sponsor of the company will be in charge of handling this matter. The sponsor is responsible for selecting the investigator(s)/institution(s). (3) They may take on the duty themselves or assign the task to the clinical research associate or other staff. A sponsor can transfer any or all of itâ?Ts obligations, including the monitoring of clinical investigators, to a contract research organization. (1) Whomever is in charge of the selection process will therefore need to follow certain guidelines. Selecting and evaluating a clinical investigator involves recognition of those with potential whom are able to carry out a successful clinical trial. The individual with this responsibility must choose investigators with the necessary experience for the trial, a sufficiently large target population, and a commitment and motivation to steadily and rapidly enroll patients in the study. Finding the right investigators is a delicate balancing act requiring specialized knowledge, years of experience, and a pinch of intuition. (2) It is therefore important that if a sponsor does select another individual to carry out the task of selecting the clinical investigator, then they should wisely choose an experienced individual, staff or contract research organization. If the sponsor assigns this task to another individual, they are still held responsible for overlooking the whole process of the clinical trial.

Knowledge &amp; Experience

The first area to examine when selecting and evaluating a clinical investigator is to determine if they have knowledge and experience in the research area. The clinical investigator that should be chosen for a clinical research trial will have done some studies that are related to the trial, are specializing in the field or a similar field of the study. Potential investigators need to have knowledge in the types of trials that they monitor. A researcher should â?oownâ?ť the science related to a diagnosis to be investigated. (4) They need to understand the background of the particular drug, device or material they are to be dealing with. They should also be familiar with the science related to the action of an intervention. (4) Not only is knowledge in the field important, but also knowledge that is necessary to manage and conduct clinical trials. This knowledge includes the basic fundamentals of conducting the clinical trial, including knowledge of the US regulations and ICH GCPs, as well as the rudiments of organizing a practice to properly conduct trials. (5) It is also highly desirable for the clinical investigator to have had successful completion of a training program, although it is not required by FDA at the moment. It is highly desirable that an investigator is trained because of noncompliance that have been reported. The United States Food and Drug Administration (FDA) and the Department of Health and Human Services (DHHS), and other regulatory agencies around the globe have observed a dramatic increase in noncompliant practices among clinical investigators. (5) Noncompliance can have a negative effect on the success of a clinical research trial. This has caused companyâ?Ts and sponsors to be more stringent on the selection process. For example, some companies now require or will soon require that clinical investigators obtain GCP/ICH (International Conference of Harmonization) training so that such noncompliance will not occur. A clinical investigator that is certified and has gone through training will not only prove that they are knowledgably in running clinical trials, but they will also have a competitive edge amongst other researchers. They will be more desirable to the research companies.

Research Practices &amp; Ethics

The next area that should be examined when selecting and evaluating a clinical investigator is positive research practices and ethics. It is important that clinical investigators carry out good research practices while making appropriate ethical decisions. Investigators should show that they are committed to promoting and advancing the highest ethical standards and practices. (6) They should maintain their compliance throughout the study. Successful completions of clinical trials will depend on these factors and also their strive of excellence. Thus, an investigator must commit to the following responsibilities when agreeing to do a trial:

* Conduct the study according to the protocol.
* Comply with the regulations.
* Personally conduct or supervise the trial.
* Obtain informed consent from subjects.
* Report adverse experiences properly
* Read and understand the material in the investigator brochure before starting the trial.
* Assure that other people assisting in the trial are aware of their obligations. (5)

The clinical investigator must show that they are able to make ethical decisions that can otherwise jeopardize a study. This requires a lot of experience and common sense in knowing what the best decision would be in a given situation. Research in human subjects is governed by FDA regulations that are written almost exclusively for the purpose of ensuring patient safety. According to the Code of Federal Regulations (21 CFR 312.60), â?oan investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigatorâ?Ts care, and for the control of drugs under investigation.â?ť (7) This regulation is basically dictating procedures for investigators to follow and it may seem that all aspects of research conduct would appear to be governed. But the truth of the matter is, is that there are many legal vagaries or â?ogray areasâ?ť that allow the investigators freedom in which to conduct their trials. The existence of these â?ogray areasâ?ť, thus creates a latitude of options in which how the investigator decides what is the best treatment for their patients without limiting their healthcare options. However, the investigators may also be faced to make critical decisions in trials in which they are paid to recruit and retain trial subjects.

The legal vagaries and â?ogray areasâ?ť in which the clinical investigator are free to make decisions can affect a study if the right ethical choices were not chosen. Investigators should not be persuaded into faulty actions due to the benefits that they may receive in completing a clinical trial or maintaining a number of subjects. They need to be able to enter into a trial with known certainty that they will only make the best ethical decisions. An example of how they should make an ethical decision is the options in treatment a patient receives. Should the investigator discover that one treatment is of superior therapeutic merit, he or she is ethically obliged to offer that treatment. (8) The investigator should have no â?otreatment preferenceâ?ť when they believe that there is a more beneficial treatment for that subject. Keeping a subject on the trial knowing that they can receive better treatment is unethical and can put the subjects health at risk. Treatment preference is an example that would fall under a â?ogray areaâ?ť and there are no guidelines in the Code of Federal Regulations (21 CFR312.60), therefore this decision is solely based on the clinical investigator. Clinical investigators should always keep the subjects best interest in mind and ensure patient safety while making decisions, especially if they fall under a â?ogray areaâ?ť category.

Many other legal vagaries and â?ogray areasâ?ť exist when conducing a clinical research trial.
The Clinical Investigator or also known as the Principle Investigator (PI) is the one whom is in charge of conducting the research trial and or is the one to supervise those who do. It is unlikely that the investigator will carry out the whole trial on his/her own and will therefore hire coordinators or even subinvestigators to carry out parts of the research. They hire coordinators to screen patients, conduct rudimentary procedures, dispense study medications, perform selected patient assessments, collect medical histories, and record adverse events. (7) There are no current regulations that require coordinators to be specifically trained or have expertise to carry out such tasks. Therefore, the tasks delegated to the coordinators are left to the discretion of the clinical investigator. The desirable investigator will be able to designate a coordinator with experience and proper handling of study procedures. The coordinators level of experience, training, and education should be of efficient standards for a successful clinical trial. It would be unethical to hire a coordinator knowing that they do not have the proper knowledge to carry out the various duties involved when coordinating a clinical trial.

In addition to clinical investigators hiring coordinators, they frequently designate subinvestigators. Most often, â?osubsâ?ť are physicians or, in the case of teaching hospitals, medical residents (although there is no requirement that they have specific training or expertise). These individuals are appointed to act as the PIs surrogates, and they work with the coordinators just as the PI would. Patients commonly assigned to physicians serving as subs rarely have any contact with the principal researcher. Of course, the requirement that PIs supervise those working on clinical trials remains, but there is no regulatory definition for what constitutes supervision. (7) This leaves clinical investigators with somewhat little regulatory guidance and thus must be cautious when choosing, training and supervising subinvestigators after delegating responsibilities to them. If subinvestigators are not properly chosen then these decisions can directly affect patient care; they are not just administrative or financial choices, but, in fact, ethical considerations. (7) It is important that a clinical investigator ensures good clinical practice compliance, not just for regulatory reasons, but to reduce the companyâ?Ts risk from potential adverse publicity or patient lawsuits. (2) The company or sponsor should thus take research practices and ethics into consideration when selecting and evaluating a clinical investigator. Potential clinical investigators should be able to make the most ethical decisions when dealing with legal vagaries or â?ogray areasâ?ť.

Bias &amp; its Effects

Another aspect that must be considered when selecting and evaluating a clinical investigator for a clinical trial is that they remain unbiased throughout the research. This is an important factor for a successful trial due to the negative consequences that may be caused if bias was present. FDA may consider clinical studies inadequate and the data inadequate if, among other things, if appropriate steps have not been taken in the design, conduct, reporting and analysis of the studies to minimize bias. (9) It is important that investigators are unbiased because conflicting interests may influence the outcome of the study. It can influence the way they carry out a study and also interfere with the protection of human subjects. Therefore, for these reasons it is in the company or sponsorâ?Ts best interest to carefully examine whom they hire as a clinical investigator and make sure that bias does not interfere with the investigatorâ?Ts decision.

What is bias? According to the glossary index of Elsevier, bias is defined as when a point of view prevents impartial judgment on issues relating to the subject of that point of view. (10) There are different types of scenarios in which bias can arise that should be looked at in the evaluation of a clinical investigator. The company and/or sponsor must be able to identify the possible situations. First of all, a desirable investigator should have no Significant Financial Interest connected to the study. Significant Financial Interest means anything of monetary value, including but not limited to, salary or other payments for services (e.g., consulting fees or honoraria); equity interests (e.g., stocks, stock options or other ownership interests); and intellectual property rights (e.g., patents, copyrights and royalties from such rights). (9) It is important that potential clinical investigators do no receive significant amounts of financial interest causing them to be persuaded by that interest. This type of bias may only cause a clinical trial results to be unreliable data and thus an ending in an unreliable study.

An example of financial bias that may arise is that the clinical investigator will get paid a substantial amount from sponsors or companies for enrolling their patients into trials. This situation will raise questions about conflict of interest because it is not known if the investigator is truly enrolling the patient for the patientâ?Ts benefit or for their own financial interest. Clinical investigators are also paid for opening their patientsâ?T confidential records so recruiters can hunt for eligible subjects. Patients are often unaware that their doctors are paid to recruit them for trials. (11) Many situations which clinical investigators are faced with put them in very difficult positions. They must try to win and retain their clinical trial contracts with the industry, but they must also find participants quickly being persuaded by the financial interests they receive. This pressure leads them to their patients confidential records, which is not only a form of bias but it is also unethical.

Another situation that may arise due to bias is that the clinical investigator will carry out a study so that a favorable outcome rather then an unfavorable outcome will result in greater compensation. This compensation can be in the form of equity interest in the sponsor of a covered study or in the form of compensation tied to sales of the product, such as royal interest. (9) They may have a financial interest resulting in the products patent, trademark, copyright or licensing agreement also known as propriety interest in the tested products. One aspect concerns trading in pharmaceutical company shares by investigators who may have premature or inappropriate communication of research results. Investigators may enter patients who have borderline selection criteria into studies, or fabricate results, or induce patients to enter by offering remuneration or better medical care. (11) Companies and sponsors need to be aware that bias in investigators may alter a clinical trialâ?Ts true outcome and therefore should be aware of this fact. They need to be cautious if the investigator has any type of significant financial interest in the study and therefore need to be cautious of what they offer to the clinical investigator.

There are ways to prevent bias. Companies that hire clinical investigators may require them to sign a disclosure agreement under an organizationâ?Ts conflict of interest policy. This will help minimize bias because clinical investigatorâ?Ts payments will be reported if it is of significance. This step taken will also help in determining if the clinical study was inadequate by FDA. The relationship between a sponsor and investigator to be productive and scientifically successful can only exist if conflict and investigator bias are stringently avoided.

Below is a guideline that is ideal for an investigator and sponsor to follow, so that bias can be avoided:

Investigator-Sponsor Relationship

1. The investigator should avoid even the appearance of conflict of interest that could compromise the investigatorâ?Ts professional integrity; the investigator should be vigilant to such potential conflicts.
2. Investigators should not have relationships with industry that could affect their objectivity as a researcher. As such they should not have direct or indirect financial interest in biomedical companies that are active in the investigatorâ?Ts area of research interest. Investigators also should not accept gifts or incentives from such companies, and should avoid paid consulting relationships with the companies for which they also serve as an investigator evaluating a company product.
3. Whenever financial relationships between investigators and sponsor exist, they should be fully disclosed to journals or other publications, medical audiences, and other relevant parties. (12)

These guidelines, if followed by the clinical investigator will not only benefit the investigator and industry but also the clinical trial subjects. The safety of the clinical trial subjects and overall outlook of the clinical trial will not be affected due to bias.

The Minority Investigator &amp; Minority Subjects

Another area to consider when selecting and evaluating a clinical investigator for a successful clinical research study is minority researchers. Minorities make up a large percentage of the population but are underrepresented. The under representation of minorities in clinical trials resulted in a 1993 congressional mandate that led to the NIH policy on inclusion of women and minorities in clinical research. (13) Promoting the inclusion of minorities in clinical trial research is important because the United States has one of the most ethnically diverse populations in the world. A third of the current U.S. population belongs to minority groups, and this proportion is expected to increase steadily. (13) Many factors affect the enrollment of minorities in clinical trials such as attitude, cultural beliefs, social issues, and investigative behavior. The selection of a minority researcher may be a key access to the minority population. Information gathered from the minority population can be essential for the implementation of health policies and interventions for the future.

The importance of minority research is crucial for the needed interventions of high disease rates occurring in minorities. Diabetes has reached epidemic proportions in many minority populations. In virtually every minority group in the United States, diabetes prevalence is greater than in the majority white populations. (14) If studies are not done involving the drug interactions with minorities than it may be more difficult to find a cure or treatment.

An example how minority researchers can be a key access to the minority population is location. Researcherâ?Ts facilities are usually located in the same demographic areas as the minorities. They may work in settings that are in terms for minority representation. Minority subjects are also more likely to choose minority physicians because they feel more comfortable.

Minority researchers are important to clinical trials because they offer cultural empathy, which acts as a bridge to minority participants. Minority researchers know the communities that are advocates for minority populations and have negotiated good relationships with organizations that offer access points to these minority populations. Strong bonds with community-based organizations can lead to partnerships to enhance not only enrollment but also retention and involvement. (13) Minority participants are more likely to feel at ease when in a trial with a researcher they trust. They may also be more open to participate in future clinical studies.

Minority investigators can be of great benefit to the pharmaceutical industry for many reasons. Thus, the inclusion of minorities in clinical studies will result in a more thorough and efficient study. Some general principles and elements that must be present to promote the inclusion of minorities in clinical research are as follows:

* Existence of active links with grassroots organizations
* Outreach and awareness of the cultural component that leads to minority-relevant research
* Knowledge of motivations for participation, that is, the perceived value of the study, the altruistic component, the desire for peer interaction, and assess to care
* Education importance and rationale for participation in clinical trials
* Accessible sites and convenient hours
* Knowledge of the role of the family in decisionmaking (13)

These principles are key to minority involvement because of the barriers that exist in promoting minority inclusion. Investigators must be able to recognize the obstacles and develop approaches in which they can overcome them. They must find ways to make minority participation more accessible. Investigators must also be able to understand the target population. An understanding of the target population is essential if an investigator is to succeed in recruiting that population. The first step is to identify and characterize the population of interest within the community in which it resides. The size of the community, the geography of the area from which the study sample will be drawn, the size of the target population, its demography and history, and where it resides are important starting points. This information is required to estimate whether there are sufficient individuals with the appropriate basic characteristics for the research and whether travel to the research site might be a challenge. (14)

Understanding the target population usually requires more than identifying and characterizing. This is barely sufficient information and additional information will be needed. Examples of additional information that is usually essential include knowledge of ethnic characteristics, cultural customs and norms, socioeconomic level, language, education, literacy, health beliefs and knowledge, and needs and values, including economic, political and religious. Although most researchers will recognize their importance when made aware of these issues, researchers often fail to recognize these factors during the planning process. Researchers put inadequate effort into learning more about the target population, particularly when compared with the effort they put into learning more about the scientific background for the study. (14) Thus a desirable clinical investigator should have done all their proper studying of the target population in order to be successful at recruiting minorities.

If a minority researcher does put in the effort to learn about the target population, they can be of benefit because they can be mentors to minority students whom would otherwise be reluctant to choose clinical research as a profession, especially due to the lack of financial incentives. The lack of financial incentives in clinical medicine is greater than in basic or clinical biomedical research. Instead of careers in research, minority physicians often enter private practice and become active in community affairs. (13) By role modeling and mentoring, minority researchers can thus foster and promote increasing numbers of minority researcher and primary investigators for future clinical trials.


The selection and evaluation of a clinical investigator involves many aspects to take into consideration. Main factors and areas of interest must be incorporated into this decision making process. The proper selection of the clinical investigator starts with the skilled and knowledgeable selector. It is important that a trained professional if not the sponsor themselves, than a contract research organization, clinical research associate or staff to carry out the evaluation and selection tasks. They should be familiar with the different key areas and know what to look for in a potential clinical investigator.

The different areas to look at in a potential clinical investigator is knowledge in the research area. An investigator that is not familiar with the research area cannot perform efficiently due to the lack of knowledge. They may put their subjects at risk which would be unethical. Investigators should also possess positive research practice and ethics. Knowing how to make the right decisions that involve legal vagaries or â?ogray areasâ?ť can be of great benefit to the trial. Also, investigators should avoid bias relating to the research trial. They should avoid any significant financial interest and not be persuaded into faulty actions. Last of all, the importance of involving minorities in clinical studies can be essential for future implementation of health policies and intervention. Therefore, it is highly desirable to consider minority researchers in the selection and evaluation process of a clinical investigator.

1. http://oig.hhs.gov/oei/reports/oei-05-99-00350.pdf
2. http://www.devicelink.com/mddi/archive/02/11/015.html
3. http://www.paho.org/english/ad/ths/ev/gcpensponsorresp.pdf
4. http://www3.us.elsevierhealth.com/promo/LaFleur/pdfs/clinicalResearchTerminology.pdf
5. http://www.diahome.org/content/Events/Clinical_Investigator_Guide.pdf
6. http://www.acrpnet.org/certification/fda/cti/fdactibro.pdf
7. http://pubs.acs.org/subscribe/journals/mdd/v04/i04/html/MDD04DeptClinical.html
8. http://content.nejm.org/cgi/content/abstract/317/3/141
9. http://www.uab.edu/irb/aahrpp/iii1a.pdf
10. http://www3.us.elsevierhealth.com/promo/LaFleur/pdfs/clinicalResearchTerminology.pdf
11. http://www.issuesinmedicalethics.org/084or119.html
12. http://www.saem.org/download/edward.pdf
13. http://www.niaid.nih.gov/healthdisparities/HDSYMPOSIUM/proceedings2/session2.htm
14. http://journal.diabetes.org/diabetesspectrum/98v11n3/pg161.htm

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Research on Humans Faces Scrutiny: New Policies Adopted


Research on Humans Faces Scrutiny: New Policies Adopted

Paul T. Kefalides, MD
Pages 513-516


Ann Intern Med. 2000;132:513-516.


Structural changes in the field of biomedical research have in turn changed the climate for research involving humans. Both Institutional Review Board (IRB) administrators and investigators are feeling new pressures. Although they are stirred by a steady increase in research projects, especially those sponsored by industry, they are challenged by new public advocacy for the protection of human participants and aggressive, punitive enforcement by government regulators. Several reforms are being drafted and may be put into place by the end of the year, intended to modernize the system of research oversight and regain the public’s trust.

Obligations of Institutional Review Boards

Institutional review boards are charged with the responsibility of reviewing and approving all research projects that involve human participants. In addition to approving new projects, IRBs are responsible for continuing reviews, a form of oversight on ongoing research. Most research institutes divide IRB duties between a small administrative staff and a committee or committees that are composed primarily of faculty members, supplemented by ethicists, attorneys, and community representatives. Most institutional IRBs meet monthly or biweekly to discuss new applications.

In its review process, an IRB must refine investigators’ proposals and preempt any potential harm to the participants by synthesizing ethical principles of human subject research with clinical practice guidelines, federal regulations, and local laws. The institution’s investigators are permitted to experiment with humans within the limits imposed by a federal contract known as the multiple project assurance. Institutional compliance with the provisions of the multiple project assurance is a prerequisite for access to federal research funds.

The Market Economy for Research

An increasing budget for the National Institutes of Health (NIH), a booming biotechnology sector, and the proliferation and prosperity of independent IRBs (see sidebar) are all markers for the continuing growth of clinical research. The expansion has put pressure on the IRBs of nonprofit research institutions that are now widely recognized as understaffed and inadequately funded. “Institutions have been focused on getting new researchers and labs and have not paid attention to monitoring the research,” observed Gary Chadwick, PharmD, director of the research subjects review board at the University of Rochester, Rochester, New York.

According to administrators, a graph of the number of research proposals submitted per year would show a constant upward-sloping line. “It’s a steady increase at 4% to 5% a year,” commented Sharon Friend, director of the research subjects protections committee at the University of California at San Francisco. “We probably have at least 700 new biomedical studies each year,” she stated. At the University of Rochester, volume has increased an estimated 25% over the past 4 years. In response to that growth, Chadwick says, administrators subcontracted a portion of their research reviews to Western IRB in Olympia, Washington.

The trend toward multicenter trials has complicated the review and reporting duties of IRBs. In addition, because research is increasingly sponsored by commercial organizations, there are financial incentives to acquiring accelerated IRB approval. Industry-supported study offers valuable overhead revenue to institutions whose clinical medicine incomes are shrinking; in fact, for many health systems, increasing revenue streams today are attributable exclusively to growth in clinical research. However, industry support also presents new challenges to a review process that has historically been marked by university bureaucracy. “The faster an IRBreviews and approves [projects], the more an institution stands to gain,” observed Moira Keane, director of the research subjects protection programs at University of Minnesota Medical School in Twin Cities, Minneapolis. “There is tremendous pressure to do things faster,” she stated.

According to Friend, industry-supported research now constitutes 50% of her institution’s studies on humans. “It’s a lot more difficult to work with industry than with the federal government,” she asserted. “Every drug company study is different…they have different staff and lots and lots of lawyers. It’s a lot more labor-intensive [to work with companies]; we estimate three times as much.”

Punitive Actions of the Government

The influx of research proposals for human study coincides with more rigorous enforcement of the government regulations that apply to research on humans. In the past 14 months, federally funded research has been restricted or suspended at several research institutions and more institutions have received federal inquiries. Although NIH officials stress that the rules for protection of human participants have not changed, it is clear that enforcement of these rules has become increasingly strict. “Prior to this year, we had not taken such global action,” stated Michael Carome, MD, chief of the Compliance Branch, Division of Human Subjects Protection (DHSP), Office for Protection from Research Risks (OPRR), National Institutes of Health.

“I don’t think OPRR should have been very surprised,” commented Erica Heath, president of Independent Review Consulting (IRC) in San Francisco, California. “For 30 years, nobody asked the question, ‘What’s going on?’ They relied on the collegiality and integrity of academics. Then in 1 year with a great deal of fanfare, there was this change in enforcement.”

At institutions where research was suspended, thousands of projects were shelved immediately. Most could not resume until they were reviewed again or until specific problems cited by the government were fixed. According to David C. Clark, PhD, director of research affairs at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, Illinois, the full effects of his institution’s suspension are difficult to quantify. “We probably lost huge amounts of revenue from clinical trials and studies that just picked up and moved. It probably set some researchers back a couple of years,” he stated.

Duke University Medical Center in Durham, North Carolina, received a 4-day suspension. “The negative effect on morale was tremendous,” asserted John M. Falletta, professor of pediatrics and chairman of the IRB. “Since then, we have been under close scrutiny by OPRR.”

According to many ethicists and IRB officials, OPRR’s new vigilance directly followed the 1998 publication of a report by the Office of the Inspector General (OIG) of the Department of Health and Human Services. The report sharply criticized OPRR’s oversight of human subject research and asserted that IRBs “review too much, too quickly, and with too little expertise.” The report also cited institutional and individual conflicts of interest that hinder the ability of IRBs to protect human participants. It concluded that reviews of continuing research were inadequate and that IRB staff members were insufficiently trained.

Public Outcry

The national media also helped create the new probing environment for human subjects research. According to several experts, renewed publicity about government-run experiments on the effects of radiation, along with accounts in the lay press that portrayed specific researchers as reckless, stimulated public awareness of human subjects research. Arthur Caplan, PhD, director of the Center for Bioethics at the University of Pennsylvania in Philadelphia, cited a cascade of events that included the radiation reports, the OIG report, and a series of improprieties involving research on children and mentally handicapped persons. “I think people still have a positive attitude towards medical research, but there is a growing distrust of medicine that has been fueled by managed care…The really driving force has been the scandals,” declared Caplan. “These incidents have led people to believe that OPRR is not doing its job.”

The new concern is reflected in the quantity of letters that OPRR receives. According to the NIH’s Carome, the number of complaints logged against researchers and received by OPRR is almost 50% higher than 1 year ago. “There is heightened public attention on human subject research,” agreed the University of Minnesota’s Keane. “[New publicity about] the Tuskegee and radiation experiments have had a profound effect on suspicion. We have changed the culture. It [IRB oversight] is no longer a quiet little ethical endeavor.”

The new sensitivity has culminated in government inquiries and more challenges to IRB administrators. Friend noted that on her staff, she needs one person whose only job is responding to the government. She commented that OPRR now sends her office so many requests for detailed information on human subjects researchâ?”most with unrealistic deadlinesâ?”that her first response is usually to request an extension.

The Most Common Institutional Review Board Mistakes

According to Carome, when the OPRR investigates an institution’s IRB, they find problems that fall into three categories: insufficient IRB staffing, inadequate training and education of IRB members and staff, and (analogous to charges against clinicians) failure to maintain proper documentation. At Duke University, for example, OPRR auditors concluded that the minutes of the IRB meetings were incomplete. At Rush-Presbyterian-St. Luke’s Medical Center, audiotapes of IRB proceedings were not accepted as substitutes for written documentation. Other institutions have enrolled more patients in a study than originally planned and have failed to use informed consent.

Carome offered an example of violations that apply to individual researchers. He stated that many investigators perform human subjects research without realizing that it should be classified as such. “If you do a survey of patients, and you ask name and address and obtain identifiable private information, that is human subject research,” he clarified.

From the perspective of a private IRB, the misunderstandings on the part of investigators are fundamental. Independent Review Consulting’s Heath complained that many of the research proposals submitted by clinical researchers demonstrate ignorance of the elementary vocabulary of science. “There are more and more clinical investigators, and they don’t even know what they’re doing…they don’t know the elements of informed consent. These problems are pretty basic,” she commented. Some of IRC’s clients are private practitioners capitalizing on the new opportunities offered by partnerships with the pharmaceutical industry and by participation in clinical trials. “Research used to be a quest for discovery. Now it is a business,” Heath lamented.

The Scope of Institutional Review Board Authority

In an effort to make the quality of research more consistent and minimize the number of ineffective and inappropriate studies, some scientists advocate a broadening of IRB duties to include assessment of investigators’ research design and their review of the literature. Ideally, this would require all IRBs to evaluate proposals within the context of related published literature using statistical methods to ensure sound methodology. “If you put a subject into a study to answer a question that cannot be answered, is that ethical?” asked James Hinson Jr. MD, Research Compliance Officer, University of Missouriâ?”Columbia School of Medicine in Columbia, Missouri.

Such an expansion of IRB responsibility referenced by Hinson was outlined in a 1996 article (Savulescu J, Chalmers I, Blunt J. BMJ 1996;313: 1390-3). The authors cited specific examples of misconduct where patients were enrolled in clinical trials that conferred risk in order to test hypotheses that had been proven and summarized previously in systematic reviews. They also criticized researchers for burying undesirable results of clinical trials. The authors argued that research ethics committees should be responsible for preventing redundant or irrelevant research and ensuring that all resultsâ?”good and badâ?”are reported to colleagues in the scientific community.

While some such as Caplan agree that it would be desirable to use the IRB mechanism to police more aggressively the quality of research, most experts in the field concede that an official broadening of IRB powers is currently not on the tableâ?”and that existing guidelines will have to serve for now. “IRBs are not intended nor constituted to be scientific review committees,” explained Chadwick, “although some IRBs have made scientific review a part of their process.”

Chadwick identified other differences in the European model for research review where the review committee has much broader powers to assess scientific merit and to investigate financial conflicts of interest. For example, in the United States, where many sponsors make small payments to investigators to cover the costs of recruiting patients for trials, Chadwick thought determining certain types of financial conflicts would be challenging. “You have to dig deep to determine what is conflict of interest…. This would turn an IRB into an accounting function. We [in the United States] have tried to focus on the interface between subject and investigator rather than investigator and sponsor.”

“This is not a specific concern that we have raised,” added OPRR’s Carome in response to the idea to broaden the scope of IRB authority. “[But] IRBs have authority to require anything they feel is necessary to protect human rights.” He added that assuring that research is meaningful is implicit in current guidelines. To determine the merit of a proposal, an IRB must involve other scientists with adequate expertise to make a judgment or else seek outside consultants.

Duke’s Falletta thought the issue of research design could be approached under current rules through consideration of the risk and benefit of the study. “If the principal investigator is not asking an answerable question, does not have the means to answer the question, or is asking a question that has already been definitively answered, then no benefit will likely be detectable from the research. If that research is risky, which most research is, then the risk vs. benefit assessment of the research is unfavorable, all risk and no benefit, and the research must not go forward.”

Hinson admits that researchers will probably have an unfavorable opinion of any new policies that create the expectation that review boards judge scientific merit. “A lot of people will say that that is out of bounds; submitters get upset when you challenge their design.”

Strategies for Reform

Currently, prospective reforms focus on ways to improve education and training of IRB professionals, educate and certify individual researchers, and establish an accreditation process for institutions that perform research on humans. The possibility of centralizing certain IRB functions is being debated, and in the distant future, a professional organization might offer board certification in the supervision and performance of research.

The University of Rochester’s Chadwick is also past president of the Applied Research Ethics National Association (ARENA), a national organization of IRBs. He reports that a certification examination for IRB professionals has been adopted and will be introduced at ARENA’s annual meeting in the fall of 2000. The examination will include a history of research, a review of the principles of bioethics, and descriptions of international codes and standards. It will also describe the features of good experimental design.

Chadwick was among the first to introduce a formal education program for researchers. All investigators whose proposals are thought to confer at least moderate risk to participants must complete a self-study manual and pass an examination before IRB approval is given. Other institutions are expected to develop similar investigator-training programs.

Education and training of investigators and IRB staff has also become the top priority at Rush-Presbyterian-St. Luke’s Medical Center. According to Clark, the IRB now has a full-time training and education director. “We instituted mandatory workshops for investigators to educate them on the history of medical research abuses, bioethics, and conflict of interest. Rush scientists will not be allowed to have studies approved or reapproved until they complete the workshops,” Clark stated. A formal examination for investigators is also in the pipeline.

Public Responsibility in Medicine and Research (PRIMR), a nonprofit organization with 35 years of experience in educating scientists and policymakers about research ethics, is drafting a voluntary accreditation program for institutions that experiment on humans. The OPRR has already endorsed the program. According to PRIMR executive director Joan Rachlin, JD, MPH, “We are in the process of developing performance standards for a self-assessment instrument, and this would be followed by a site visit team.” Institutions will be able to apply for accreditation as early as the fall of 2000.

Some ethicists, such as Caplan, have suggested creating a centralized review board, although others, who seek to maintain local standards in research review, oppose the idea. It has been suggested that a national review board would be a particularly important means of expediting multicenter trials of new therapies for cancer. Caplan sees further gains of centralization. He believes that IRBs are ill equipped to monitor negative aspects of trials, such as adverse events, because they are frequently the last to be informed of them. In his view, it would be helpful to have a national IRB for high-risk experiments. Caplan argued that the recent death associated with a gene therapy experiment at the University of Pennsylvania was a case study in three ways: “One, the ability to collect adverse event information was limited; the IRB didn’t know. Two, there was no connection between the data safety and monitoring committee and the IRB. And three, once the IRB approved the study, they were uninvolved.”

Independent IRBs, such as Heath’s IRC, are also looking to the future and anticipate that they will have to adapt to the new regulations. The proposed reforms emphasize knowledge about ongoing research projects rather than such issues as initial informed consent. Firms like IRC will need to subcontract with monitoring companies to meet the need for on-site auditing.

Chadwick agreed that investigators should anticipate more ongoing inspection of their work and should understand that protection of human participants does not begin and end with the informed-consent document. “The biggest issue that investigators run afoul of is in the consenting process. Informed consent is not just a document; it is a process,” he explained. In 1976, the Belmont Report of the National Commission for the Protection of Human Subjects identified the three key elements of the consent process: information, comprehension, and voluntariness. Friend considers the Belmont Report required reading for any clinical investigator who wants the work to go smoothly. “This is not something that will go away,” she stated. “Research standards change, and investigators need to work with their IRB office.”

Private Institutional Review Boards

Not all institutional review boards (IRBs) are affiliated with research institutions. Privately organized IRBs now review clinical projects and compete with traditional IRBs by offering faster research reviews and approvals. Indeed, in today’s research environment, the for-profit IRB market is rapidly expanding. The oldest and largest of such enterprises is Western IRB (WIRB) in Olympia, Washington. Its president, Angela Bowen, MD, says that business is going “straight up.”

Thirty years ago, Bowen founded the panel that would become WIRB when she relocated from a large research center to a private practice in Olympia. She asked a nonprofit organization to create a group of reviewers to read and offer suggestions on her own clinical studies. “I felt I needed somebody to test my judgment against,” she recalled. Fortuitously, the group that she helped organize contained all of the personnel that federal regulations would later mandate.

By the 1980s, WIRB was serving small and medium-sized hospitals. In recent years, it has added several universities to its list of clients. As the largest private IRB, WIRB employs 157 people and maintains 40 alternates for its 9 board members. Western Institutional Review Board charges $550 to review a protocol and expects to review 1400 proposals this year; it is a subcontractor for 4 universities and 15 hospitals. In 1999, WIRB was selected to perform a comprehensive audit of all of the research projects at the University of Colorado in Boulder, Colorado. The audit is a prerequisite for the removal of the university’s research suspension, which was imposed by the Food and Drug Administration.

According to Bowen, speed is a key factor the success of her business. “We usually have a board meeting every day, sometimes twice a day,” she explained. She noted that WIRB usually reads, analyzes, and gives an opinion on a research proposal in 10 working days. At a nonprofit IRB, the average turnaround time is approximately 1 month.

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Research & Development and Clinical Trials


Research &amp; Development and Clinical Trials

The research and development of new drugs is the American and European pharmaceutical industries greatest strength. Novel therapeutic drugs have gone on to achieve blockbuster status and have brought about tremendous profits for these companies. For example, Lipitor from Pfizer made about USD$ 10.9 billion in sales for 2004. Similarly, Advair from GlaxoSmithKlien made over USD$ 4.5 billion in same year. 9 The list goes on with top products from the top 10 pharmaceutical companies in the billions. However, the cost of research and development has escalated with a corresponding decline in productivity. Furthermore, more stringent requirements to show prove of efficacy and safety of new drugs has also added to the cost of bringing new drugs to the market.

It is estimated by the FDA that it requires about USD$ 1.7 billion to get a new drug into the market. 10 Besides the cost of getting the drug into market, there is also the time factor. On the average it takes about 12 to 14 years for the process in U.S. This lengthy process has many stages that are strictly regulated. The drug discovery period may take 1 to 3 years and this is followed by pre-clinical trials that can last another 2 to 3 years. The activities may overlap and it most cases they do. less, it takes about 5 years before a potential drug candidate can reach clinical testing. The new drug is required to undergo three phases of clinical trial test where in Phase I the new drug is determined for its pharmacological effects, dosage and safety. Phase II concentrates on a larger population, in the hundreds, made up of patients with the ailment the new drug is intended to treat. This phase investigates the new drugâ?Ts effectiveness and potential side effects. Phase III is an extension of Phase II where the patient pool required are in the thousand to obtain statistically significant results and to determine adverse experiences under long term use of the new drug. Phase I is generally accomplished in about a year and Phase II takes about 1 to 2 years. Phase III generally takes about 3 years to complete. Each Phase is conducted separately as the result of one phase is critical to the approval of the next phase. All in all the clinical trials of a new drug takes about 5 to 6 years to complete. The FDA review and approval process itself can take another one and a half years or longer depending on how well the clinical trial was conducted. There is also the post-approval monitoring period that can last up to 2 years. 11

Conventional research and development methods have relied heavily on screening vast databases of potential chemical compounds. Time has always been the limiting factor but this has been solved to certain extent with the progress made in high throughput screening machines. The ever increasing requirements of efficacy and safety of new drugs have also significantly reduced the probability of finding potential new drug candidates using this hit and miss method of discovery and development. In reality, out of every 5,000 to 10,000 potential new drugs discovered only about 250 make it to preclinical trials. Out of these 250 potential new drugs about 3 to 5 ever make it to clinical trials. Eventually, only 1 out of 5 new drugs under clinical trial is approved by the FDA. 11 All these figures amplify the point that the development of a new drug is an extremely costly and risky undertaking for any pharmaceutical company. The prevailing approach taken by most big pharmaceutical companies is to only pursue new drugs that has the potential to achieve blockbuster status, new drugs that can have more than USD$ 1 billion in sales per year. Otherwise, companies may not see beneficial returns from their investments.

The sheer scale of the investment as well as the high risk nature of drug discovery and development effectively prohibits many new companies particularly from developing countries outside of the USA, Europe and Japan triad to attempt going into the developing new drugs by themselves. In fact, the amount of investment required often far exceeds many countries annual budget. This aspect of the pharmaceutical industry has the least potential for any significant global participation. However, the adoption biological based research and development techniques have the potential to reduce cost and time of new drug development.

The acceleration in advancements of molecular biology, genetics and other related fields and their application in medicine have inevitably attracted the pharmaceutical industry. The biopharmaceutical products have the potential to deliver more effective and targeted therapy with lesser side effects. Studies have shown that pharmacogenomics clinical trials have the potential to be shorter by as much as half time with patients prescreened for responsiveness to the therapy. Herceptin made by Genentech is successful pharmacogenomic product where it is targeted towards specific breast cancer patients with an over expression of the HER2 protein. Such success should be example and catalyst for developing nations, particularly China and India, where there are a sufficiently large talent pool of experts to venture into novel new drugs discovery and development. These capabilities are already recognized by big biopharmaceuticals like Roche, Pfizer and Norvatis have established R&amp;D centers in China as early as year 2004. 12

Such developments and expansion of R&amp;D facilities into developing countries have significant consequences. New drugs or therapeutic agents can be brought to the market faster thus reducing cost. Savings in cost and time can also encourage more new drugs to be developed, particularly targeted at diseases that are more prevalent in other regions as well as diseases with a smaller market since there is a less dependence on block buster products. Bringing a new drug into market will not largely be restrained by the financial capability but by the technical capability of the company. This should be the fundamental driving force in new drug development and truly encourages a global effort.

The biopharmaceutical industry like any other industry faces enormous challenges in todayâ?Ts global business environment. It is also one of the most regulated industries in the world especially in approval and marketing of products. The big players in todayâ?Ts pharmaceutical industry originate mainly in US, Europe and Japan. U.S. and Europe have almost equal share of companies in the top 50 while Japan has only half the number of companies in this list as compared to U.S. or Europe. Of the 50 companies; 20 are from the USA, 19 from Europe and 11 are from Japan. A further analysis of the top 20 companies shows a similar distribution with only 2 Japanese companies coming in at positions number 15 and 19. The top 10 pharmaceutical companies in the world in terms of revenue are all from USA and Europe with USA having a greater share with 6 companies and Europe with 4 companies. 9 Therefore, it is not surprising the first concerted efforts to work together under common grounds were made up of representatives from these locations in the form of the International Committee for Harmonization (ICH).

An analysis of the distribution of the top 50 pharmaceutical companies in the world in terms of sales shows that all of them originate from USA, Europe and Japan. The total sales of these companies amounted to USD$ 387.81 billion dollars in the year 2004 with the American manufacturers contributing 47.8% at USD$ 185.45 billion, Europe contributing 43% at USD$ 166.84 billion and Japan a distant third at 9.2% amounting to USD$ 35.52 billion of the total sales. A further analysis of the sales figures by region, however, reveals a different distribution. 47.8% of the global sales come from North America with a market value of USD$ 248 billion while Europe constitutes 27.8% of the world market at USD$ 144 billion. Japan is at 11.1% at USD$ 58 billion and the rest of Asia, Africa and Australia contributes 7.7% at USD$ 40 billion. Latin America sales contribution is at 3.8% amounting to USD$ 19 billion and the rest of Europe, non EU member countries, at 1.8% totaling USD$ 9 billion. 9

A simple comparison of the sales figures against the population of the countries shows that on the average each person in the USA spends USD$ 831 per year. In Japan this figure is USD$ 454 per year and in Europe Union it is USD$ 311 per person per year. The difference stem mainly from how the drug market is regulated in the difference regions. In the United States health care is provided by the private sector managed mainly by insurance companies and Health Managed Organizations (HMOs). Thus the market is open to free competition among the pharmaceutical companies and prices are generally determined by the efficacy of the drug and cost of development. This has generally made drug prices in USA the highest in the world and also the most attractive market for all biopharmaceutical companies.

The European Union itself has a few models to determine pricing of drugs. The criteria used in France to determine pricing are based on assessment of R&amp;D efforts, therapeutic advantages and novelty of the new drugs. In Italy, pricing is directly based in production cost. While in countries like Germany and United Kingdom where there is supposedly free market determined by competition, purchasing of drugs are tightly controlled through few purchasing bodies like the regional or national health authorities. 11 Similar situations can be seen throughout developing countries where the need to provide adequate health care has been used as the reason to impose price control.

Emerging pharmaceutical companies particularly those from India, Eastern Europe and Middle East are making inroads into the U.S. and European markets mainly with generic products. The use of generic prescription drugs increased from 18.4% in year 1984 to 54% in year 2004. The sales value of this market is estimated to be USD $ 30 billion. 13 The use of generic prescription is estimated to keep on increasing as generic drugs are one the ways identified to reduce health care cost in the U.S. The number generic drug applications received by the Office of Generic Drugs (OGD) in 2004 was 563 and this increased by 33% to 766 applications in year 2005. In the first six months of 2006 the OGD approved 275 generic drug applications while for the corresponding period in 2005, 230 applications were approved. This represents an increase of 19.6%. In 2005 between January and June 34.3% of the generic applications were for first-time generics and tentative approvals. This figure increased to 46.6% for the corresponding period in 2006. 14 This is a clear indication that the generic manufacturers are well prepared to enter the market with their products when the patent expires for the existing branded products. IMS has reported that by 2009 USD $80 billion worth of top selling drugs would have lost their patents expired. The same report detailed that the world generic market in 2005 was worth USD $45 billion and increase of 14% from the previous year. 15

The generic manufacturers participating in the U.S. market is manly made up of local and EU based companies. However, the participation from other regions is far better in this sector compared to branded drugs. In the first six month of 2005 29.1% of the generic drug approvals were to â?oforeignâ? manufacturers (excluding EU) while the same period in 2006 saw the figure increased slightly to 30.6%. The approvals can be seen as quite consistent over the last year and half, but the main focus of foreign manufacturers are in the tentative approvals where they have obtained 48% share of the approvals. It is clear that these companies are well prepared to provide generic version of branded drugs as and when their patents expire. These â?oforeignâ? companies are from Israel, Taiwan, Canada, Jordan, Australia but a majority of the approvals were obtained by companies from India. 16

The overall generic market in the EU is significantly smaller in value than that of the U.S. The use of generic market varies in the EU member countries with Germany at 41% followed by Sweden at 39%, UK at 22% and Netherlands at 12%. France generic market accounts for only 3-4% of the pharmaceutical market while in Italy, Spain and Portugal the generic market is barely 1% of total pharmaceutical sales.17 The generic drug market is also expected to grow in Europe as governments are looking for ways to control health care cost. Over the past years many Indian pharmaceutical companies have targeted European manufacturers in their attempts to have a bigger share of the market. Some notable acquisitions are Dr Reddyâ?Ts Laboratories (DRL) buy over of Betapharm of Germany for USD $570 million, Matrix Labsâ?T USD $263 million purchase of Docpharma of Belgium and Nicholas Piramal purchase of Avecia Custom Drug Synthesis from UK for USD $16.7 million. Nicholas Piramal also bought Pfizerâ?Ts Morpeth facility in UK while Ranbaxy has acquired Allen SpA in Italy, Terapia in Romania and Ethimed in Belgium.18

In all the aspects of the pharmaceutical industry that we have looked, they have participation from almost all regions of the world. The degree of participation may be varied with some aspects like production being contributed by all regions while in others like research and development and clinical trials are still dominated by the more established countries like USA, European Union and Japan. However, it is clear that other regions like Asia, mainly from India, China, Singapore as well as Australia is making tremendous progress and is becoming ever more attractive places to carry out these activities. Therefore, it is without doubt that the industry is a global industry. A common set of regulations for drug development governed by Good Clinical Practice (GCP) are being followed and similarly Good Manufacturing Practice (GMP) are universally adopted for manufacturing activities.

The global biopharmaceutical industry as a whole is also unique compared to other industries. Its products cannot be viewed solely to make money as in other consumer goods like in the electronic or automotive industry, but also to provide health care to the people of the world. The industry must uphold their social responsibilities to ensure that health care is accessible to everyone and at the same time remain an innovative, profitable and sustainable industry. Therefore, the challenges ahead are to ensure that drugs will not become too expensive and only accessible to the rich, as it is becoming more so in the USA, but available to all those who need it. At the same time the market conditions in the industry must also stimulate research, innovation to provide better drugs to overcome disease and a more even playing field for all players in the industry. These ideals are by no means insurmountable especially in a truly global biopharmaceutical industry.


1. Definitions of Globalization on the Web

2. Definitions of Globalization on the Web

3. Definitions of Globalization on the Web:

4. Official Website for ICH.

5. JPMA (Japan Pharmaceutical Manufacturers Association) Home Page, Member Companies.

6. 2006 DIA, Round 1, FDA Highlight. eCliniqua, Bio-IT World. July 10, 2006.

7. The Biopharmaceutical Industry: www.infocollective.org/biopharm.html

8. India set to overtake Italy in API production
Gregory Roumeliotis, DrugResearcher.com, Decision News Media. 10/05/2006

9. Untying the Gordian Knot
Nicole Gray, PharmExec 50, Our Sixth Annual Report on the Worldâ?Ts Top 50 Pharma Companies. Pharmaceutical Executive May 2005.

10. Research universities join effort to reduce costs of drug development, manufacturing
Emil Venere, Purdue University News. November 3, 2005

11. The Global Pharmaceutical Market – International Trade and Competition in High Technology
Pantea Hadaegh, Sherry Y Lin, Luca Schenato, Chi Wai Yiu &amp; Professor Michael Borrus, Haas School of Business, University of California Berkeley. May 15, 2002.

12. Costs, Controversies Frame 2005
Gina Shaw, Drug Discovery &amp; Development, Reed Business Information. http://www.dddmag.com/

13. Generic Drugs (Presentation)
Ted Sherwood, Office of Pharmaceutical Science, Centre for Drug Evaluation and Research, Food and Drug Administration, 2006.
14. Statement of Gary Buehler, R.Ph, Director of the Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration before Special Committee on Aging United States Senate July 20, 2006.

15. The World Generics Market 2006-2011 â?” Abstract. May 18, 2006 by Visiongain

16. Generic Drug Approvals, Office of Generic Drugs, Centre for Drug Evaluation and Research, Food and Drug Administration. http://www.fda.gov/cder/ogd/approvals/default.htm

17. Generic Medicines
Health and Pharma, Published 16 April, 2005. EurActiv.com EU News &amp; Policy Positions.

18. Destination Europe
Sapna Dogra, Express Pharma, Fortnightly Insight for Pharma Professionals, 1 â?” 15 July 2006. Indian Express Newspapers (Mumbai) Limited (Mumbai, India). www.expresspharmaonline.com


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Global Biopharmaceutical Industry: Myth or Reality


Global Biopharmaceutical Industry: Myth or Reality

Yean Hoh
Clinical Research Associate Program
Kriger Research Center

Summary / Abstract

The myth or reality of a global biopharmaceutical industry cannot be simply decided by looking at its markets alone. The industry and its various organizations as well as governmental agencies play important roles in determining the structure and business activities of the industry world wide. The biopharmaceutical industry is unique in that all its activities from research and development, manufacturing and marketing are strictly regulated by governments. The ICH, International Committee for Harmonization, with its entire decision making members from U.S., EU and Japan are dictating the direction of development. Similarly, research and development are done mainly in these regions. However, with R&amp;D routes shifting from traditional chemical synthesis methods to biological based and offering targeted therapy, smaller companies as well as developing countries are able to participate in a much larger scale. Shifts towards generic drugs to reduce health care cost as well as patent expirations have increased opportunities for more players in the industry. Therefore, each aspect of the industry; R&amp;D and manufacturing, marketing and regulations must be viewed individually with respect to participation and impact to provide a clearer perspective of the biopharmaceutical industry as a global industry.

Global Biopharmaceutical Industry â?” Myth or Reality?

Global biopharmaceutical industry â?” what do we really mean by it? What does it mean to be global? The Oxford dictionary (Advanced Genie version) describes global as â?ocovering or affecting the whole worldâ? . Globalization is a much used term to describe the current affairs of the world and this phenomenon has affected all of us. Some definitions of globalization are as follow:

1. The increasing economic, cultural, demographic, political, and environmental interdependence of different places around the world. 1

2. A set of processes leading to the integration of economic, cultural, political and social systems across geographical boundaries. 2

3. Generalized expansion of international economic activity which include increased international trade, growth of international investment (foreign investment) and international migration, and increased creation of technology among countries. Globalization is the increasing world-wide integration of markets for goods, services, labour and capital. 3

Globalization holds different meaning for different peoples, cultures, societies and economies. We will examine the current state of the biopharmaceutical industry through various aspects of its operation, its impact and determine if its fits a global industry.

The pharmaceutical industry exits in some form or other in almost every country in the world. The early days of the industry is characterized by the production of traditional remedies extracted from plants and other natural sources. The advances made in chemistry and medicines have shifted the perspective and approach to more scientific means of producing medicine. These traditional medicinal establishments still exist today and in some instances may have seen some kind of renaissance in popularity due to the rising cost of modern medicines and their side effects. Some of the side effects brought about by these medicines are sometimes as harmful or more than the ailment that they are intended to treat. We will restrict the discussion of the global biopharmaceutical industry based on modern scientific based methods of producing medicines.

The activities of the biopharmaceutical industry as a whole can be divided into its various components. The industry can be essentially divided into research and development, clinical trails, production, markets and regulations. The pharmaceutical industryâ?Ts products can be divided into two major categories; prescription based drugs and over the counter drugs. Within these two categories you also have the branded items and the generic ones.

The biopharmaceutical industry is a highly regulated industry with strict requirements and controls from the development, production, licensing and marketing of a product. Individual countries have different sets of laws and regulations governing these processes based on the experiences and natural development of the industry within their borders. Selling a new drug in another country often requires complete reassessment and re-evaluation of the development and production aspects in order to meet local requirements. Cost and time delays were the natural obstacles of marketing into different countries but more importantly crucial life saving drugs were inaccessible or severely delayed due to regulatory differences.

The International Committee for Harmonization is the first and currently the only multinational effort to work together to set and achieve some common goals. The origin and purpose of the organization is detailed in the excerpt below extracted from their website.

ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines.

The focus of ICH has been on the technical requirements for medicinal products containing new drugs. The vast majority of those new drugs and medicines are developed in Western Europe, Japan and the United States of America and therefore, when ICH was established, it was agreed that its scope would be confined to registration in those three regions.

The membership of the ICH is made up of organization from the USA, European Community and Japan. There are a few observers comprising of Health Canada, WHO and European Free Trade Area. The three main parties are represented by six members from the industry and regulatory bodies. The participating members are the FDA, PhRMA, EU, EFPIA, MHLW and JPMA. 4

The FDA (US Food and Drug Administration) is the premier regulatory body and the largest single regulatory agency in the world responsible for the approval of all medicinal products in the USA. It is responsible for establishing guidelines, regulations and enforcing them for drugs, biologicals, medical devices, cosmetics and radiological products. The U.S. industry is represented by PhRMA (Pharmaceutical Research and Manufacturers of America) made up of sixty-seven research based pharmaceutical companies that are involved in the discovery, development and manufacture of prescription medicines. There are also twenty-four research affiliates that conduct biological research in the development of drugs and vaccines.

The European component of the ICH is represented by the European Commission that is made up of 25 member countries. Technical and scientific support for ICH activities on behalf og the European Union is affected through the Committee for Medicinal Products of Human Use (CHMP) of the European Medical Agency (EMEA). The commercial and industrial interests of the EU pharmaceutical companies are represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). The organization is made up of experts and country coordinators from Member Associations, of 44 leading pharmaceutical companies involved in research, development and manufacturing of medicinal products in Europe.

Japan is the only Asian country to have direct representation in the ICH. The regulatory and technical aspects are represented by the Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA), respectively. The Japan Pharmaceutical Manufacturers Association (JPMA) represents the Japanese pharmaceutical industryâ?Ts interest in the ICH. JPMA is made up of 75 research-based pharmaceutical companies operating in Japan of which 17.3% are direct foreign investment companies and the rest are made up of indigenous and or joint venture companies. 5

Canada is the only other country that has its own representative in the ICH in the capacity of an observer. Other observers are the World Health Organization (WHO) and The European Free Trade Area represented by Swissmedic based in Switzerland. The other notable organization involved in the ICH is the International Federation of Pharmaceutical Associations (IFPMA) that runs the ICH secretariat. The IPMA is made up of 56 member countries throughout the world representing the pharmaceutical industry from individual nations. 4

The make up of the ICH lends itself to be lopsided in decision making processes as its representation is only from selected countries and region. However, it can be argued that ethical, quality and safe drug development processes are universal goals and values that are common to all. The efforts of ICH are beginning to bear fruits as about half of the FDAâ?Ts inspections are in Europe and 18 are from Asia. Therefore, the intended purpose of the ICH has been effectively applied to areas beyond its original intended locations. However, there are still issues being brought forward by the FDA concerning the applicability of a new drug development to the U.S. population and the definition of qualified investigators. These are legitimate concerns and warrant consideration but the ultimate decision should be based on technical considerations and not political or market influences. The manner which this can be achieved effectively is not only through internal reviews but also extended dialogue with counterparts outside the ICH circle. Increasing direct participation in the ICH from countries in Eastern Europe (non EU members), Asia and Australia should be given due consideration as these regions have proven themselves to be efficient and professional in conducting clinical trials. Their participation will be like a self policing process to encourage stricter controls and better adherence to regulations and standards set by the ICH. 6

It is important for regulatory bodies to work closely with the industry such that regulatory requirements are achievable and adhered to. However, controlling bodies should be as independent as possible in determining the appropriate regulations. The same approach should be adopted within a country and on a global scale. Studies have shown that in the U.S. the biopharmaceutical industry is the single most influential industry in shaping policy decision in Washington. About 60% of the lobbyists on Capitol Hill work to ensure that the interests of the pharmaceutical companies are protected in every major piece of legislation. The regulatory component of the industry should be as immune to such influences as possible on a global scale to create a fair and effective regulatory environment. 7


Despite the concentration of the pharmaceutical market mainly in Europe, USA and Japan, many of the big biopharmaceutical companies have manufacturing facilities overseas mainly in developing countries. This is mainly to take advantage of the low cost of labour, less stringent environmental controls as well as less capital investment in setting up equivalent facilities. There have been studies to show that the average wages for a worker in an API plant in Europe is about 10 times more than that in China or India. Furthermore, the cost of setting up a manufacturing plant complying with international regulatory requirements is only about 25 to 30 percent that in
Europe in developing countries. Therefore, it is not surprising that China and India are ranked first and third in the world in production of active pharmaceutical ingredients for generic pharmaceuticals. The more phenomenal aspect of the industry in these to countries is the yearly increase in API sales. India has a yearly increase in sales of 19.3% while for China it is at 17.6% annually. Meanwhile, Italy, currently the second largest API producer in terms of sales at USD$ 3.2 billion is projected to stagnate and will achieve only about USD$ 3.3 billion by year 2010. In contrast, the API sales in China and India will have increased to USD$ 9.9 billion and USD$ 4.8 billion respectively, if the current rates of yearly increases are maintained. 8

For example; Pfizer currently the biggest biopharmaceutical firm in the world has 79 operation sites including manufacturing in 33 countries. AstraZeneca ranked 6th in year 2004 has various manufacturing facilities in Japan, U.S., United Kingdom and India. The same scenario will apply for almost all of the big pharmaceutical companies. The wide distribution is a result of direct investments as well as through mergers and acquisitions. Many of these overseas plants are manufacturing certain components of the drug which is then shipped back to the parent country for final production.

The savings gained by locating production and manufacturing facilities may or may not have benefited the health care system or the consumer. Certainly there has not been any reduction in drug cost but instead there are increases every year. However, it is undeniable that the production component of the biopharmaceutical industry has significant socio-economic impact on a global scale. Wherever production facilities are setup, jobs are created and significant knowledge and know-how are transferred to the local population. Business and service opportunities that are necessary in supporting such facilities will be taken up by the locals resulting in a positive contribution to the economy.

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Global Harmonization and Mutual Recognition Efforts: Keeping Up The Pace


Global Harmonization and Mutual Recognition Efforts: Keeping Up The Pace

Fred S. Halverson
An executive specializing in international regulatory affairs assesses the current movement toward globalization and identifies key areas requiring the most urgent action.
In both the drug and device industries, we are seeing significant movement toward bringing international regulatory systems in line with one another. But many Americans continue to wonder whether we, as industry members and as a country, are ready to move along this road, and if so, how fast and how far should we go? What are the various tools we can use to reach the desired destination, and what is the role of each? Does any of this diminish the role of FDA in protecting the health of the American public?

My thoughts on these questions reflect the perspective of a company that operates in more than 120 countries, producing implantable, critical-care devices that are subject to the most stringent controls of a wide range of regulatory systems. They also reflect my observations regarding what is happening around the world in the broader context of healthcare delivery.

The first question that must be answered is whether there is solid justification for moving toward harmonization. For an answer, we must take stock of today’s medical environment. First of all, medical technology manufacturers such as Medtronic are now developing products to meet the demands of patients and the medical community in a global medical marketplace. In addition, in all countries, the pressure to control healthcare costs is growing. Because the proliferation of divergent regulatory systems significantly slows the dissemination of new technology across borders and increases total healthcare costs, the world is naturally progressing toward globalized regulatory requirements.

If harmonization of medical device regulation is occurring naturally, the real issue thus becomes a question of where that process should be leading us. The end result must be able to keep unsafe medical devices off the market. But this doesn’t mean that a system like FDA is needed. In fact, FDA-like regulatory systems are inappropriate and impossible in most countries, especially those in Asia. All developed nations are rapidly moving toward the same level of sophistication when it comes to the evaluation of medical devices, be they Class I, II, or III. The European Union (EU) has created a regulatory mechanism that ensures the highest level of safety for patients, while quickly moving beneficial products to the market. The EU has already established a very credible review system for medical devices through efforts such as basing the process on quality system standards, using the world-class, globally recognized ISO 9000 series of standards.

In fact, as countries update their regulatory procedures, most are following the lead of Europe. The EU is aggressively pursuing mutual recognition agreements (MRAs) with many non-EU partners, including Switzerland, Canada, Australia, and some Asian countries. Even without an MRA with the EU, some Asian countries, notably China, are unilaterally adopting an EU-style regulatory approach. The United States cannot remain insular; the world is moving ahead, and we cannot afford to be left behind.

I want to be clear that I believe we need a strong FDA that has the confidence of the American people. But I do not believe that globalization of medical device regulationâ?”including both a move toward harmonization and the achievement of device MRAsâ?”is in conflict with protecting the sovereignty of the United States or the ability of FDA to carry out its mission. We cannot reach our goal overnight, but we need to keep progressing, and FDA must continue to play an active role in the process. There are places we can start right now, and there are other areas that need enhanced industry support.

I’d like to suggest five such areas in which global harmonization efforts should be focused. They are:
Moving ahead quickly regarding an MRA with the EU, particularly on quality systems.

The acceptance of a universal data set for clinical trials.

The recognition of international performance standards.

Steady progress toward an MRA with the EU on product approvals done according to a manufacturer’s own country’s requirements by accredited third parties, starting with 510(k) devices.

The acceptance by regulatory authorities in Asia of a common dossier.
A brief review of these five areas will perhaps offer some justification for my thoughts. First, with regard to reaching an MRA for quality system standards, FDA deserves significant credit for progress made in this area. The agency’s new quality system regulation (QSR), which replaces good manufacturing practices (GMPs), is nearly identical to ISO 13485/13488. Both are based on a quality system approach, a concept that did not exist when GMPs were first developed, and both ensure a higher degree of product quality than ever existed before. FDA’s new QSIT inspection program is another positive development. The agency should continue to be open to new approaches and to learning, and not push its own system. Given these developments, the MRA and harmonization can move ahead quickly. Both efforts are important. The MRA can help the harmonization effort by bringing together FDA and the EU, including industry, resulting in confidence building, learning, and longer-term benefits.

I have emphasized the quality systems portion of the MRA, because it is so fundamental for worldwide harmonization and for assurance of device quality. Any new regulatory scheme should be established based on the ISO 9000 series, not on local testing, extensive dossiers, or local requirements that are out of step with international practice.

The second area for action is the need to move toward a universal data set that will satisfy worldwide clinical requirements. Two factors weigh strongly in favor of this goal. In the area of clinical research, most of what is being done in Europe is widely accepted in this country. In fact, European research now makes up the majority of papers presented at many leading medical conferences, and, most importantly, FDA routinely accepts clinical data from European trials in product approval submissions. The other factor is that any company involved today with developing a Class III product tries to create one set of data that can be used universally for all regulatory bodiesâ?”the only way to cost-effectively develop clinical data. However, in doing so, manufacturers often exceed the requirements of any one regulatory authority, and presenting the data differently in numerous submissions is not cost-effective.

We should begin discussions aimed at achieving a harmonized clinical philosophy under which the boundaries of clinical data collection are properly defined and agreed upon, including harmonization of clinical controls. Frankly, this means recognizing, as Europe and various nations have done, that certain dataâ?”most importantly, data on cost-effectiveness, relative effectiveness, and medical outcomesâ?”should not be required as part of the product approval process unless explicit claims referring to such are being made. This kind of data is important and has an increasingly appropriate role in healthcare delivery, but not in product approval.

The third area requiring immediate action concerns the recognition of consensus performance standards. These standardsâ?”designed with the input of industry, government (including FDA), and medical professionalsâ?”represent state-of-the-art norms for ensuring the safety of medical devices. They are developed at both the international level, by groups such as the International Electrotechnical Commission and the International Organization for Standardization, as well as by groups like the European Committee for Standardization in Europe and AAMI, the American National Standards Institute, and the Underwriters Laboratories in the United States. The standards can be horizontal, applicable to all devices across the board, or vertical, covering only a specific device or type of technology.

Recognition of consensus standards is important because they ensure that products are evaluated according to the best possible criteria. Standards also produce a transparent system, under which manufacturers can know the relevant criteria during the product development process, which increases the efficiency of review. The rapid acceptance of the European regulatory system as an efficient and credible process can be traced in large part to its reliance on consensus standards, together with a procedure for company declarations of conformity.

Domestically, FDA deserves credit for its willingness to move forward, as with the QSR. One of the things to come out of FDA-reform discussions in the last Congress was an agreement by FDA, Congress, and industry that recognition of international standards makes sense and should be a part of any legislative reform. Here, again, FDA deserves credit for acting quickly in this area following passage of the FDA Modernization Act in late 1997. FDA has worked with the National Electrical Manufacturers Association on a pilot program under which FDA accepts certification of compliance with identified consensus standards, such as IEC 601-1 (the safety standard for electrical medical equipment), as part of the 510(k) process. This pilot program has reduced product review times by as much as 50%. Expanding recognition to the fullest extent possible, as FDA is now doing, is critical to moving toward true harmonization.

The fourth area I would like to examine is both an occasion to urge continued progress and a statement of the goal to which I believe we must aspire in our harmonization efforts. The ultimate objective must be a comprehensive MRA covering product approvals for 510(k) devices. The building blocks are already in place, or close to it. They include the acceptance of consensus performance standards, an agreement on quality system regulation, and the accreditation of third partiesâ?”including some European notified bodiesâ?”as part of FDA’s pilot project for the performance of product review functions. These three elements would produce a U.S. system for device regulation closely mirroring that of Europe. Both systems could then ensure the highest degree of device safety, while at the same time providing better, more timely access to advanced therapies for the patients who need them.

A series of recent MRA discussions between the EU and FDA have provided opportunities to get this process on the proper footing. I believe these discussions should be aimed at producing an MRA that focuses on the points I have specified: mutual recognition of quality system regulation for all devices, adoption of consensus performance standards, and mutual recognition of approvals by third parties for 510(k) devices.

The final area I want to emphasize is the need for harmonization in Asia. The current situation in Asia is reminiscent of the messy regulatory landscape of Europe in the late 1980s. Each country is developing a unique approach to device regulation, comprising various mixtures of local testing, different data requirements, different products regulated, and, inevitably, too few staff. The result is a fast-growing problem of regulatory overkill, proliferation of divergent requirements, and product-introduction delays. And while there is no convenient organization such as the EC for Asia, HIMA has organized an Asian Harmonization Working Party consisting of regulatory authorities and area managers of U.S. companies. This group should now serve as a forum for discussion of Asian harmonization, including acceptance of a common dossier and ISO 9001 certificates. We can also work on this problem with the assistance of the U.S. government in regional organizations such as Asia Pacific Economic Cooperation (APEC).

The environment is right for efforts between government and industry to produce real progress in these areas. If this comes to pass, both patients and the enterprise of medical research will surely benefit.

Fred S. Halverson is vice president of international regulatory strategy and reimbursement policy at Medtronic Inc. (Minneapolis).

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BioMedical Informatics


Biomedical informatics lacks a clear and theoretically grounded definition. Many proposeddefinitions focus on data, information, and knowledge, but do not provide an adequate definition ofthese terms. Leveraging insights from the philosophy of information, we define informatics as thescience of information, where information is data plus meaning. Biomedical informatics is the scienceof information as applied to or studied in the context of biomedicine. Defining the object of study ofinformatics as data plus meaning clearly distinguishes the field from related fields, such as computerscience, statistics and biomedicine, which have different objects of study. The emphasis on data plusmeaning also suggests that biomedical informatics problems tend to be difficult when they deal withconcepts that are hard to capture using formal, computational definitions. In other words, problemswhere meaning must be considered are more difficult than problems where manipulating data withoutregard for meaning is sufficient. Furthermore, the definition implies that informatics research,teaching, and service should focus on biomedical information as data plus meaning rather than onlycomputer applications in biomedicine.

grants to automate and improve screening methods [4]. Recent developments have thrust
informatics into the national spotlight as part of a massive economic stimulus package known
as the American Recovery and Reinvestment Act.
Yet there is still no universally accepted definition of medical, health, bio- or biomedical
informatics. Often, any activity that relates to computing is labeled “informatics” [5,6]. There
is even some debate regarding the desirability of a definition since any meaningful definition
has the potential to exclude good work [5] or restrict the use of informatics as a marketing
term. We emphasize that a definition is not a value judgment. By defining informatics we are
not claiming that informatics is better or worse than other. In order for there to be a field of
informatics, there must be definable activities that are not informatics.
Academic informaticians, on the other hand, recognize that a compelling theoreticallygrounded definition of informatics as a science is desirable [7]. In addition to our desire to
define our academic field, a definition can help the field address practical issues, such as:
• Educational program design: provide a clear vision of our field to students, guide
curriculum development and evaluation within training programs
• Administrative decisions: make a clear and consistent case for resources to
administrators, to guide informatics units (academic and service-oriented) with
respect to hiring faculty or staff, relationship to other organizational units and
performance metrics
• Communication: including internal communication among informaticians and
external communication with those outside of our field; a definition can help match
current and potential collaborators, guide informatics societies such as the American
and International Medical Informatics Associations (AMIA and IMIA, respectively),
and help funding agencies and members of the general public understand our role and
• Research agenda: provide a basis for identifying fundamental research questions, and
to distinguish basic research in informatics from applied work
Still, articulating such a definition of our field has proven difficult. In this paper, we review
the literature regarding definitions of informatics and propose a definition of informatics as a
science that is grounded in theory. We then consider a number of important impplications of
this definition that begin to address some longstanding issues within the field.

The “quest” for a definition of biomedical informatics and related concepts such as medical
informatics, bioinformatics, clinical informatics and others is not new. Although, compiling
an exhaustive list of definitions is not practical, it may be useful to consider categories of
definitions modified and expanded from [8] and [9]. Although originally applied to definitions
of nursing informatics, these categories are applicable to other areas [10] and the more general
field of biomedical informatics. For each category, we briefly define the category, cite
examples and discuss its advantages and limitations.
Information technology-oriented definitions focus on technologies and tools as being the
defining property of informatics. These definitions usually emphasize computer-based
technologies. Terms such as “clinical computing,” “computers in medicine” and “medical
computer science” are often used as definitions of informatics [7]. Similarly, Berman [11]
defines biomedical informatics as “the branch of medicine that combines biology with
computer science.” Clearly, computers are very important tools for biomedical informaticians.
Many activities associated with biomedical informatics such as data mining or electronic

medical records would not be meaningful without computers. However, by focusing on
computers, technology-based definitions emphasize the tools rather than the work itself [7]. A
commonly cited simile is that referring to biomedical informatics as “computers in medicine”
is like defining cardiology as “stethoscopes in medicine.”
There are at least two unfortunate consequences of focusing on computer technology. First,
emphasizing computers encourages us to insert computers whenever possible to solve problems
in biomedicine. However, the question should not be: “how do we computerize health care.”
Indeed, recent studies show that computerizing health care does not necessarily improve
outcomes [12,13]. The focus should remain on improving health care, rather than
computerizing it.
Second, such definitions generally do not capture important informatics work that does not
rely on computers (or computer science). For example, the study of information flow in clinical
environments does not necessarily involve computers. Rather, it can focus on interruptions
[14], errors [15] or how information is presented to the user [16]. Similarly, computerizing
health care requires understanding culture, processes and workflow; indeed a great deal of
work in this area has been done and published in informatics journals and/or widely cited in
the informatics literature. Lorenzi listed change management among the four cornerstones of
medical informatics [17]. Diane Forsythe’s work on the influence of culture on information
systems resulted in a prize named for the late Dr. Forsythe presented by AMIA [18].
Role, task or domain-oriented definitions focus on the roles of informaticians within
organizations. For example, nursing informatics emphasizes the role of informatics – trained
nurse specialists in supporting nursing practice and their grounding in nursing science: a
specialty that integrates nursing science, computer science, and information science in
identifying, collecting and processing, and managing information to support nursing practice,
administration, education, and research and to expand nursing knowledge [19].
Role, task or domain-based definitions such as nursing or medical informatics imply that
informatics projects are applicable only to the group included in their name (e.g., only applying
to nurses, the domain of nursing or the tasks of nurses). Further, they imply that the techniques
developed by informaticians are embedded in the “role, task or domain” where they were
developed. There are multiple examples to the contrary. For example Protégé, developed at
Stanford Medical Informatics, has been used for a wide variety of applications including
ventilator management and elevator configuration [20].
Concept-oriented definitions focus on concepts such as data, information and knowledge. For
example, Coiera [21] defines health informatics as “the study of information and
communication systems in healthcare.” Musen focuses on ontologies and problem solving
methods as tools for organizing human knowledge and are therefore fundamental to biomedical
informatics [7]. Such definitions focus on more fundamental concepts rather than tools, but
often fail to provide definitions of those concepts that are sufficiently detailed or
operationalized to provide a theoretical foundation for informatics as a science.
The following is a selected list of definitions including several authoritative textbooks:
• Greenes and Shortliffe [22] defined medical informatics as “the field that concerns
itself with the cognitive, information processing, and communication tasks of medical
practice, education, and research, including the information science and the
technology to support these tasks.” (task and domain-based)
• Shortliffe and Blois [23] define “biomedical informatics as the scientific field that
deals with biomedical information, data and knowledge – their storage, retrieval and
optimal use for problem solving and decision making.” (Concept-based)

• Van Bemmel [24] writes that medical informatics “…comprises the theoretical and
practical aspects of information processing and communication, based on knowledge
and experience derived from processes in medicine and health care.” (task and
• Musen and van Bemmel [25] write that “[i]n medical informatics we develop and
assess methods and systems for the acquisition, processing, and interpretation of
patient data with the help of knowledge that is obtained in scientific research.” (role,
task and domain-based)
Formulating a definition of informatics based on data, information and
Despite the lack of agreement, most definitions, regardless of their category, focus on data,
information and knowledge as central objects of study in informatics. However, there are no
consistent definitions for data, information, and knowledge. Thus, these terms are often used
interchangeably. Since data, information and knowledge are central to informatics, precisely
defining them is a good starting point for an operational definition of the science of informatics.
A review of the literature on data, information, and knowledge revealed two main schools of
thought: Ackoff’s Data, Information, Knowledge, Wisdom (DIKW) hierarchy [26], and a
related, but more precise set of definitions from philosophy (Table 1). In Ackoff’s hierarchy,
data are symbols. Information is data that have been processed to be useful. For example, to
answer “who,” “what,” “when,” or “where” questions. Knowledge is the application of data
and information to answer “how” questions. Understanding is the appreciation of why, and
wisdom is evaluated understanding. Since Ackoff first proposed the DIKW hierarchy, many
have tried to clarify the meanings of the terms and their relationships. However, a review of
recent textbooks describing the DIKW hierarchy found a lack of consensus with the only
constant being that knowledge is something more than information, and information is
something more than data [27].
In contrast to the DIKW hierarchy, philosophers who study information have developed more
precise, operational definitions of data, information, and knowledge. Although they have not
yet reached consensus and issues remain to be clarified, these definitions are relatively precise
and provide a useful starting point. To philosophers of information, a datum is simply a lack
of uniformity, information is meaningful data, and knowledge is information that is true,
justified, and believed [28].
As an example of how the philosophical definitions of data, information and knowledge can
be applied, consider a mother who checks her toddler’s temperature with a tympanic
thermometer. She sees 102.1 on the display. The symbols “102.1” are data: a lack of uniformity
on what would otherwise be a uniform surface (the thermometer display). The mother interprets
these data as meaning that the baby has a temperature of 102.1 degrees Fahrenheit. This is now
information (i.e., the symbols “102.1” refer to the baby’s temperature). The mother next notes
that since 102.1 degrees is higher than 98.6, the toddler has a fever. The difference between
the normal body temperature and the toddler’s is also a data item (or datum), whereas the
resulting interpretation of this difference as fever is information.
We can only say that the mother “knows” the baby has fever, if that information is true and
the mother has a justification (or understanding) of why it is true. In philosophy what counts
as adequate justification is an open question [29]. Normal body temperature varies and the
accuracy of tympanic thermometers is +/- .5 degrees at best. Thus, the mother can never be
absolutely certain that her toddler has a fever. Given a looser interpretation of what counts as
an adequate explanation, if the toddler feels hot to the touch (another datum) and the mother

takes one more confirmatory reading then there is sufficient justification for “knowing” that
the toddler has a fever.
In informatics, we often use knowledge in a related, but slightly different sense: as general
information believed to be justifiably true. For example, we record temperatures because we
believe, on the basis of prior experience with many individuals over time, that deviations from
the normal range may be dangerous. For example, very high or low temperatures may be
indicative of an infection that can kill if not properly treated.
These definitions produce a natural hierarchy: there will always be more data than information,
and more information than knowledge. Indeed, a significant amount of the information that we
use and produce every day is not knowledge, either because it has no truth value (such as
instructions like “Close the door on your way out”), or we cannot adequately justify why it is
In the above definitions, we have defined information using the terms “data” and “meaning.”
However, it also possible, and sometimes more convenient, to refer to data as the syntactic part
of information and meaning as the semantic part. Syntax refers to the systematic arrangement
of data in a representational system or language. Often a datum by itself does not have any
meaning unless it is combined with other data according to an accepted syntax. For instance,
a black dot on a white page may not mean anything. However, if that dot appears between two
numbers, such as “5.2”, the dot tells us that this is a decimal numeral and which parts of the
numeral are fractional and which are integral.
The data part of a representational system may also be called its “form”, in which case meaning
is called its’ “content.” The use of the word “form” is important because of its relationship to
formal methods, which are essentially methods that manipulate form using systematic rules
that are dependent only on form, not content (meaning). Some symbols or inferences are
meaningful. However, this is not captured in the formal rules of symbol manipulation. Formal
methods, including computer programs, depend only on systematic manipulation of form
without regard for meaning. Thus, ensuring that input to and output from formal methods
correctly capture and preserve meaning remains essentially human.
For example, modus ponens:
If P then Q
Therefore Q
does not depend on the meaning of P or Q. If P denotes the character string “birds fly” and Q
denotes the character string “cows fly” then modus ponens tells us that we can write the
character string (i.e., we can logically conclude) “cows fly.” This statement is just as legitimate
a logical statement as “If xxqqyy then ppzz; xxqqyy; Therefore ppzz.” Thus, the statements
above are formally correct, but meaningless. To summarize, information can be identically
defined as data + meaning, syntax + semantics, or form + content.
Definition of informatics
We propose that informatics is the science of information, where information is defined as data
with meaning. Biomedical informatics is the science of information applied to, or studied in
the context of biomedicine. Some, but not all of this information is also knowledge.

Informaticians study information (data + meaning, in contrast to focusing exclusively on data),
its’ usage, and effects. Thus, practitioners must understand the context or domain, in addition
to abstract properties of information and its’ representation.
The definition of information as data + meaning, immediately identifies a fundamental
challenge of informatics: how to help human beings store, retrieve, discover, and process
information, when our tools (information technology) are largely limited to manipulating data
and have only rudimentary information processing capabilities. In other words, the
fundamental challenges in informatics result from the difficulties of automating the processing
of meaning using tools that actually process data. Since all knowledge is also information,
manipulating knowledge using currently available tools is also difficult.
The gap between human information needs and the capabilities of our information technology
is at the heart of informatics. Human beings are best at constructing and processing meaning;
whereas computers are best at processing data. Although formal methods such as algebra and
logic are very useful, they do not manipulate meaning. Compared to computers, human beings
are slow and error prone at formal manipulation of data. In contrast, computers are much faster
and more accurate when processing data, but have only a rudimentary ability to process
meaning. Difficult problems in informatics often involve trying to get computers to process
meaning, or at least to appear “as if” they are processing meaning. Although this gap presents
a problem, it also means that human beings and computers are naturally complementary.
To better illustrate the fundamental differences between data processors and meaning
processors–between computers and human beings–we need only examine some basic results
from cognitive psychology. The first general result is that human beings tend to remember the
meaning of a sentence or picture instead of its exact form [30-33].
Experimental subjects tend to classify sentences with the same or similar meaning as being
identical, ignoring wording differences (syntactic forms). For instance, given the sentence “The
doctor diagnosed the patient with pneumonia,” participants are more likely to make errors when
later presented with sentences like “The doctor decided the patient had pneumonia,” or “The
patient was diagnosed with pneumonia,” than when they are given “The doctor diagnosed the
patient with a brain tumor,” even though the latter is syntactically (but not semantically) more
similar to the original sentence. This is exactly the opposite of computers, which excel at storing
and matching exact syntactic forms, but require considerable programming to have even a
rudimentary ability to equate different forms with the same meaning. Similarly, recent
experiments in ecological psychology have shown that many of the psychological biases found
in classic studies of human reasoning and decision making can be greatly reduced or eliminated
when human beings are given meaningful problems that relate to their real-world experience
Earlier we indicated that a clear definition of informatics will help the field address practical
issues, including educational program design, administrative decisions, communication, and
to develop a research agenda. The definition we proposed above does not, by itself, resolve
these issues. However, it does offer a perspective on informatics that has significant
implications for the field that can help us to address these issues. In this section we discuss
several of these implications.

Implication #1: Defining informatics as the study of data + meaning clearly distinguishes
informatics from important related fields
Defining the central object of study of informatics as data + meaning allows us to distinguish
informatics as a science from computer science, mathematics, statistics, the biomedical
sciences and other related fields. It also clarifies the role of each of these fields in informatics.
Computer science is primarily the study of computation. Computer scientists seek to provide
solutions to general problems by classifying computational problems in terms of formal
abstract properties and deriving effective, efficient algorithms (sequences of syntactic rules)
for solving them. For instance, computer scientists talk about network traversal problems and
algorithms for traversing networks. What is meant by networks in this context are not the
myriad real world objects we might think of as networks but the formal mathematical objects
categorized as networks. The meaning of the data being manipulated by an algorithm is not
important. An algorithm to find the shortest path connecting two nodes in a network depends
only on the length of the edges, not whether the edges and nodes represent a geographical map,
computer network, or social network.
On the other hand, computer science plays an important role in informatics. There can be no
information without data, and computers are the best medium we have for reliably storing,
transmitting, and manipulating data. Thus, some informaticians develop methods that allow
computers to process data “as if” the computer understands the meaning; and to produce tools
that allow human beings to make more sense of data displayed by the computer, thereby turning
it into information. Information retrieval and formal ontologies are examples of research on
the former; whereas work on data visualization and exploratory data analysis are examples of
the latter.
Within computer science, the field of artificial intelligence (AI) deserves particular attention
in regard to the issues of representation and meaning. There are a variety of definitions of AI
and considerable controversy regarding its scope, achievements and appropriate goals for the
discipline. John McCarthy, one of the founders of AI, defined the field as “the science and
engineering of making intelligent machines, especially intelligent computer programs.” [37]
He goes on to define intelligence as “the computational part of the ability to achieve goals in
the world.” Clearly, there can be a variety of goals, some of which depend on meaning and are
difficult to reduce to formal methods (e.g., identify “sick” patients) and some that are relatively
simple (e.g., 5+2=?). Some AI researchers spent decades attempting to develop machines that
can process meaning. Indeed, a (somewhat pejorative) definition of AI is “[t]he study of how
to make computers do things at which, at the moment, people are better” [38]. Thus, biomedical
informatics does not have an exclusive claim on “processing meaning.” AI researchers have
been trying for decades. However, AI researchers generally (but not exclusively) focus on
computational aspects of intelligence; as per McCarthy’s definition. In contrast, informaticians
are concerned, more broadly, with information and our use of it, either individually, as teams,
or in concert with the artifacts that we use to store, transmit, and manipulate it (e.g., paper,
whiteboards, phones, computers, etc.).
Like computer science, mathematics and statistics provide important tools and methods for
informatics, but their central object of study relates to formal abstract patterns and features of
data, not meaning. Their utility in informatics projects is due to their ability to manipulate and
reveal patterns in data and to draw formally correct conclusions that we (human beings) may
then see as meaningful. For example, we can apply statistical methods to text and provide
semantic similarity measures that, in some cases, closely correspond to human judgment. There
are also sophisticated statistical tools for detecting differences, and hence new data to which
we may choose to attach a meaning.

In a similar way, biomedical science is fundamentally different from informatics because
biomedical science seeks to answer questions concerning biomedical issues, such as genetic
factors that may affect lung cancer. Within biomedical science, informatics has grown in
importance because of the increasing amount of information, both research and clinical,
required to solve important problems. As we discuss below, biomedical science is a challenging
application domain for informatics, because the relevant concepts are difficult to relate to
formal representations.
Human factors and cognitive science are increasingly recognized as important in the design
and application of information systems. Information systems are designed to support human
activity. Therefore, to design usable and useful information systems, it is important to
understand human cognition. Further, since current information systems process data (form),
rather than meaning, human beings must ultimately assign meaning to the data, thus turning it
into information. Thus, there is significant overlap with informatics. However, “[c]ognitive
science is the interdisciplinary study of mind and intelligence…”[39]. Thus, its’ object of study
is cognition, not information or knowledge.
Finally, biomedical engineering is sometimes confused with biomedical informatics. Again,
there are some projects that blur the distinction. However, biomedical engineers seek to solve
biomedical problems using engineering methods. These solutions may take the form of devices
or computer programs (e.g., simulation of biomedical processes). However, the focus is on the
biomedical problem to be solved, not data, information or knowledge.
Please note that the above discussion does not imply computer science, statistics/mathematics
or biomedical engineering are somehow less important than informatics; only that they have
a different primary focus. In some cases, these fields adopt a different perspective on the same
problem. Clinicians care for patients. Informaticians develop methods for applying and/or
retrieving the information needed to support effective care. Computer scientists provide
efficient algorithms to manipulate the data underlying the information.
There are, of course, frequent areas of overlap and we do not argue that the world is clearly
demarcated into informatics and non-informatics. For example, magnetic resonance imaging
(MRI) of the human brain may be the subject of research for computer scientists. In those cases,
the question becomes: to what extent is information the “central” focus of the activity? For
example, if the goal is to transmit images that happen to be MRI images of human brains, then
the goal is more within the scope of electrical engineering or computer science, not informatics.
On the other hand, if the goal is to deal with the information from an MRI and diagnosis of
human disease (e.g., retrieve all patients whose MRI shows glioblastome multiforme), then the
project is more related to informatics than to computer science.
It is worth noting that “information science” is an active field of study. There are schools of
information science. If information science focuses on information, where information is
defined as data + meaning, then information science is fundamentally and scientifically the
same as informatics. The distinction between information science programs and biomedical
informatics programs is thus a matter of application domain, rather than fundamental science.
Indeed, some schools are changing their names to “schools of informatics” (e.g., Indiana
University School of Informatics).
Finally, we do not wish to imply that these are the only fields of importance to informatics.
Because human beings ultimately construct and manipulate meaning, any field that has
meaning as a central object of study must use techniques, theories and results from fields such
as cognitive science, psychology, linguistics, and sociology, among others.

Implication #2: Computation is an important tool for informatics, but is not the primary object
of study and is neither a necessary nor sufficient condition for informatics
In our definition, information, not computation, is the primary object of study of informatics.
Many activities in informatics have nothing to do with computation (i.e., computers). Within
health care, time-based, source-based, and problem-oriented medical records are all important
informatics products that predate computers. Thus a central concern in informatics is: what
information is needed and how it is best represented to support a specific set of human activities
[40]. Information architecture, ontologies, and book indices are all important informatics tools
that do not depend on computers. Computation is increasingly important as the amount of
available information increases exponentially. Simon pointed out some time ago that scarcity
of attention, rather than scarcity of data is a fundamental barrier to effective use of information
Implication #3: Defining informatics as the study of meaningful data informs informatics
curriculum design
Our definition provides clear guidance regarding the core skills and knowledge sets required
of a well-trained informatician. The primary goal of an informatics education should be to
prepare students to work with information (data + meaning). Academic informaticians may
develop new theories, models, and tools for solving problems that deal with information, such
as information needs, information architecture, information retrieval, and the characteristics
of information. Since all information must have some data representation, informaticians must
also be well versed in tools that help us store, retrieve, and manipulate data. This includes skills
in computer science such as databases, data warehouses, and so on. They must also understand
techniques for deriving new data, and possibly new meaning, from existing data. For example,
artificial intelligence (AI) techniques, such as machine learning, can reveal relations among
data that may be meaningful.
Another class of skills relates to the study of representations and algorithms that permit
computers to appear as if they understand meaning, even if in a rudimentary way. Thus,
ontologies and semantic applications are essential to informatics. Finally, since human beings
construct meaning by looking at representations, informaticians must understand how
representations (such as visual, haptic, aural, etc.) and a person’s interaction with them affect
a person’s ability to construct meaning. Thus data visualization, exploratory data analysis tools,
and human factors engineering all play a major role in constructing tools that help human beings
discover, understand, and use information.
Implication #4: The emphasis on meaning allows us to see why some informatics problems
are easier than others
This definition allows us to understand why some informatics problems are easier than others.
Consider the banking system.
Clearly it is quite complex and involves a great deal of data and
meaning. Why do all banks use computers? In contrast to biomedicine, we hear no arguments
regarding the suitability of computers to track accounts. Why is this? We argue that in the case
of banking, there is a very narrow “semantic gap.” In other words, the correspondence between
the data (numbers) and information (account balances) can be very direct. As we manipulate
representations of numbers, the meaning of these manipulations follows easily.
Namely, if the problem relates strictly to form (data), or is easily reduced to a form-based
problem, then computers can easily solve it. Retrieving all abstracts in PubMed containing the
string of characters for the term “obesity” is a question related to data and is easily reducible

to a form-based data query; whereas retrieving all abstracts in PubMed that report a positive
correlation between beta blockers and weight gain is an information retrieval question that
depends on the meaning of the query and the meaning of the text in the abstracts. This is not
easily reducible to form and is therefore much harder to automate.
In general, concepts definable with necessary and sufficient conditions are relatively easy to
reduce to form, and thereby permit some limited automated processing of meaning. However,
concepts without necessary and sufficient conditions (e.g., recognizing a cup or a sick patient,
or defining pain) cannot be easily reduced to data and are much more difficult to capture
Biomedical informatics is interesting, in part, because many biomedical concepts defy
definition via necessary and sufficient conditions. This is true because biomedicine studies
naturally evolved systems as opposed to human-engineered systems. Evolution implies a chain
of propose, copy and modify with a selection pressure. In other words, a population of
individuals with (usually minor and relatively random) variations is exposed to an environment
in which some are better able to reproduce (and their progeny to survive) than others. The
population is, in most descriptions, composed of individual biological organisms such as plants,
animals or human beings. Representations and symbol systems can also be created using a
copy, modify and test method [42]. Variation between individuals is tolerated over time as long
as it has a neutral or positive effect on reproduction. Variation that imparts a reproductive
disadvantage relative to competitors is gradually removed from the population.
Systems that evolve tend to have specific properties that make them difficult to represent
mathematically and thus, to compute upon. Evolved systems tend to be non-decomposable or,
at best, nearly decomposable [41]. For example, consider the functional systems of an airplane.
In order to fly, it must generate lift (force that counteracts gravity) and thrust (force that propels
the airplane forward). The airplane has two distinct subsystems to develop lift and thrust: wings
that develop lift and engine(s) that develop thrust. Clearly, these systems interact (a stationary
wing develops no lift), but they are clearly distinct. We note that engineered systems often go
through multiple iterations based on experience (e.g., Boeing 707 → 737). However, this
process is better described as “re-engineering” than evolution.
On the other hand, a bird’s wing develops both lift and thrust and these are not decomposable.
One cannot remove the “thrust” component of a bird’s wing. In addition to lift and thrust, a
bird’s wing has multiple other functions such as protecting the vital organs from trauma,
conserving body heat, etc. Thus, one cannot consider (and model) the functions of a bird’s
wing in isolation from each other except as an approximation.
Similarly, it is difficult to clearly separate body systems. For example, the kidneys are not
generally considered to be part of the circulatory system, but they have a very important role
in maintaining blood pressure and preventing fluid overload. Indeed, some of the most common
treatments for congestive heart failure, diuretic medications, act primarily on the kidneys and
not the heart. Consequently, drawing distinct boundaries between evolved systems and their
components is difficult.
Blois [43] argued that, in order to compute upon a system, one must first determine the system’s
boundaries. In other words, one must define all of the relevant components and assume that
everything else is irrelevant. However, this is very difficult to do for evolved systems. If we
want to model the circulatory system, can we exclude the renal system? The endocrine system
that includes the adrenal glands (releases epinephrine that constricts blood vessels and raises
blood pressure)? The nervous system? And so on.

Evolution tends to satisfice [41] and not optimize. If an individual survives long enough to
reproduce and pass on its genetic material, that is good enough. There is no requirement for
optimal fitness. Thus, some variability is tolerated in a population and is even desirable since
the future environment progeny will encounter is unpredictable. No two human beings are
exactly the same. In contrast, engineered systems are made identical in many important
characteristics. They have interchangeable parts – a wing from one airplane will fit another
airplane as long as they are the same model. All other things being equal, an airplane will react
the same as another example of that model to damage or set of environmental conditions (e.g.,
wind shear, turbulence). In contrast, two human beings may react very differently to the same
drug or the same surgical procedure.
We note that engineered systems are not necessarily less complex than evolved systems.
Indeed, quantifying and comparing the complexity of two systems is not straightforward.
However, few would argue that a Boeing 747 or the space shuttle are not complex systems.
Thus, the evolved systems are not simply complicated or more complicated than engineered
systems. Instead, they are complex in a different way compared to engineered systems. This
property makes them less likely to be reducible to form and thus amenable to automation
through computation.
Biomedical informatics is the application of the science of information as data plus meaning
to problems of biomedical interest. This definition is sufficiently broad to include the majority
of activities currently considered to fall within the scope of biomedical informatics while
excluding activities that are traditionally considered to be outside of our field. As such, our
definition can serve as a guide to students, educators, practitioners and researchers. Significant
work remains be done to understand and operationalize the implications of this perspective.
However, we believe that this definition captures the intuition behind many of the definitions
of informatics, while also opening the door for a paradigm shift in how we view and practice
Patel and Kaufman [44] argued that biomedical informatics is a “local science of design.” Local
in the sense that biomedical informatics is a “science where principles simplify and explain
parts of the domain of interest rather than provide universal coverage or a unifying set of
assumptions.” However, “the collection of particulars (derived from specific systems and
approaches) advanced by individual institutions leads to the development of notions that are
nearly universal (i.e., principles, paradigms, and theories), and they in turn shape the discipline
and guide development.” We hope that this work is a step toward the development of such
(nearly) universal principles, paradigms, and theories. Informaticians are often asked by
collaborators and members of the general public – “What is informatics? It behooves us to have
a clear answer.
The authors thank Drs. M. Sriram Iyengar and Dean F. Sittig for valuable discussions regarding the ideas expressed
in this manuscript. Supported in part by the Center for Clinical and Translational Sciences at UT-Houston

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