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.
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.
1. Gamache V. Minimizing Volunteer Dropout. CenterWatch Monthly. 2002;1:9-12.
2. Lightfoot GD, Getz KA, Hovde M, Sanford SM, Stepp PM, Vogel JR. ACRPâ?Ts White Paper on Future Trends. Spring 1999.
3. Kermani F, Findlay G. Pharmaceutical R&D Compendium (2000). Available at:
4. Lovato LC, Hill K, Hertert S, Hunningshake DB, Probstfield JL. Recruitment for Controlled Clinical Trials: Literature Summary and Annotated Bibliography. Control Clin Trials. 1997;18:328-357.
5. Nathan RA. How important is Patient Recruitment in Performing Clinical Trials? J Asthma. 1999;36:213-216.
6. Ross S, Grant A, Counsell C, Gillespie W, Russell I, Prescott R. Barriers to Participation in Randomised Controlled Trials: A Systemic Review. J Clin Epidemiol. 1999;52(12):1143-1156.
7. Hunningshake DB, Darby CA, Probstfield JL. Recruitment Experience in Clinical Trials: Annotated Bibliography. Control Clin Trials. 1987; 8:6S-30S.
8. Tufts Center for the Study of Drug Development. Impact Report 2002, 4(5): Sept/Oct 2002.
9. Peck CC. Drug Development: Improving the Process. Food Drug Law J. 1997;52(2):163-167.
10. Sullivan J. Subject Recruitment and Retention: Barriers to Success. Applied Clinical Trials. 2004. Available at:
http://www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=89608. Accessed November 14, 2004.
11. Spilker B, Cramer JA, eds. Patient recruitment in Clinical Trials. New York, NY: Raven Press, 1992.
12. Sinackevich N, Tassignon J. Speeding the critical path. Applied Clinical Trials. 2004. Available at: http://www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=82018.
Accessed November 17, 2004.
13. Herschel M. Patient recruitment and the Internet. Business Briefing: Future Drug Discovery. 2003;16-18.
14. Cassileth BR. Clinical Trials: Time for action. J Clin Oncol. 2003; 21:765-766.
15. Guidance for Industry E6 Good Clinical Practice: Consolidated Guideline. Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: 1996. Available at:
http://www.fda.gov/cder/guidance/959fnl.pdf. Accessed November 8, 2004.
16. Questions & Answers about ICH. International Conference on Harmonization: 2001.
Available at: http://www.ifpma.org/ich.html. Accessed November 15, 2004.
17. 67 Federal Register 53182 (codified at 45 CFR Â§ 160-164). August 14, 2002.
18. Groundbreaking European survey identifies pressing need for stepped-up education surrounding clinical trials, June 10, 2004. Available at:
http://www.bbkhealthcare.com/news_archive/will_why.shtml. Accessed November 16, 2004.
19. BBK Healthcare, Inc. The Will and Why Survey. June, 2001.
20. Penslar RL. National Institutes of Health, Office for Protection From Research Risks. Protecting Human Research Subjects: Institutional Review Board Guidebook: 1993. 2nd ed. Bethesda, MD: Office for Protection From Research Risks, National Institutes of Health, 1993.
21. Schultz S. Drug trials are clamoring for kids but scrutinize the study before signing up. US News & World Report. April 17, 2000.
22. Food and Drug Administration, Office of Health Affairs. Information Sheets. Guidance for Institutional Review Boards and Clinical Investigators. Rockville, MD: Food and Drug Administration, Office of Health Affairs; 1998. Available at:
http://www.fda.gov/oc/ohrt/irbs/toc4.html. Accessed November 17, 2004.
23. Bowden M, Mackenzie-Lawrie S. Accelerating patient recruitment. Available at:
http://www.healthdec.com/downloads/patient.pdf. Accessed on November 10, 2004.
24. Foley JF, Moertel CG. Improving Accrual into Cancer Clinical Trials. J Cancer Educ. 1991;6:165-173.
25. Penn ZJ, Steer PJ. Reasons for Declining Participation in a Prospective Randomized Trial to Determine the Optimum Mode of Delivery of the Preterm Breech. Control Clin Trials. 1994;15:284-293.
26. Taylor KM, Margolese RG, Soskolne CL. Physiciansâ?T Reasons for not Entering Eligible Patients in a Randomised Clinical Trial of Surgery for Breast Cancer. N Engl J of Med. 1984;310:1363-1367.
27. Cutler S, Redmond C. Reducing drug development time â?” Focus on patient recruitment. Drug Info J. 1995;29:1709S-1718S.
28. Liauw W, Williams K, Day R. Protocol Appraisal: A study siteâ?Ts viewpoint. Applied Clinical Trials. September 1, 2004. Available at:
http://www.actmagazine.com/appliedclinicaltrials/. Accessed November 24, 2004.
29. Spilker B. Guide to Clinical Trials. New York: Raven Press; 1991.
30. Schaffner K. Ethical Problems in Clinical Trials. J Med Philos. 1986;11(4):297-315.
31. Haegerstam G, Huitfeldt B, Nilsson BS, Sjovall J, Syvalahti E, Wahlen A. Placebo in clinical drug trials â?” a multidisciplinary review. Methods Find Exp Clin Pharmacol. 1982;4:261-278.
32. Klerman GL. Scientific and ethical considerations in the use of placebo controls in clinical trials in psychopharmacology. Psycopharmacol Bull. 1986;22:25-29.
33. Sniderman AD. Clinical trials, consensus conferences, and clinical practice. Lancet. 1999;354:327-3306.
34. Hall L, Hall S, Sergeant E. Clinical Trial Recruitment & Retention. Pharmaceutical Times. 2001;(June):46-50.
35. Welton AJ, Vickers MR, Cooper JA, Meade TW, Marteau TM. Is recruitment more difficult with a placebo arm in randomized controlled trials? A quasi-randomized, interview based study. BMJ. 1999;318(7191):1114-1117.
36. Hill AB. Medical ethics and controlled trials. BMJ. 1963;1:1043-1049.
37. Rothman, KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394-398.
38. Zisson S. Anticipating a clinical investigator shortfall. CenterWatch. 2001;8(4):5-8.
39. Miller A. Trial Run. American Medical News. 2000; 42(36):17.
40. Harris SM. Issues to consider in clinical trial agreements. American Medical News. 2000;43(12):17.
41. Evans P, Smith I. The weakest link. Available at:
http://www.synexus.co.uk/Scrip%20April%2003.pdf. Accessed November 8, 2004.
42. Schwain WS. Barriers to Clinical Trials Part II: Knowledge and Attitudes of Potential Participants. CANCER Supplement. 1994;74 (9):2666-2671.
43. Taylor KM, Kelner M. Interpreting Physician Participation in Randomized Clinical Trials: The Physician Orientation Profile. J Health Soc Behav. 1987b;28:389-400.
44. Department of Health and Human Services. Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research. Office of Inspector General; June 2000.
45. Maguire P. Community-based trials under scrutiny. ACP-ASIM Observer. July/August 1999.
46. Larkin M. Clinical trials: what price progress? Lancet. 1999;354:1534.
47. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289:454-465.
48. Neuer A. Treating Study Volunteers as Customers. CenterWatch Monthly. March 1-7, 2003.
49. Farrell B. Efficient management of randomized controlled trials: nature or nurture. BMJ. 1998;317:1236-1239.
50. Gennery BA. Good Clinical Practice. In: Luscome D, Stonier PD, eds. Clinical Research Manual. Cardiff: Euromed Communication; 1994:12.1-12.24.
51. Training clinical investigators and their staff on good clinical practice standards. The European Forum for Good Clinical Practice; 1994.
52. Bachenheimer JF, Brescia B. Good Recruitment Practice = Patient Pull. Available at:
http://www.bbkhealthcare.com/news_archive/downloads/GRP_PDF.pdf. Accessed November 17, 2004.
53. Yelland M. Achieving good follow-up in clinical trials. Available at:
http://www.phcris.org.au/publications/pdfs/Yelland_followup.pdf. Accessed November 23, 2004.
54. Zimmerman JF. The importance of standard operating procedures for investigators. Innovative Methods for Providing Advanced Clinical Training. Available at: