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Drug Advertising


The Erice Statement on drug advertising to consumers
A group of clinical pharmacologists, physicians, pharmaceutical industry representatives, medical and general journalists, communications professionals, and consumer advocates met in Erice, Italy, on May 9-13, 2002 to discuss drug advertising to consumers.
The meeting was triggered by proposed changes to European Union legislation on the advertising of prescription medicines to the public. Its purpose was to consider the wider implications of direct-to-consumer prescription medicine advertising and its relationship to the information needs of the public and of patients, throughout the world.
Everyone agreed on the fundamental need for high quality medicines information, but participants differed in their view on advertising of prescription medicines to consumers. Some wanted to maintain the present prohibition of direct-to-consumer advertising; others would allow advertising subject to strict control by an independent, non-commercial, multi-representative statutory body, affiliated to the Regulatory Authority or the Ministry of Health. The arguments supporting each of these views are summarized below.
The relationship between promotion, advertising and information

The World Health Organization defines drug promotion as all informational and persuasive activities by manufacturers and their agents, the effect of which is to induce the prescription, supply, purchase and/or use of medicinal drugs. [1]

Advertising is one form of promotion, partial in its selection of information, usually with commercial benefit to the promoter as its sole or principal intent.
It is important to distinguish these forms of communication from information that aims to educate and/or inform.
The need for good quality information

Personal health care involves choices among many possible treatments. Although the use of a prescription medicine is mediated by a health professional, patients need relevant information of good quality on benefits and harms related to the available options, presented in a way that enables them to choose appropriate treatment together with the doctor, and to manage their treatment subsequently.
The information must be scientifically valid, up-to-date and balanced. It should allow comparisons between drug and non-drug treatments, and the option of no treatment. Facts, hypotheses and conclusions should be distinguished, uncertainty acknowledged. Sources of information, and their particular bias should be identified, including all potential conflicts of interest. [2]
Education on the appropriate use of drugs, including the interpretation of safety information, is essential for the public as well as for patients. Such education requires commitment and targeted resources.
Drug information directed to the public, in whatever form, should be balanced in its account of benefits and harms. Trustworthy sources should be mandated to provide balanced information about all healthcare options in a readily accessible and understandable form. Such information should aim to support good doctor-patient interactions.
All the evidence needed to understand benefits and harms, including comparative information, must be openly available to the public. Vested interests and any other constraints on communicating parties that hinder their ability to meet this goal must be identified and understood.
Information of any kind must never damage, distort or subvert the true interest of public health, or the essential needs of individual welfare.
Should direct-to-consumer prescription drug advertising be allowed?
Arguments against legislative changes to allow such advertising

Medicines sold directly to the public are used for self-diagnosed conditions and can be self-prescribed, but prescription medicines require professional knowledge and understanding for safe and appropriate use.
1) Advertising and other forms of drug promotion aim to increase sales and cannot meet the criteria of quality information as described above, even when they are disease-oriented. Promotional information distorts the interaction between doctor and patient by focusing on the advertised treatment rather than on the necessary diagnostic and therapeutic decisions.
2) Experience in the United States and New Zealand has shown that direct-to-consumer advertising of prescription medicines has repeatedly misinformed the public.[3] It has increased prescribing of the advertised drugs,[4] leading to unnecessary increases in drug expenditure. [5]


3) Prohibitions on prescription drug advertising to the public are consistent with the WHO Ethical Criteria for Medicinal Drug Promotion and the EU Precautionary Principle. The latter supports action, â?owhere preliminary objective scientific evaluation indicates that there are reasonable grounds for concern about potentially dangerous effects on the environment, human, animal or plant healthâ?¦â? .
4) These considerations lead to rejection of changes to EU pharmaceutical advertising regulations,[6] as well as similar proposed changes in other countries. Liberalisation is likely to have a profound negative impact, not only in Europe but throughout the world, in reducing the appropriateness and safety of medicine use.
Arguments in favour of cautious, controlled approaches to the introduction of prescription medicine advertising:

1) The aims of commercial and non-commercial promotion can coincide. When this is the case, commercial promotion may be in the interest of public health. However, each case must be considered individually, and the motivation and biases need to be transparently described.
2) A recent review of some experience on direct to consumer advertising in the United States drew the conclusion that there was little impact on the doctor-patient relationship (7). Data from another survey were also interpreted as suggesting a positive association between advertising and compliance with the use of a medicine, which may in turn lead to health benefits and reduced wastage (8).

These references are however preliminary and not peer reviewed.
3) Research into the impact of general ethical promotion of prescription medicines should be permitted under the following experimental conditions:

· The evaluation of positive and negative effects under strict experimental protocols

· The promotion of medicines only after sufficient patient exposure to ensure reliable knowledge of their effectiveness-harm profile.

· The promotion of appropriate use

· The provision of information about the medicine which is factual, balanced and fair

· The inclusion of appropriate warnings and cautions and encouragement to patients to consult their doctor

· Before it is used all such promotional material should be reviewed by an independent, statutory body, affiliated to the Regulatory Authority or the Ministry of Health

· Clear ethical and practical guidelines should be developed by this body and strict adherence to them ensured by regular monitoring and evaluation of promotional materials


(7) Aikin K. J., Division of Drug Marketing and Communication, FDA. 2002 DTC Advertising of Prescription Drugs: Preliminary Survey Results.

(8) Slaughter E., Schumacher M. Preventionâ?Ts International Survey on Wellness and Consumer Reactions to DTC Advertising of Rx Drugs. Prevention Magazine, Rodale Press, 2000/2001.

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Benchmarking and metrics


I have taken the liberty of fowarding along this article about the use of benchmarking in the Human Resources field. While not specific to patient recruitment, this article does provide some further, helpful information for your reference. Please take the time to review it.

By Rebecca A. Richards B.Psych, Dipl.Tech (Hons.), CHRP and Tracy D. Gordon Dipl Tech (Hons)
Rebecca Richards, a Human Resource practitioner and author of nine books on Human Resource Management topics, is the director of Core Elements Outsourcing, a Vancouver-based firm. Her company has developed a complete range of Human Resources procedures and products to provide busy managers with practical, no-nonsense guidance on employee matters. Rebecca is the recipient of various academic and achievement awards and takes an active interest in development of the Human Resources discipline. Visit her web site @ www.coreelements.com.
Tracy Gordon is Client Service Manager of The Saratoga Institute Canada, Canada s leading benchmark surveying firm. Based in Vancouver, BC, The Saratoga Institute produces an annual benchmarking survey report, which provides organizations with over 85 metrics in all key areas of the Human Resources function. Currently over 180 Canadian organizations participate in the survey. The report has been produced in Canada since 1995.

The Emerging Role of
Benchmarking in Human Resources
As we approach the new millennium, Canadian businesses face some significant business challenges, but also see new opportunities to build sustainable success and competitiveness.

Those challenges and opportunities are being addressed through the people side of the business more than ever before, and thus impact directly on the role, transition and evolution of the human resources function within the organization.
It is critical to the ongoing business success of an organization to improve the return gained from its human assets. This allows the organization to consistently demonstrate the people management function and the value of their people assets.

For human resource managers this means leaner structures; a key focus on adding value, positioning for the future, and consistent benchmarking to ensure relevant and effective service structures and delivery systems.

What is Benchmarking?
One of the most quoted definitions of benchmarking is attributed to the CEO of Xerox,
David Kearns, who defines benchmarking as the continuous process of measuring products, services and practices against the toughest competitors or those companies recognized as industry leaders . It has also been defined as a systematic approach to identifying the benchmark, comparing yourself to the benchmark, and identifying practices that enable you to become the new best-in class .

How does it Work?
Benchmarkers aim to locate organizations that do something exceptionally well. That something becomes the benchmark. The process of benchmarking can be accomplished through various mediums: telephone calls, surveys, questionnaires or site visits to benchmarking partners. Once the data is collected, metrics applied and percentiles established, the investigating organization identifies the gap between its own performance and the benchmark.
In formalized benchmarking reports, data is presented using a range of percentiles. As a result, the investigating organization can chose to look at a market average, or strive higher and find the companies in the top 10 percent of the survey. Take for example, a financial services organization dealing with increasing turnover. They are interested in discovering what other banking organizations face in separation each year. Through benchmarking, they find that the average separation rate in their industry is 13.9%; but they decide they would like to measure themselves against the top 10% of their industry. This takes them to the 90th percentile and a separation rate of 6.7% – a significant difference from the industry average. They can now analyze the gap between their separation rate and the 6.7% benchmark.
Once the gap is discovered, organizations may wish to move to the next step â?” Best Practices. Best Practices is an associated process that identifies the reason that certain organizations are high performing (i.e. they describe the practices of top performing organizations.) It should be noted that while Best Practices reports describe what the top performing organizations do, the question of how to introduce changes in the investigating company to best help them close the performance gap, is left up to the specific organization. Best Practice reports provide benchmark metrics1, values and practices. The organization itself must decide how to adapt the information. Indeed, a key point in any benchmarking project is the idea that each organization has to figure out what to do with the data from the exercise (i.e. how to use it in a way that is most beneficial to their own operation).

Benefits of Benchmarking
Benchmarking can help key executives better understand the challenges ahead, make better decisions, develop stronger positioning and performance of the human resources function and increase the value of and contribution from the human assets, who are after all, the key drivers to future and sustainable success.1 A quantitative measurement or standard of performance on which a company can judge its performance.
Overall, the process can help a company determine its industry direction, trends and standards by forcing people on the inside to look out.
Specific to the Human Resource manager, benchmarking allows her/him to show senior management the human resource s contribution to the organization â?” to show that Human Resources is not only an expense partner â?” but that it actually adds value to the organization. Internal Human Resources benchmarking can aid in improving staff functions such as the hiring process or the exit interview process. It will tell a Human Resource manager when the department is understaffed or overstaffed; when the recruitment process is taking twice as long as their competitors; when the separation rates are rising, and where the problems lie. It is an infinite book of information. Finding internal Human Resources flaws and improving on them can add to the bottom line of the department and the organization. Benchmarking can show the Human Resources manager where to focus their priorities and attention. It can stimulate an objective review of Human Resources processes, practices, and systems and present a common target for improvement.

Key Areas of Benchmarking
There are several key areas of human resources which provide very meaningful and relevant insight into, and evaluation of, the performance and effectiveness of the people management and development within the organization. They include:
1. Organizational Performance & Effectiveness
2. Human Resources Structure & Resources
3. Compensation
4. Benefits
5. Separations
6. Staffing
7. Education, Training & Development
Having available measurement data of these areas helps the Human Resources department focus on where changes or improvements are needed and what action or intervention will provide the best results. They can: provide, assist and evaluate operating results; make relevant comparisons within the related industry group(s) or focus on top performing organizations; and take actions to improve operating performance and the return on investment in the human assets. Key trends in each of the areas of measurement will also indicate the changing and/or improving performance of the company as well as a comparison with the industry standards over the past several years.

Current Canadian Benchmarking Trends
Within the stronger-performing Canadian companies across all industries, overall performance has shown a small but consistent strengthening over the past four years. Revenue and productivity are up slightly (within these groups), while the operating expenses (resources used to achieve the revenue) have been very stable â?” at $302,749 in 1995 and $301,947 in 1998. The investment in the human assets and the return on that investment, both show a reasonable and consistent gain. The human resources function is generally in transition to a more focused, strategically based, client and consulting-oriented and change agent management resource within the organization. Again with leading companies in Canada, this transition is more apparent and the investment in and effectiveness of the Human Resources function has shown consistent increase and improvement over the past three years. We have seen the Human
Resources Expense Percent (the percentage of a company s operating expense that is attributed to the cost of operating an entire Human Resources department) move from 0.79% in 1995 to 0.86% in 1998. We have also seen the number of company employees per Human Resources personnel grow from 93 to 105.
The investment in compensation and benefits and the return on that investment has been very stable over the past four years. This however, has been very positive when related to the small and consistent improvement in productivity and the increase in revenues. Compensation as a percentage of revenue has moved slightly from 22.1% in 1995 to 22.5% in 1998; and the same is true for benefits as a percent of revenue, which we saw move from 6.1% in 1995 to 6.3% in 1998.
Over the past four years, separations have declined slightly on average, on both a voluntary and involuntary basis. Detailed information about where separations occur, by length of service, and when matched to demographic statistics, provide an excellent view of where the real issue is specifically, thus interventions can be very focused and direct. Hirings have closely matched the separations, although on a slightly higher level, thus indicating a very small increase in and a realignment of the work force in some cases. External candidates are approximately two thirds of all hirings, with about one third of job fills being for newly created positions. Hiring costs (the total investment in the recruitment process) have increase marginally, with the more significant adjustment being in supervisory, professional and management groupings.
The hiring cycle time has remained quite constant overall, for the past four years, with the only area of change being a slight increase in external hiring timeframes, especially in more specialized areas of employment.

Note: The above data is very general and may not apply to every industry. It is also derived from several different sources; hence one statement does not necessarily relate to another. It is however, a starting point. Other places you can find current benchmarks on training activities are the Internet and some private suppliers of benchmark information (e.g. the Saratoga Institute Canada).

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Good Manufacturing Practice Guidance: Can We Make It Global?


Good Manufacturing Practice Guidance: Can We Make It Global?
Damon Warren

Good Manufacturing and Distribution Practice is a necessary practice to ensure the overall safety and well being of society as a whole. The issue of whether it can be made global is simplistically complicated. Simplistic in the fact that, yes, globalization of Good Manufacturing Practice can be done and should be done, however complicated in the fact that while easy to agree to do, hard to actually implement or get other countries to all agree to a standard set of practices. Just about every country has some set of standardize practice and they are similar to varying degrees but they are not universal and while one country has a set of standards that are deemed exceptional there are othersâ?T that are deemed marginal at best which then requires other counties to employ their own standards. While this multiple checking is beneficial and can only improve quality control it is expensive and time consuming. If the three pharmaceutical industry regions can get together and form the International Conference on Harmonization and set a standard and greatly and contentiously improve the overall industry, it just greatly increases the likelihood that globalization of GMP is plausible and needs to be done.



The devolvement of new potential drugs is vital to the treatment of diseases and improving the quality of life for the worldâ?Ts population. With the research and development of these potential life saving drugs comes the testing and ultimately the distribution of these drugs. Over the past decades extensive research has gone into the best effective efficient and safest way to test these drugs. The whole process of Clinical trails has been examined under a microscope and the outcome has led to extensive rules and regulations both in the USA and other counties abroad. These rules and regulations are the corner stone of safety and they were created to ensure that the publicâ?Ts best interest is always first and foremost. With that being the priority, the leading countries have gotten together to globalize safety standards and to ensure compliance. It was the desire to improve standards and create harmonization among countries all while acting in the best interest of its people that has lead to the success of the International Conference on Harmonization. The success of the ICH just makes a case that globalization of GMP is possible and only serves to streamline the overall process and ensure efficiency and effectiveness and reduce overall errors, delay and repetitiveness.



Good Manufacturing Practice or GMP (also referred to as ‘cGMP’ or ‘current Good Manufacturing Practice’) is a term that is recognized worldwide for the control and management of manufacturing and quality control testing of foods and pharmaceutical products.5 â?oThe World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in more than one hundred countries worldwide, primarily in the developing world. The European Union’s GMP (EU-GMP) enforces more compliance requirements than the WHO GMP, as does the Food and Drug Administration’s version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Singapore and others having highly developed/sophisticated GMP requirementsâ?ť 5


Compliance with GMP principles ensures that medicinal products are consistently produced and controlled to appropriate quality standards. Unlike a number of EU member states, the UK does not require manufacturers to manufacture IMPs in accordance with the principles of GMP. However many UK manufacturers voluntarily follow the European legislation on the principles of GMP for manufacturing marketed products and the detailed guidance on IMPs. Currently, medicines manufactured for clinical trials are produced to a specification agreed by MHRA, but there is no certification or inspection of their manufacture.2


While many of most of the regions practice GMP and have various ethic and compliance committees in place, the standards by which these regulations are enforced and monitored vary greatly by country. The Food and Drug Administration (FDA) announced a new initiative that will greatly improve its overall regulation and monitoring of pharmaceutical manufacturing. The Pharmaceutical Current Good Manufacturing Practices, is â?ointended to modernize FDA’s regulation of pharmaceutical quality for veterinary and human drugs and select human biological products such as vaccines.â?ť 4

The FDA recognized the benefits and importance other countries have in the manufacturing of marketed products so it has reached out to the international community to expand its current paradigm. â?oThe FDA has increased its collaboration with international health and regulatory partners and will continue to actively collaborate with other regulatory authorities, in multilateral and international forums, to harmonize pharmaceutical quality standards or requirements to the fullest extent possible.â?ť 4


The ICH established an agreement with the FDA to create a plan that would harmonize the pharmaceutical manufacturing of marked products. This establishment involved the creation of two expert groups that serve to balance the risk and quality for a product. â?oIn November 2003, an agreement was reached by ICH to work on an internationally harmonized plan for developing a pharmaceutical quality system based on an integrated approach to risk management and science. FDA is developing bilateral and multilateral confidentiality agreements and specific information exchange agreements to facilitate these activities. To implement its vision, ICH established two Expert Working Groups (EWGs) on pharmaceutical development. The first (ICH Q8 EWG) seeks to incorporate elements of risk and quality by design throughout the life-cycle of the product. â?o 4


In the United Kingdom, The Medicines Inspectorate was established to ensure compliance with standard provisions set fourth for any applicant with licences in the UK.2 It was under the Therapeutic Substance Act that the Medicines Inspectorate now oversees the functions of the Department of Health (DH) Inspectorate, broadening its scope to biological products, and bestowing the authorization to inspect manufacturers in other countries that export products to the UK.2 It was not until 1991 that GMP and their manufacturing authorizations became universal within the European Community.


In Australia their quality control is guided by strict regulations and their systems are extensively monitored to ensure compliance. Any product imported or exported out of the country must follow the same rigorous standards set fourth. This system, while strict, ensures a quality product. The Therapeutic Goods Act of 1989 required any manufacture wanting to manufacture a therapeutic good obtain a licence.â?ť It is an offence, carrying heavy penalties, to manufacture therapeutic goods for human use without a licence unless the manufacturer or goods are exempt from this requirement.â?ť 3 Obtaining a licence to manufacture therapeutic goods requires an applicant to demonstrate complete compliance with manufacturing principles, which is observed with an on site factory audit.


The TGA even extends to overseas manufacturers, who also must pass the same standards of GMP required by Australian manufactures if they expect their goods to be accepted into the country. These sponsors must provide proof in the form of documentation that their products are manufactured to the same standards as those deemed acceptable in Australia. In the event that a sponsor is unable or unwilling to provide such evidence, the TGA will conduct an onsite audit of the factory following the same SOP as it would if the factory was in Australia.


â?oCompliance with the Codes of GMP and / or Quality System requirements in Australia is ascertained by carrying out regular on-site audits. The purpose of the audits is to assess compliance with the relevant manufacturing standard, the conditions specified in the manufacturing licence and compliance with the relevant marketing authorizations. Each audit involves a detailed examination of the operations and procedures of the factory, and includes a detailed review of all processing activities, process validation, batch documentation and quality control testing. Product samples may be taken for testing by TGAL (Therapeutic Goods Administration Laboratories). The audit is concluded with an exit interview during which the manufacturer is provided with a summary of the findings of the audit. This summary is confirmed in writing at a later date by means of an audit report. The manufacturer is required to respond satisfactorily to the audit report before the audit is closed out. â?o 3

The UK Inspectorate currently carries out regular inspections in a number of countries, including USA, India, China and Japan both in connection with national requirements and on behalf of the European Medicines Agency (EMEA).

The Natural Health Products Directorate (NHPD) in Canada requires that before any site license will be given out, a location must meet all regulations of GMP set fourth by the NHPD, this includes any site that intends to manufacture, package, label or import products for sale in Canada.â?ťThey are also responsible to provide evidence that imported NHPs will be manufactured, packaged, labeled, imported, distributed and stored according to GMPs as set out in part 3 of the Regulations or their equivalent. â?o 1
Each of these countries are mere examples of the steps they are taking to ensure that manufactured products are met with the upmost quality and care. Some have gone as far as to require it for both its imports and exports of products. It just shows that countries worldwide are committed to the safety and quality of any and all products and that the overall safety of its citizens is top priority. To take this information and combine it with that of other countries can only improve the already effective system. Where one country is lacking another country, can add strength.

Each country can greatly benefit for each otherâ?Ts SOP and regulations. A more streamline process can ensure the ease of products reaching those people who need it without compromising the integrity or safety of the product. The process could be efficient and cost effective, eliminating the need for double and triple inspections and thus lessen the number of sample products needed to ensure compliance. Globalization of GMP will allow for better communication between the regions and will decrease the delay in response and having a central compliance committee will allow for a more effective monitoring system.

The biggest obstacle would be compliance and the enforcement of the new standards but that can be overcome with an agreed upon committee to head the monitoring. Every country involved would have a representative and from this a committee would be formed. This committee will set fourth and enforce the agreed upon new quality GMP standards and then be charged with the task of ensuring compliance. Established time lines, sanctions, penalties authorized personnel will be established from this committee. The success of this committee will greatly depend on the overall commitment and reliability of the countries involved. Each represented country must understand that their success of this project is dependent on their involvement and commitment of its success.

The globalization of GMP is a vison but not an impossible one, fore many countries have already shown their commitment to the overall quality and safety of manufactured products both imports and exports. Someone just needs to take the initiative and to get the ball rolling in making this vison an actual success. While the FDA has committed to working with the ICH on global GMP those countries involved and other countries as well need to take the initiative as well for this to be a major success. We have the idea and the resources, but itâ?Ts just a matter of using them to the benefit of our citizens.
Works Cited
Health Canada. (2007, August 20). Good Manufacturing Practices Guidance Document. Retrieved August 17, 2007, from http://www.hc-sc.gc.ca/
MHRA. (2007, January 02). Good Manufacturing & Distribution Practice. Retrieved August 15, 2007, from http://www.mhra.gov.uk/
Therapeutic Goods Administration. ( 2007, February 26 ). Good manufacturing practice for therapeutic goods. Retrieved August 17, 2007, from http://www.tga.gov.au/
U.S. Food and Drug Administation. ( 2006, July 28). Pharmaceutical CGMPs for the 21st century A Risk- Based Approach Final Report. Retrieved August 15, 2007, from http://www.fda.gov/
Wikipwdia The Free Encyclopedia. ( 2007, August 20). Good Manufacturing Practice. Retrieved August 17, 2007, from http://wikipedia.org

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Ariel E. Quinio, Ph.D. candidate
The philosophical and ethical principles that guide modern clinical trials centered on the voluntary nature of human subjects, protection of patients rights to consent, safety, autonomy, dignity and inviolability. Reports of serious adverse events resulting in deaths of volunteers have been a phenomena in recent years. A literature on selected cases of serious adverse events were reviewed for the purpose of identifying parties responsible for the occurrences of such unlikely situations. It is difficult to identify a single entity who can be accounted for any of these serious adverse events considering that clinical trial is a shared responsibility. Although substantial responsibility for ensuring the protection of human subjects is vested in Institutional Review Boards (IRBs), in all trials, ensuring the safety of participants is not solely the responsibility of IRBs, but also significant others including clinical investigators, sponsors, FDA, the Office for Human Research Protection from Research Risks ,and data monitoring committees (DMCs). Responsibilities and roles expected of each entity were discussed and recommended that better interaction and effective communication among various groups be established to improve clinical trials and enhance patientsâ?T safety.


The advancement of knowledge in scientific disciplines has been phenomenal in recent years. New therapeutic discoveries for various types of illnesses emerged as a result of continuous research and development efforts in the medical arena. Scientific investigations has remarkably improved the quality of modern life and broaden human perspective by acquiring a deeper understanding of ourselves, the society, and the world we live in. Undeniably, modern advances in science and technology now serves as essential foundations of our societyâ?Ts material, intellectual, and social progress. For some members of the society, scientific discoveries have alleviated the degree of human agony caused by disease and disability. Notwithstanding these tremendous benefits that can be derived from medical research, the pursuit of scientific knowledge through experimentation should not compromise the rights and dignity of human subjects.

Clearly, therapeutic advances for present diseases are by-products of experimentation. The proliferation of powerful drugs and therapies, the range of options in treatments, and the idiosyncracies of patientâ?Ts reactions make it imperative that sound medical practice be supported by scientific evidence. The interrelationship between therapy and scientific investigation of a systematic kind has become the embodiment of current medical practice. The physician being knowledgeable about research uses his best efforts to alleviate the patients disease. The patientâ?Ts duty to participate in research depends larlgely on the assumption that the potential social benefit significantly outweighs the hazards posed by experimentation. Thus, the responsibility for achieving the right balance between conservation and innovation as well as between benefit and risk represents the necessary calculus for conducting research involving human subjects (Feund, 1972).
Philosophical Controversies and Ethical Principles on Research
Involving Human Subjects

The moral justification for involving human subjects in research has not been thoroughly discussed in the literature on human research and codes of research ethics. The major controversy that underlie the subject of human research appeals to the principle of beneficence. It asserts that the social benefits to be gained from such research are substantial and the harms resulting from the cessation of such investigations would be exceedingly grave (Beauchamp & Walters, 1989). Corollary, Eisenberg (1977) supported such claim by pointing out that the only alternative to a perpetual plague of medically induced illness is the vigorous pursuit of biomedical research specifically research involving human subjects.

Beauchamp and Walters (1989) proposed that a second approach to the justification of human research is based on a joint appeal to the principle of beneficence and justice. According to this principle, beneficence requires that each individual should make a modest positive contribution to the society as a whole. If our participation in research offered significant benefit to others, at little or no risk to ourselves, then such participation may become a duty of beneficence. Furthermore, if we fail to fulfill this modest duty while most of our contemporaries make it, we may be acting unjustly, since we are not performing a fair share of a communal task. This only follows that every person currently alive is the beneficiary of earlier subjects involvement in research. To be specific, the willingness of past human volunteers to take part in studies of antibiotics and vaccines has contributed to the health of the whole society . This can be interpreted to mean that it seems unfair for us to reap the benefits of researches without making a reciprocal contribution to the alleviation of disability and disease.

Jonas (1969) contradicted both the principles of beneficence and justice that explained the general justification of human research. In response to the consequential argument advanced by Eisenberg (1977), Jonas asserted that while human research generally contributes to medical progress, most research involving human subjects is not essential to the well-being or survival of the human species. Jonas emphasized further that medical progress to be specific, is â?oan optional goal, not an unconditional commitment.â?ť In this regard, only a national health emergency or similar â?oclear and present dangerâ?ť would provide a sufficient justification for non-therapeutic human research.

The voluntary nature of human research as explicitly characterized by Jonas is an exact contradiction of the central focus of the moral justification to participate in research. The manner in which present-day clinical trials are conducted have been influenced largely by philosophical thought and ethical principles set forth by Jonas. Thus, there is no injustice involved in not volunteering to take part in clinical trials. In Jonasâ?T view, most volunteer of the past including investigators involved in clinical research, performed acts of altruism and moral heroism. Should man of the contemporary society owe debt of the past, it is a debt of gratitude to these bygone heroes, and not an obligation required by a reciprocity of principle of justice (Beauchamps & Walters, 1989). It is evident that Jonasâ?T propositions on the general justification of human research primarily centered on protecting the rights, safety, autonomy, dignity, and inviolability of patients in clinical research.

Review of Selected Serious Adverse Events (SAEs) in Clinical Trials
The ethical principles as previously presented provided insights on how patients should be dealt with in clinical trials. The succeeding parts highlight a review of literature on selected cases of serious adverse events and the controversies, actions and recommendations that ensue towards determining whether a violation of ethical principles has occurred as well as identifying parties responsible for patientsâ?T safety.
Jesse Gelsinger
The most controversial SAE in clinical trials was reported by Thompson (2000) about the death of a patient from a reaction to gene therapy treatment in September 1999 at the University of Pennsylvaniaâ?Ts Institute of Human Gene Therapy, Philadelphia. Jesse Gelsinger was an exuberant 18-year old from Tucson, Arizona who suffered from a broken gene that causes one of the puzzling metabolic diseases of genetic medicine. He went to Philadelphia to participate in clinical research hoping to find a cure for his type of illness. On the contrary, the experiment killed him. The aftermath of his death created a concerted actions among various groups to minimize the occurrence of related incidents in the future. The Food and Drug Administration (FDA) and the National Institute of Health (NIH) conducted a series of investigations of the University of Pennsylvania studies. Findings revealed that gene therapy researchers at the University of Pennsylvania committed violations with federal rules which include failure to report unexpected adverse events associated with the gene therapy trials. The report also mentioned that scientists were even asking that this incident not be made public. The worst case scenario was that only 35 to 37 of 970 serious adverse events from a common type of gene therapy trials were reported to NIH. Results indicated clearly that the system of protecting the safety of research subjects is not properly working.

The investigation of this incident by FDA revealed serious deficiencies in the way how the University of Pennsylvania conducted the ornithine transcarboxylase deficiency (OTCD) gene therapy trials. This was evident when researchers entered Gelsinger into the trial as substitute for another volunteer who dropped out. It was reported that Gelsinger should have excluded from the study because of his high ammonia levels during the time of his treatment. Moreover, the university failed to immediately report that two patients had already experienced serious side effects from gene therapy which was required in the study design, and that the deaths of monkeys who were given a similar treatment were never included in the informed consent decision.

As a result, the Department of Health and Human Services in collaboration with FDA and NIH initiated the Gene Therapy Clinical Trial Monitoring Plan designed to strengthen the level of scrutiny for study sponsors with additional reporting requirements. A series of Gene Transfer Safety Symposia were conducted to provide a means of communication among researchers to share their results about unexpected problems and to increase their awareness about rules and regulations. In addition, the FDA conducted a random inspections of 70 clinical trials in various gene therapy programs across the United States and instituted new reporting requirements for serious adverse events.
Hoiyan Wan
Steinbrook (2002) reported a case of a healthy 19-year old nursing student, Hoiyan Wan who volunteered in March 1996 for a study at the University of Rochester. As part of the study, she underwent bronchoscopy, and then she died two days after. The report mentioned that she received a fatal dose of lidocaine. This tragedy created so much finger-pointing on the part of concerned authorities in their effort to identify who were primarily responsible for this unlikely event. The report pointed out the state investigations criticizing the researchers, the institutional review board (IRB), and the university. In response to this, the University of Rochester instituted several changes which include the establishment of training programs for investigators and the overhaul and expansion of the universityâ?Ts IRBs.
In the same article, Steinbrook (2002) cited another serious adverse event concerning a nurse, Holden-Able, who enrolled in a study of the metabolism of the amino acids methionine and homocysteine in people with Alzheimerâ?Ts disease. She was a part of the age-matched healthy controls study to test the hypothesis that amino acids are metabolized differently in the two groups. On April 4, 2001, several hours after drinking a mixture of methionine, which is sold over the counter as a nutritional supplement, orange juice, Holden-Able became severely ill. She became confused and vomited repeatedly. Severe respiratory distress developed, and died on May 6. The cause of Holden-Ableâ?Ts death was not accurately determined but an internal investigation could not rule out an accidental overdose of methionine. This was believed to be the most reasonable explanation considering that she had a very high blood levels of methionine. As a result, the medical center implemented new procedures for dispensing nutritional supplements.
Ms. Roche
The John Hopkins University External Review Committee (2001) reported a case of a healthy volunteer named, Ms. Roche for a clinical research on mechanism of deep inspiration airway relaxation conducted by Dr. Alkis Togias, Principal Investigator at the John Hopkins University. The facts and chain of event as outline in the internal committee report are not in dispute. Accordingly, Ms. Roche received inhaled substances in Dr. Togiasâ?T laboratory. Within 48 hours, she developed a cough, fever, rhinorea and myalgia. This illness progressed to ARDS and she died of this illness on June 2, 2001. This unlikely incident had set a stage among responsible entities to review the initiation, evaluation, conduct and oversight of clinical research at John Hopkins University at various levels including the principal investigator, the preparation of pharmaceutical materials, scientific internal peer review at the departmental or research center level, and the IRB.
Reflections on Cases of SAEs
In Gelsingerâ?Ts case, the problem was apparently resulted from investigatorâ?Ts failure to report unexpected adverse events associated with the gene therapy trials. The presence of data safety monitoring committee is also necessary in order to examine the accruing data for indications that clear benefits or harm may be occurring. Moreover, this serious adverse event could have been prevented should the IRB and other regulatory agencies conduct a regular monitoring on clinical trial. IRBs are responsible for conducting regular independent reviews of research. The problem with the system is that the IRB have been criticized for reviewing too many protocols, reviewing too quickly, having insufficient expertise, and providing too little training for investigators and board members (Steinbrook, 2002).

The case of Ms. Roche provided meaningful insights and suggestions that served as catalyst for John Hopkins University towards further improving and strengthening their research endeavors. The John Hopkins External Review Committee (2001) identified specific areas of concerns that constituted limitations of their system with the end in view that these suggestions will be relevant to improving clinical research in other academic medical centers. Suggestions for improvement were directed towards the role of principal investigator; protocol review by the department, IRB and pharmacological review; consent form; and the culture of possible coercion.

Findings revealed that the Principal Investigator with Ms. Rocheâ?Ts case did not report an adverse event in the first patient, performed an adequate but not outstanding toxicology literature review, and changed the protocol without notifying the IRB. In addition, the committee report specified that the informed consent was misleading such that it suggests more assurance of safety with hexamethonium than was known, and suggested that the agent is a medicine in use in anesthesia. It did not mention its limited use as an inhalant. Moreover, inhalant preparation was not sterile. It was not analyzed, and it was not prepared in a fashion appropriate for medical use.

With regards to protocol review by the department, there was no identifiable expert internal peer review or discussion conducted at the level of the whole Asthma and Allergy Center. It was discovered that the protocol review process was grossly inadequate and it did not conform to current standards. The interview conducted by the review committee suggested that there appears to have a possible subtle coercion in the solicitation and recruitment of volunteers to the Asthma Center Studies.

The John Hopkins University External Review Committee (2001) recommended that an oversight at their institution must be significantly strengthened. There should be an institutional requirement of expert internal review and discussions of every protocol at the department or research center level before a proposal is forwarded to the IRB. The IRB must be recognized and expanded as necessary so that each proposal has a full discussion at a meeting of the whole committee. Special care must be taken to ensure the safety of volunteers in studies which have no therapeutic potential. In addition, there must be greater sensitivity to possible subtle coercion of volunteers. Participation by staff in studies within an academic units should be prohibited . Time spent in study should be separated from regular working hours. Lastly, the quality of the substance and integrity of the preparation should be ensured by an institutionâ?Ts research pharmacy or its equivalent.

Responsibility for Patients Safety in Clinical Trials

The tragic case of Gelsinger, Wan, Holden-Able, and Ms. Roche are few selected SAEs that brought tremendous challenges on various research entities involving human subjects. It is difficult to pinpoint a single entity who can be accounted for any of these serious adverse events considering that clinical trial is a shared responsibility (Steinman, 2001). Although substantial responsibility for ensuring the protection of human subjects is now vested in institutional review boards (IRBs), in all trials, ensuring the safety of participants is not solely the responsibility of IRBs, but also of significant others: clinical investigators, sponsors, FDA, the Office for Human Research Protection from Research Risks (formerly Office for Protection from Research Risks), and data monitoring committees (DMCs) also called data safety and monitoring committees. A federal regulations or â?ocommon ruleâ?ť has been provided to govern the conduct of studies among investigators by obtaining voluntary and informed consent from subjects, protecting patients safety, and ensuring that the risk of their participation is reasonable in relation to anticipated benefits (45 CFR Part 46, 1991). Protecting the rights and safety of participants in research is an ethical mandate. Considering that risk is inevitable in clinical research, it is essential that this risk is minimized and that any unanticipated harm be rapidly detected and contained (Califf, et al., 2003).

The preceeding reports of SAEs is ethically indefensible reflecting a fundamental flaw in the current oversight system (NBAC, 2001). For the purpose of improving the conduct of clinical trial, what follows are discussions designed to clarify important roles of those who are primarily responsible in protecting, monitoring, and ensuring patients safety in clinical trials.

Clinical Investigator(s)

The safety of patients is best served by clinical investigators and their staff who have a systematic approach to collecting and reporting study data and are attentive to details of study conducted such as strict adherence to inclusion and exclusion criteria and stopping rules, accuracy in collecting and recording data, expeditiously report adverse events (AEs) to RERBs and study sponsors, and obtaining valid informed consent. An investigator is also responsible in maintaing as well as ascertaining all relevant data regarding the agent or procedure under study, to rigorously assess AEs and to minimize conflicts of interests. An example of a systematic approach to collecting and reporting data is adherence to Good Clinical Practice (GCP). The GCP standards were developed to provide guidance to clinical investigators that would result in common approaches that are consistent with scientific, legal and ethical imperatives to clinical trials performed in different countries (Califf, et al., 2001). Adherence to GCP standards or to another rigorous standard should help ensure that the trial data and recorded study results are credible and accurate, and that the rights, health and confidentiality of participants are protected.

Research Ethics Review Board (RERBs)

This term is used to include groups such as Institutional Review Boards (IRBs), Research Ethics Boards and Institutional Ethics Committee (IEC) who are empowered to protect trial participants by reviewing initial research plans and providing continuous review of approved research (21 CFR 56, 1981). They are responsible for reviewing the protocol and its informed consent document and make an initial judgment about the potential risks relative to the potential benefits of the proposed study as well as benefits to potential participants (OIG, 1998). Many institutions that have corrected serious problems with their programs for protecting research subjects such as those mentioned earlier including John Hopkins University have markedly increased their spending and increased the number of IRBs.

Current federal regulations require that each IRB have â?oat least one member who is not otherwise affiliated with the institutionâ?ť and â?oat least one member whose primary concerns are not in scientific areasâ?ť (45 CFR 46, 1991). In particular, RERBs have generally been provided with safety data in AE reports from several sources, usually with little explanation of their significance. However, they do not typically receive aggregated data on AEs nor are they aware of the number of participants currently enrolled in the clinical trial as a whole which would provide denominator for calculating the incidence. In this context, RERBs functions are limited to the extent that they are not capable of unveiling the data to find out whether a reported event has occurred in the trialâ?Ts experimental or control arm. In addition, RERB cannot determine the potential causality of an AE occurring after administration of an investigational agent. Consequently, RERBs in general cannot use reports of AEs for reliable, ongoing assessments of changes to determine balance between risks and benefits for trial participants, making it impractical for them to have sole responsibility for protecting the ongoing safety of participants.

Data Safety and Monitoring Committee (DSMC)

The data monitoring committees or otherwise known as â?odata safety and monitoring committeesâ?ť are primarily responsible for assessing the appropriateness of continuing clinical trials based on the evolving data. They are typically composed of experts in the disease or condition under study, biostatisticians, ethicists, and patient representatives. In order not to bias the conduct of the trial by revealing early the data, DSMCs act independently of the sponsor and the study investigators (Morse, et al. 2001). The sponsor or steering committee normally charges the DSMC to protect the patients safety by examining the accruing data for indication that clear benefits or harm maybe occurring for individuals participating in the trials (Gordon, 1998).

Corollary, Cairns (2001) cited that a DSMC shares responsibility with the IRBs, government agencies, and with individual investigators who are responsible for ensuring that the trial appropriately balances the risks and rewards for individual subjects. The DSMC also works with the Steering Committee and the trial sponsor who altogether have the operational responsibility for the trial.


A sponsor takes responsibility for initiating the clinical research study (21 CFR Part 312.3b, 1999). These include any entity that funds the research including the medical products (pharmaceutical and medical devices) industry, foundations, governmental agencies and institutions conducting the research study (Califf, 2001). At the outset of human testing of new interventions, sponsors must be able to show that a particular product or behavioral interventions will likely be safe enough to justify such research. Although this determination is always fraught with some uncertainty, it is typically based on the results of preclinical testing (Newell, et al., 1999).

Sponsors have the responsibility to design trials in line with the principle of Good Clinical Practices (GCP) which were developed by ICH to address the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials (GCP, 2002). The sponsor should also ensure that research personnel at clinical research sites are knowledgeable about these practices and how to implement them for a clinical trial. Furthermore, it is the responsibility of the sponsor to review and interpret initial adverse events.

Clinical Research Sites

The site of the clinical trial serves as a venue to conduct primary observations that ensures patients safety. In addition to the clinical investigator and study coordinator, the clinical research sites may be composed of various entities that participate in the clinical trials including local scientific reviewers, pharmacy staff, and grants contract personnel. It is normally expected that each clinical trial has a detailed set of standard operating procedures that promote adherence to the specifics of how study protocols are to be executed according to the principles of GCP (Califf, 2001).
These consist of federal agencies including FDA and the Office for Human Research Protections who are responsible for ensuring that products that come out in the market are safe and effective for public consumption. The FDA is also tasked to ensure that human participants in research have been protected (21 CFR Part 50, 1980). The FDA in collaboration with the Office for Human Research Protections regulate the conduct of clinical trials including the testing of new drugs and medical devices. The latter has greater authority over research entities through their written assurances that they will comply with the federal regulations. So that research entities will ensure compliance with federal regulations, fines are imposed on clinical investigators or institutions found to be in violations.
Conclusion and Recommendation
The major players in clinical trials such as investigators, research ethics review board, data safety monitoring committee, sponsors, research sites, and regulators should be guided by philosophical viewpoints and ethical principles in conducting research involving human subjects. In recent years, the moral justification of human research not to mention the principles of beneficence and justice have paved the way towards medical progress. It was not until Hans Jonasâ?T philosophical thoughts that laid much of the ground work for ethical principles governing the present-day clinical trials. A review of four selected serious adverse events from the literature revealed their own stories to tell and the fundamental flaws that led to an inquiry into the issues and the programmatic suggestions that ensue to protect safety of human subjects.

The Jesse Gelsingerâ?Ts case pointed the blame on investigatorâ?Ts failure to report unexpected adverse events associated with the gene therapy trials; state investigation results criticized the role of researchers, the institutional review board (IRB), and the university on Hoiyan Wanâ?Ts death from fatal dose of lidocaine; investigatorâ?Ts and the multitude of others were held responsible for Holden-Ableâ?Ts death from accidental overdose of methionine; and Ms. Rocheâ?T death was likewise accounted for several factors ranging from principal investigatorâ?Ts inability to report adverse event, misleading informed consent, inadequate protocol review by IRB to a culture of possible coercion in the solicitation and recruitment of volunteers. Considering that patientsâ?T safety in clinical trials is a shared responsibility, it is of utmost importance that each party involved in research has thorough knowledge of their responsibilities. The responsibility for patients safety in clinical trials were presented with the objective of identifying roles that are expected of them.

It is hereby recommended that effective channel of communications be established among various groups or entities involved in the conduct of clinical trials to prevent the occurrence of related incidents in the future. Based on the earlier discussions, there seemed to be no single group who can provide a complete protection of patients. A programmatic plan or strategy is required so that appropriate inputs from various entities can be combined together for inclusion in the clinical trial oversight. Each entity should function as indispensable part to contribute towards ensuring patientsâ?T safety. Ideally, better interactions and effective communications among various entities need to be enhanced. Morever, it is about time for various groups to come to an understanding of their complimentary and unique roles in the conduct of clinical trials.
Beauchamp, T.L. and Walters, L.R. (1989). Research with human and animal subjects, In Contemporary issues in bioethics (3rd ed.) (pp. 415 â?” 419). CA: Wadsworth Publishing Co.

Cairns, J.A. Hallstrom, A., & Held, P. (2001). Should all trials have a data safety and monitoring committee? Vancouver: Mosby, Inc.

Califf, R.M., Morse, M.A., Wittes, J., et al. (2003). Towards protecting the safety of participants in clinical trials. Controlled clinical trials, 24 (2003), 256-271.

Eisenberg, L. (1977). The imperatives of medical research. Science, 198, 1105 â?” 1110.

Feund, P.A., (Ed.). (1970). Experimentation with human subjects. London: Academy of Arts & Sciences, pp xii-xviii.

GCP Consolidated Guideline. Available at <http://www.ich.org/pdfICHc6.pdf>>. Accessed December 2, 2004.

Gordon, V.M., Sugarman, J. &amp; Kass, N. (1998). Towards a more comprehensive approach to protecting human subjects. IRB, 20, 1 â?” 5.

John Hopkins University Internal Investigative Committee, (2001). Report of internal investigation into the death of a volunteer research subject. Available at <http://www.hopkinsmedicine.org/press2001/July/report_of_internal_investigation.htm>>. Accessed December 1, 2004.

Jonas, H. (1969). Philosophical reflections on experimenting with human subjects. In P.A. Feund (Ed.), Experimentation with human subjects (pp. 1-31). London: Academy of Arts &amp; Sciences.

Morse, M.A., Califf, R.M., &amp; Sugarman, J. (2001). Monitoring and ensuring safety during clinical research. JAMA, 285 (9), pp. 1201 â?” 1205.

National Bioethics Advisory Commission (2001). Ethical policy issues in research involving human participants, Vol. 1. Bethesda, Md.

Newell, D.R., Burtles, S.S., Fox, B.W., Jodrell, D.I., &amp; Connors, T.A. (1999). Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapies. Br J Cancer, 81, 760-768.

Office of the Inspector General (OIG). Institutional review boards: A time for reform. OEI-01-97-00193. June 1998.

Steinbrook, R. (2002). Improving protection for research subjects. N Engl Med, 346 (18), pp. 1425-1430.

Steinman, M.G. &amp; Musick, D.W. (2001). Protection of human subjects with disability: guidelines for research. Archives of Physical Medicine and Rehabilitation, 82 (12 Suppl 2): s9-14.

Thompson, L. (2000). Human gene therapy: Harsh lessons, high hopes. FDA Consumer Magazine.Available at <<http://www.fda.gov/fdac/features/2000/500_gene.html>>. Accessed December 1, 2004.

U.S. Food and Drug Administration. Definitions and interpretations. 21 CFR Part 312.3(b). 1999.

U.S. Food and Drug Administration. Institutional review boards. 21 CFR Part 56, 1981.

U.S. Food and Drug Administration. Protection of human subjects, 45 C.F.R., 46 (June 18, 1991).

U.S. Food and Drug Administration. Protection of human subjects. 21 CFR Part 50, 1980.

U.S. Food and Drug Administration. The common rule. 45 CFR Part 46, Revised June 18, 1991.

Ariel E. Quinio, Ph.D.*


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Recall of informed consent information by healthy volunteers in clinical trials


Recall of informed consent information by healthy volunteers in clinical trials
P. Fortun, J. West, L. Chalkley, A. Shonde and C. Hawkey
From the Department of Gastroenterology, University Hospital Nottingham, Nottingham, UK
Address correspondence to P. Fortun, Department of Gastroenterology, University Hospital Nottingham, UK.

Received 5 March 2008 and in revised form 24 April 2008
Background: Information sheets for clinical research are becoming increasingly complex but the extent to which they are understood is uncertain.

Aims: To assess, as our primary outcome, recall by healthy volunteers of key facts in a patient information sheet in a phase 3 clinical trial. As secondary outcomes, we examined whether there was a difference between medical student and non-medically trained volunteers.

Design: Questionnaire to determine recall by healthy volunteers of informed consent information.

Methods: Eighty-two healthy volunteers participating in a capsule endoscopy study were given a 13 page written information sheet and allowed to asked questions. After indicating they were ready to give consent they were asked to complete a 6-item questionnaire covering the identity and adverse effects of trial treatments and of the procedure, the duration of the trial and value of the inconvenience allowance.

Results: All 82 healthy volunteers were questioned. Of the volunteers, 74 (90%) had university level education and 49 (60%) were clinical medical students. However, only 10 subjects (12%) could name the three trial drugs. The maximum number of risks remembered was 6 (n = 2) of 23. Only 14 (17%) could name three or more potential risks of the medication they might be exposed to, whilst 17 (20%) could identify none. Most subjects (77/82, 90%) identified capsule endoscopy as the trial procedure and impaction/obstruction as its main risk (52/82, 64%). All but one subject (98.8%) could recall the exact value of the inconvenience payment.

Conclusion: A comprehensive information sheet resulted in limited recall of trial risks. Shorter information sheets with a test and feedback session should be trialled so that informed consent becomes valid informed consent.

The full article can be found at: QJM Advance Access originally published online on May 16, 2008 QJM 2008 101(8):625-629; doi:10.1093/qjmed/hcn067

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Data Entry and Data Processing in Clinical Trials: Training Aspects


Data Entry and Data Processing in Clinical Trials: Training Aspects


By Malgorzata Krzeminska-Flowers, Ph.D

[email protected]

Smetany 14/53

Lodz, 92-503 POLAND




Quality of data collected during the clinical trial is the single most important key to its success. There are numerous factors influencing accuracy and timeliness of data collection, entry and processing. This article discusses several issues concerning data quality, data entry and processing. A variety of methods that assure complete and legible data collection and accurate data entry should be used. Adequate training of all personnel involved in data collecting, entry and processing can lower the error rate and therefore increase timeliness of data retrieval. Methods for data acquisition, recording and entry are presented together with techniques to decrease error rate and ensure final high data quality. Final part focuses on the importance of personnelâ?Ts training in this area. The article also includes personal training plan design which needs to cover important topics regarding data collection, entry and processing.




“No study is better than the quality of its data” [1]


Quality of data collected during the clinical trial is the single most important key to its success. The need for high quality standards for data used in clinical trials has been acknowledged for more than two decades now. Efforts in quality assurance in clinical data management have been increasing, as reflected in the increase of related publications, books, industry guidelines.

Today, the need continues and has become even more important as government agencies and other regulatory bodies rely more and more on the evaluation of electronic data, i.e. the data, which is electronically collected, stored, transmitted, and archived data for critical data-based decision making. Despite the success of harmonization of Good Clinical Practice (GCP) in Europe, Japan, and the United States, no harmonized guideline on good clinical data management is available yet.

There are several sources of errors in study data at the level of data collection, entry and processing [2]:

Deviations from misinterpretations of the protocol when making measurements and observations, or preparing primary documents eg. CRFs
Inaccurate, illegible, or incomplete data recording
Inaccurate or incomplete data transcription to electronic files
Errors or omissions in data and materials transferred between field sites and the coordinating center, between field sites and resource centers, and between the resource centers and the coordinating center
Excess data collection to the extent that it jeopardizes the quality of essential data
Inadequate training of study personnel, especially new or replacement personnel recruited after the start of the study
Intentional data fraud
In the following paragraphs I would like to discuss the issues of data quality in modern clinical trials. The first part of this article will describe in short the procedures of data collection, entry and processing. Based on this information, in the latter part I will present training requirements and solutions to improve data quality by ensuring smaller error rate through adequate training and auxiliary materials.




In 1999 report [3] Institute of Medicine (IOM) defined data quality as â?odata that can be used without further revisions or data that will produce conclusions and interpretations that are equivalent to those that would be derived from error-free data, that is, data that are accurate, reliable, and fit for useâ?ť. In the same report, it was recognized that the only way to produce such data is to engineer data quality into the entire clinical trial process. This means that â?oduring all phases of a study, sufficient effort should be spent to ensure that all key data critical to the interpretation of the trial are of high qualityâ?ť[1].

Data quality can be viewed in two aspects: inherent and pragmatic. Inherent quality refers to the â?ocorrectness or accuracy of dataâ?ť and pragmatic quality is â?othe value that accurate data has in supporting the work of the enterpriseâ?ť[4]. In case of clinical trials, the pragmatic quality of data is ensured by scientific validity of the protocol and proper statement of the research question or problem. Inherent data quality comprises a wide range of other elements: complete and accurate recording of results, proper performance of tests and evaluations, and appropriate record verification and retention, to name just a few. After a suitable study is designed and thoroughly reviewed, assurance of quality is dependent on the behavior of the clinical trial personnel, which is affected by staff training and integrity [5].

Several changes have occurred over the years which make attention to data quality an issue of highest importance. From their beginnings, clinical trials have evolved dramatically. Firstly, clinical trials are no longer primarily conducted at a single center. Nowadays, they are primarily not only multi-centered but also multinational, therefore trial conduct has become much more complex, both administratively (multiple entities involved in aspects of trial conduct) and scientifically (the number of procedures performed, the number of observations, and design complexity). Increasing scientific complexity of trials is creating constant challenges for the clinical research community, the pharmaceutical industry, and the regulatory agencies.

In addition, the use of electronic record-keeping in the studies has increased dramatically and we can expect for it to continue to grow exponentially. Remote data entry allowed the industry to improve the integrity of clinical trial data collection in the 1980s. Additional timesaving processes evolved during the 1990s via the advent of the Internet [6]. Nowadays, thanks to electronic methods, a high integrity of data collection is obtainable in a relatively easy way. Introduction of regulations (e.g. 21 CFR Part 11 in the U.S.[7]) enabled consideration of electronic records and signatures as generally equivalent to paper records and handwritten signatures. However, it set specific requirements regarding procedures on creation, modification, maintenance, and transmission of to ensure the authenticity and integrity of the records. In addition, the adopted systems must ensure that electronic records are accurately and reliably retained.






Data acquisition

Data acquisition, i.e. the actual â?omeasurement processâ?ť, whether it is a blood pressure reading,

Electrocardiogram, or interviewing the participant, and recording of data, is the first and probably most crucial stage in overall data quality management process. Any errors made at this first stage are more difficult to detect and correct than those made later in the process [8].


Data recording

Data should be recorded directly on forms that have been specifically designed for data collection in the particular trial. The primary issue in designing data collection forms for a research study is a decision what data should be collected at what time points or intervals. The caveat should be â?oCollecting too much data can be problematicâ?ť and â?oAs volume increases, quality can be compromisedâ?ť. In practice, large chunks of data concerning e.g. clinical care or administrative issue are not needed as part of trial database. Data management process in clinical trial starts with development of trial-specific case report form, which should be designed to (1) capture all data required per the study protocol, (2) collect data elements in standardized format, (3) capture data elements in a fashion that ensures that data are suitable for summarization and analysis, (4) facilitate transcription and subsequent comparison to source documents, (5) avoid redundant and unnecessary collection. It is essential that all and only the necessary data is collected [9].

It is important that all data is recorded directly on the forms at the time of measurement to minimize the possibility of notes losses or transcription errors. All subsequent changes to both paper and electronic data should be done in a manner enabling identification of primary value, correct data, date of change, and a person who made the change [10, 11].

Data recording refers to transcribing information onto case report forms. Such forms used to be created on paper, but a new trend is to shift towards direct computer entry and computer screens that resemble forms. The success in both approaches equally depends on proper design of forms/data entry screens [10]. Besides traditional paper CRF and newly introduced e-CRFs, other methods of data recording and collection are common: scannable forms (NCR), fax-based forms (Teleform), or data collection directly from patient with the use of touch-tone telephone systems (interactive voice randomization system â?” IVRS). The choice of case report form type may pay a crucial role in later speed of data entry/collection, and, what may be surprising, the e-forms are not always the best choice considering the speed of data collection.


Data entry

Data entry refers to various modes of entering information into a computer for further processing. Data entry may take a form of direct computer entry by a person transferring data from paper-based CRFs into a computer database, optical mark reading (scanning) or optical character recognition (DATAFAX) for scannable/faxable forms. With electronically captured information the case of data entry per se is practically non-existent, as it is reduced to electronic transfer of information from portable medium into a main database. Aside from the selection of CRF format, each clinical trial faces another choice: the type of data entry system. Information can be entered locally at each site, centrally, upon collection of CRFs from all study sites, or in a web-based format. The choice depends of available resources and clinical trial size, and each of the options has its advantages. In case of local data entry system, data is keyed in onsite by clinic personnel. This allows for quick resolution of data omissions, errors, and inconsistencies, however, it also raises the need for additional local staff training in terms of data entry. When the sponsor/CRO decides to apply a central data entry system, all forms are sent to sponsor or data coordinating center and stored centrally. Only there data is entered by experienced clerks. This allows for speeding up the actual entry process, assuming quick delivery of forms from each clinical site. On the other hand, resolving any issues regarding data omissions, errors, and inconsistencies, will take longer. Another mode of data entry is gaining more and more popularity over the past couple of years, i.e. a web-based data entry system. It combines features of the two previously mentioned systems: data entry by local staff, directly into the central database. There are no specific software or hardware requirements and with wide spread of the Internet, the only specific necessity is providing a secure link for data transmission, using proper protocol, e.g. 128 bit SSL (Secure Socket Layer), or secure hypertext transmission protocol (HTTPS) which are nowadays a standard in most web-based transactions.


Errors in data entry process

â?oTo err is human, but to really mess things up takes a computerâ?ť

During the conduct of any observational studies, including clinical trials, two types of data errors can occur. One type is due to deliberate falsification; the second type results from human or measurement error (such as inaccurate data entries, inaccurate transfers of data, misinterpretation, and inherent limitations of the measurement instruments). Errors resulting from falsified data are always serious and must be dealt with accordingly; other errors may be serious or trivial.

Errors inevitably occur during data entry. The most common errors that usually occur during data entry include (1) typographical errors, (2) copying errors, (3) coding errors, and (4) range errors [9]. Typographical or printing errors, usually take place when someone is typing at a very high key rate. Copying errors are usually the result of poorly filled-in CRFs with a not very legible handwriting, when data entry clerks cannot differentiate between certain letters or numbers. Coding errors occur when personnel filling the CRFs with given codes or data entry clerks make a mistake with wrong assignment of given codes to items on the CRFs. Range errors occur where lower and/or upper limits of known values are exceeded when typing. This type of error can be easily detected with proper database design. In case of scannable and faxable forms, the errors may occur when the optical recognition program is not able to recognize illegible handwriting.


Decreasing error rate in data-entry processes

It is obvious that every clinical study must include procedures to avoid or minimize data errors. A good practice to implement in order to avoid data entry errors is double data entry (i.e., entry by two different entry clerks), which can be considered while using paper-based CRFs. Upon the receipt of CRFs, a working copy of the original CRFs will be made and reviewed by the data manager prior to entry. Data from the working copy of the CRFs will be entered into the database. CRFs will be initialed, dated, and stamped entered after the initial entry. A second entry will occur after the initial entry. The two files are then checked for differences by running a verification program that compares the two files. If the records do not match, discrepancies are printed out and corrections are made. The process is repeated until such a time that each file is an exact replica of the other. Any missing or inconsistent information will be entered on the Query Form forwarded to the clinical monitor for processing. After the information has been verified, i.e., there are no inconsistencies between the initial and the second entries, the CRFs will be initialed, dated, and stamped verified.

Verification ensures that data entered are actually on the CRFs. The data quality of the resulting database is inversely proportional to the chance of having the same in a field by two persons, which is hopefully negligible. The overall error rate from double data entry can be as low as 0.001% [9].

Logical data verification should be routinely performed in all trials. In addition to logic checks other data quality inspections in on the database are also highly desirable to determine the data quality level regardless of the type of CRFs used. There are statistical methods utilizing sampling techniques to estimate the error rate and data quality quantification.


Data Query

The process of data entry and verification will most likely result in detection of omissions, errors, or items requiring clarification or changes to CRF. These items need to be written down on the Query Form and forwarded to the clinical monitor for processing. Data queries can be generated at any step during the CRF review, data entry and verification, and data analyses by the data management personnel and/ or trial / project statistician. All data clarifications, regardless of whether they require CRF alterations or not, should be entered on the Query Form and forwarded to be resolved by the designated monitor.

Data Corrections/Validation

Both ICH and FDA guidelines require that all subsequent changes and corrections must be made in a manner which does not obscure the initial value. Each correction on CRF must be initialed and dated by the investigator or other authorized person and a reason for the change made should be documented. All corrections upon data entry into the database should be made based on information provided on the Query Forms. Upon completion of data entry, original Query Forms should also be dated, initialed, and stamped Corrected to indicate that the entry of the data update is completed.




In order to standardize clinical trial procedures and minimize data collection and entry errors it is necessary to provide centrally operated training and certification program for field site personnel. The training should include: local data coordinators or managers, key entry personnel, technicians, examiners, counselors, physicians, or dietitians, depending on the study design. Before trial begins, the coordinating center staff should take proactive measures to assure that these individuals understand the study protocol and design, including participant eligibility criteria and plans for analyzing primary and secondary outcomes of interest. All the personnel involved in data entry and collection process, especially site data coordinators and key entry personnel should be certified in study procedures (as described above) for data entry, data transmission, and error correction. They also should be prepared to use the trial’s system for electronic mail, if applicable, and other communication and tracking mechanisms. At least two people at each field site should be trained for each task requiring study certification so that at all times one individual is available to the trial. Because of the time and resources required for training, especially in case of fully or partially electronic data capture, entry and processing, the on-line training program can be considered. Learning via Internet can consist of life no-line meeting and conferences, lectures provided by experienced trainers, real-time tasks, etc. This way staff localized in many centers, even throughout the globe, may access diverse training material at any time, at their own working place. Studying in a well-known environment and possibility to apply gained knowledge immediately in real-life situations was found very effective [12].

Not every organization remembers that it is prudent to include some review of medical and other research issues as part of the training program, also for data entry and data processing personnel. Coordinating center staff who participate in training programs for field site personnel often are dismayed by how little training in the medical aspects of the study local investigators have provided. Introduction of some medical background information, trial objectives and statistical analysis increases the understanding of whole process and the meaning of data which the staff processes, reducing the amount of logical errors. The training for local data entry and processing personnel should include:

Principles of good research practice regarding documentation and data handling
The quality assurance and monitoring program for the study
Expectations regarding communications with resource centers, in performance monitoring reports, and during site visits.
During the training of personnel, it is advisable that field site staff is given a practical exercise, which they are to solve utilizing the field site microcomputers and their operating systems, data collection procedures, and various study-related procedures. After completed training, the staff members should perform a more detailed certification test. Including practice into the training program allows the staff members to be better informed and more comfortable in their responsibilities [2, 13].

It is very important to remember that physicians and clinical investigators participating in the study also must be trained in all aspects of the study protocol, including data collection, entry and reporting. Other data quality assurance efforts are irrelevant if the physicians do not understand the basic principles of data collection and study design [2].

Typically, training program for study personnel should be followed by a competency tests for procedures or examinations required by the study protocol, which includes topics of handling data.


Training for data entry and processing personnel

Clinical trial management must ensure that appropriate training is provided for all procedures so that all personnel are able to fulfill their functions. Detailed training records for each individual should be kept in their personnel file. These training records detail three levels of ability [14]:

1. Under supervision

2. Competent

3. Competent to train

Prior to the use of any procedure, management should assess and record each staff memberâ?Ts level of competency for the procedure in his or her training record.

When a trainee requires specific training, the category â?oUnder Supervisionâ?ť should be entered in the training record. Each record and record change needs to be confirmed by signature by both: the trainer or assessor and the trainee. When sufficient training has been given so that the trainee can carry out a procedure without supervision, they will be certified as â?oCompetentâ?ť. Competent individuals, who have sufficient knowledge of a procedure, and necessary skills to transfer their knowledge and expertise, may be certified as â?oCompetent to Trainâ?ť.

Attendance at internal or external training courses on specific topics relating to their work should be recorded in the individualâ?Ts training record, together with the name of the training institution or trainer and the dates of attendance. The maintenance of the training record is the responsibility of the concerned individual. However, it is the responsibility of clinical trial management to ensure that an updated curriculum vitae (CV) is maintained on file for all staff, therefore all personnel should advise management of any significant changes (e.g. increased qualification, finished courses and trainings).

The daily work environment of personnel dealing with data following is affected by various topics. The following is an all- inclusive list of training, which may serve as a reference guide for the development of a master training plan and individual development plans [13]:

Standard Operating Procedures and Departmental Policies
All employees are required to understand and follow these SOPs. Simple confirmation by an employee that a SOP has been read and is understood often constitutes required SOP training, however it is rarely enough. To increase understanding and effectiveness, the trainer should discuss required SOPs with employees and explain how they affect their daily work routine.

Computer Software and Technical Skills
Modern clinical trial environment utilizes various computer software applications to enter, clean and analyze data. These applications, including clinical databases, CRF imaging software, edit specification development, discrepancy management, and others, require practical training for all those employees who use them.

Regulations and Industry Standards
Data management personnel are required to work within the constraints of codes and regulations. Industry standards should not be treated as â?orestraintsâ?ť; they give employees guidance in their common work practices. To improve training schedule for data entry and processing employees, a trainer can make references to information regarding standards such as GCP, ICH Guidelines, FDA Regulations, 21CFR Part 11, as well as GCDMP, which can be found in various publications, educational seminars or Internet web sites.

Professional Growth
For many employees, individual development plans provided by a company are a very important part of a training schedule, especially when they allow for the employeeâ?Ts growth outside of the technical skills that are required. Often, the concept of â?otrainingâ?ť is being supplanted by â?olearningâ?ť; this is a shift toward developing learning skills. The main objective of learning is to help an individual become self-directed, with a clear set of objectives and maintenance of records of their progress, such activity is commensurated

with the existence of documented procedures in the regulated environment.

A good learning program will allow individuals to realize their full potential

to the benefit of both parties.


Interdepartmental Processes
For the data collection and processing to be fully effective, employees must also understand the processes that occur before and after the data is handled by them.


Beyond training: aids and reminders

Another way to improve data collection and processing timeliness and lower the error-rate is creating a number of aids for use by field site personnel. These aids may include data collection schedules for study participants, reminders of upcoming examinations, lists of participants for whom data reporting is delinquent, data records or other items associated with an examination that have not been received at the coordinating center, and lists of edit queries that have not been resolved.


How to Assess Training Effectiveness?

Assessment of the traineeâ?Ts theoretical and practical skills is a necessary part of the training experience. Trainers should cooperate with their colleagues to monitor the traineeâ?Ts development throughout the training period. Continuous feedback from colleagues will help the trainer and trainee to identify areas that require further development or to identify areas in which the trainee has shown significant skills.

The first and most obvious method of assessment whether the trainee gained the intended skills or knowledge is assured through observation by the trainer. If this method is not possible or is too labor intensive (e.g. in case of very wide-spread training programs in global organizations) other assessment options can be applied, such as providing written tests for personnel utilizing questions based on material covered during the training. Especially in the larger organizations, â?oe-learningâ?ť is much more useful as a lot of personnel can be trained in their own time or spare time. The subsequent test usually has a form of multiple choice questions based on instructional material with certain pass mark set. Of course, paper-based systems also can be used, but these require delegation of human resources to produce and to mark the responses, whereas the electronic assessment process saves a considerable amount of time and human resource.

It is obvious that no matter what the form the training, there must be always some robust method of examination or assessment; else we cannot be sure that we have covered all the bases.

Whatever form of assessment is used, it is essential that appropriate records are maintained of these operations in the training records. Therefore, it makes good sense to have a system that can automatically produce a written assessment report. This latter component is another bonus that makes an electronic training and evaluation system so much more attractive [14].




Completeness and accuracy of clinical trial data greatly affects the statistical conclusions from the data analyses. Data accuracy can be enhanced when researchers do some advanced planning and follow careful procedures. A variety of methods should be used that assure complete and legible data collection and accurate data entry. Adequate training of all personnel involved in data collection, entry and processing, can lower the error rate and therefore increase timeliness of data retrieval. In fierce business such as modern pharmaceutical industry, time means money, and every delay in obtaining accurate and complete trial data means huge losses for the company. This is why the importance of prior training of all staff involved in data handling should not be underestimated. Time and money spent on staffâ?Ts training is never lost, and actually brings a quick return of investment in form of better personnel performance during the clinical trial.





[1] Friedman L, Furberg C, DeMets DL: Fundamentals of Clinical Trials. John Wright-PSG Inc., Littleton, MA, 1981

[2] Gassman JJ, Owen WW, Kuntz TE, Martin JP, Amoroso WP: Data Quality Assurance, Monitoring, and Reporting. Controlled Clinical Trials 16:104S-136S, 1995

[3] Davis JR, Nolan VP, Woodcock J, and Estabrook RW (Eds): Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision Making: Workshop Report. Division of Health Sciences Policy, Institute of Medicine, National Academy Press, Washington, DC, 1991; available on-line at: http://www.nap.edu/catalog.php?record_id=9623

[4] English LP: Improving Data Warehouse and Business Information Quality. Wiley, New York, NY, 1999

[5] Concept Paper: Quality in FDA-Regulated Clinical Research. Background to HSP/BIMO Workshop; available on-line at: http://www.fda.gov/oc/initiatives/criticalpath/clinicalresearch.html

[6] Mitchel JT, You J, Kim YJ, Nardi R, Cheng L, Fein S, Lau A: Clinical Trial Data Integrity.

Applied Clinical Trials, Mar 2, 2003; available on-line at: http://actmagazine.findpharma.com/appliedclinicaltrials

[7] Title 21 Code of Federal Regulations (21 CFR Part 11) Electronic Records; Electronic Signatures

[8] Hosking JD, Newhouse MM, Bagniewska A, Hawkins BS: Data Collection and Transcription. Controlled Clinical Trials 16:66S-103S, 1995

[9] Chow SC, Liu JP: Design and Analysis of Clinical Trials: Concepts and Methodologies, Second Edition, John Wiley &amp; Sons, Inc., 2004

[10] Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB: Designing Clinical Research: An Epidemiologic Approach. Lippincott, Williams &amp; Wilkins, Philadelphia, PA, 2001

[11] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: Guideline for Good Clinical Practice. 1996

[12] No More Pencils, No More Books, Future Pharmaceuticals Podcast, available at http://www.futurepharmaus.com/Default.aspx?mc=no-pencils&amp;page=tl-viewwebevent

[13] Good Clinical Data Management Practices. Society for Clinical Data Management, Version 2, January 2002

[14] Ogg GD: A Practical Guide to Quality Management in Clinical Trial Research. Taylor &amp; Francis Group, LLC, Boca Raton, FL, 2006

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Regulatory Questions and Answers: the Investigator’s Brochure


Regulatory Questions and Answers: the Investigator’s Brochure
By Douglas Fiebig

I work for Novo Nordisk and I’m responsible for our IB SOP. I’ve been asked if I know about any official guidelines for the
format of AE tabulations for IBs. I have not been able to find any, so our AE tabulations are based on the tabulations we
use for our clinical trial reports. Do you know if there are official guidelines? And then I have another question. Does your
department ever receive comments such as, ‘No comments on the content, BUT, I have a general comment that I have
raised many times, must our IB’s be such boring documents, not at all inviting the investigators to read them? I think they
should be written much more like our product monographs, using colours, figures, graphs, and even pictures, etc. I mean
this very seriously!’


The first part of the question is quickly answered. The only official guidance for preparing an IB is given in the ICH E6
guideline on GCP (e.g. CPMP/ICH/135/95). However, this guideline provides only general recommendations for the
structure and content of an IB, and the style of presentation is left to the discretion of the sponsor. Thus the most
pragmatic approach to generating AE tabulations in IBs is to use the format chosen by the sponsor for other
documentation, such as study reports or registration summaries. In this way, data programmers don’t have to establish a
specific format for IBs, and often it will probably be possible to use tabulations in the IB that were originally generated for
other documentation.


Regarding whether IBs could be made less ‘boring’, as most of us know from personal experience, boring literature
tends not to be read in any detail, if at all, and so a boring IB is unlikely to be regarded by an investigator as an essential
resource from which relevant information can be gleaned about the product being tested. The issue of what exactly
constitutes a boring document (IB or otherwise) is undoubtedly subjective, but in general terms I would consider a
document as inherently boring when its style of presentation, for whatever reason, tends to deter the intended audience
from reading it.


The style of presentation in any document has two basic components: the organisation of the material to be included
and the formatting of the content (the colour, figures, pictures, etc. referred to in the question). As medical writers, we
generally have little influence on the scope of the material to be included in an IB, and no influence on whether an
investigator is predisposed to consult an IB, but what we certainly can and should aim to influence is the ease with which
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investigators can access the material presented should they turn to the IB for information.


So the question is: what is an appropriate style of presentation to achieve this aim? Personally I see no need for flashy
colours, input from graphic artists, luxury quality papers, etc. We have to remember that a common problem confronted
by medical writers when preparing an IB is a shortage of time and information. The realities of deadlines being brought
forward, reports often existing only as drafts, if at all, (particularly the case with preclinical studies in early-stage IBs),
‘final’ tables of data needing further cycles of revision, etc, mean that preparing an IB often becomes the classic dilemma
of doing the best job with the information available, in the time available. Under these conditions, the scope for artistic
input to an IB is obviously limited, especially for early editions in view of the high attrition rate of compounds in Phase I of
clinical development. The time involved for any such artistic input would not be justified under the generally tight timelines
involved when preparing an IB, where the emphasis clearly has to be placed on ensuring the accuracy and
completeness of the material presented (i.e. the quality of the content). Perhaps we also shouldn’t underestimate the
potential for glossy literature produced by the pharmaceutical industry to arouse suspicion.


Apart from the general lack of time for artistic input, while it might be tempting to think that the use of colours and
pictures might make an IB inherently more interesting, in fact a user-friendly layout, the intelligent use of in-text tables
and graphs, and a clear and concise text are undoubtedly the medical writer’s most potent weapons for reducing
boredom in any documentation. The basic principle behind a well-prepared IB that captures the reader’s attention is
much the same as in all medical writing, which is to highlight the important features of the development programme to
date in a competent fashion, with the medical writer providing the competence. In essence, given the often extensive
amount of research that has to be reported, the readability of the IB really needs to be ensured by having the main body
of the text provide a series of take-home messages for the investigator. Further details are then provided in a hierarchical
manner, with the text supported by in-text tables and graphs, which in turn are supported by the tables of all studies,
which themselves are supported by the original reports archived by the sponsor. Realistically, the items most likely to be
read, at least in the first instance, are the high-level summaries (one to two pages for each major section) and perhaps
selected in-text tables and graphs, so special attention has to be paid to ensuring that these summaries really do convey
the required messages.

My take-home messages in response to the original questions are therefore:
– There are no official guidelines on AE tabulations for IBs. Use the format your company uses for other documentation.
– Elaborate artwork is generally not justified or necessary to make IBs less ‘boring’.
– The use of clear and concise text together with intelligently planned in-text tables and figures ensures that an IB is not
only a document that fulfills a legal obligation, but also a useful resource for investigators who need to be informed about
the product they are testing.


Dr Douglas Fiebig, Aventis Pharma Deutschland, [email protected]

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The study design is the framework for all research
by Cullen T. Vogelson
In truth, the experimental design is central to all trials, and it contributes to their successes and failures. In fact, no matter how safe and effective a drug may actually be, a poorly conceived research program ultimately will fail to prove its virtues; for example, the FDA will not approve a medication if the research meant to demonstrate its worth included insufficient sampling sizes (a statistical problem), was analyzed using suspect mathematical models, or failed to support the declared claims of therapeutic value.

As a result, a new pharmaceutical product (also known as a â?onew chemical entityâ?ť, NCE) is never investigated haphazardly. Further, because of research costs and various inherent time elements associated with the development process (see â?oWe are the world?â?ť, June 2001, p 36), it is critical that clinical experiments be designed carefully and accurately to address key questions of which patient populations should be studied, what the hoped-for results will be, and how the study design should be constructed to provide a credible foundation from which to interpret the data and reach meaningful conclusions.

Before delving too deeply into the design of the clinical trial itself, though, it is important to describe the scope and content of its documentation, known as the â?oprotocolâ?ť. This document delineates the purpose of a trial, the nature and composition of an NCE, the patient population, the number of clinic visits the subjects will be expected to make, the assessments that will be included at each visit, the manner in which those assessments will be conducted, the investigatorâ?Ts responsibilities (beyond those in the U.S. Code of Federal Regulations), the oversight delegated to contract research organizations, and the statistical review that will analyze the collected data.

The framework
Phases of clinical trials in humans
(specifics for each phase may vary)
Phase No. patients Duration Location Purpose
I 20â?”80
(healthy) 36 hours, over 2â?”6 weekends Single site Bioavailability, pharmacokinetics, safety, dosing regimens/ranges
II 50â?”200
(diseased) 36 hours, over 1â?”4 weekends Single site Safety and preliminary efficacy
III 100â?”2000
(diseased) 6 monthsâ?”
3 years 30â?”40 sites Immediate and long-term safety and efficacy
IVa 100â?”2000
(diseased) 6 monthsâ?”
3 years 30â?”40 sites Efficacy for alternate indications
aPhase IV studies are known as â?opostmarketingâ?ť and are conducted only after an NCE is approved by the FDA and the pharmaceutical company wishes to explore a further use of their medication in treating different indications (i.e., medical conditions).
All clinical trial designs begin by addressing the issues of study intent, size, and population. Clinical trials consist of four phases, and each one requires a different set and number of patients (see box, â?oPhases of clinical trials in humansâ?ť). The participant population is defined on the basis of phase and therapeutic need; the protocol outlines the specific inclusion and exclusion criteria. The purpose of the trial is also outlined in the protocol: Generally, only one study each is conducted in Phases I and II, and their purposes are universally defined. However, later phase trials may be multiple as different effectiveness measurements are obtained. For instance, one Phase III study might test the NCE versus a placebo, another might pit the NCE against a competitorâ?Ts product, and still another might consider the combined effect of the NCE and an additional, marketed medication.

Once the intent of the study is established and the patient population identified, the specifics of the trial must be determined. A primary consideration involves how many â?oarmsâ?ť the study will have and what those arms will be. For example, in a two-armed study, the total patient population would be divided in half, with each half receiving a different course of treatment, such as the NCE or a competitorâ?Ts drug. Once the number and type of arms are defined, a choice must be made on whether the research will be blinded, and if so, to what extent. The term â?oblindingâ?ť refers to how much information the patients, researchers, and study monitors will possess about a particular patientâ?Ts treatment course. In general, to remove all biases, clinical trials are either double- or triple-blinded; commonly, only the statistician who developed the methodology for the trial can determine to which arm a particular patient has been assigned. Although this may sound unsafe, itâ?Ts not. The investigating physicians are provided with codes that can identify a particular patientâ?Ts medication in the case of an emergency. This procedure is known as â?obreaking the blindâ?ť.

The experiment
The â?omeat and potatoesâ?ť of the study design, however, involves the actual patient visits and the events that occur during them. Obviously, it is not possible to describe the vast array of schedules that are used within different studies, but a general review of their high points is instructive.

During Phases I and II, there are commonly only a few short visits, which are carefully controlled to reduce the number of extraneous variables. Specifically, patients are required to eat identical foods, consume the full portions of those meals, record the quantity of all additional ingestions such as water, and sleep or at least rest quietly for a pre-set period. In addition, patients in these trials start and stop their meals, are dosed, and have their blood drawn at carefully timed and precise intervals so that metabolic information regarding the medications can be accurately determined.

These trials are known commonly as â?obleed and feedsâ?ť, because the primary assessment method involves blood assays. As such, patients begin a typical visit by arriving at night for dinner and then beginning the next day with breakfast, followed by a dosing of the NCE, and then a series of 10â?”15 blood draws before lunch. Often, a total of five more draws are then performed throughout the afternoon and evening, concluding with a final draw before dismissal the next morning.

Phase III and IV trials, by contrast, are markedly uncontrolled. Their purpose is, in part, to test the NCEs under â?oreal-lifeâ?ť conditions; patients make visits just as they would go to a doctorâ?Ts office, and the visits typically last just as long. At each visit, patients are asked about their physical well-being and any adverse events or concomitant medications that are new since the last visit. (Visits are often spaced a month apart and may continue for many years.) In addition, the patientâ?Ts dosing regimen is reviewed and altered if necessary, laboratory tests are completed, and assessment exams are conducted as appropriate (see â?oIn the mindâ?Ts eyeâ?ť, June 2001, p 21).

The protocol details every visitâ?Ts events (these assessments often vary from visit to visit, particularly in later phase trials), the allowable interval between patient visits, the requirements for record keeping, and instructions for completing unique facets of the trial. For example, the protocol for a study that includes patient diaries might feature directions for their use.

The nitty-gritty
A key component of every protocol is the scientific/mathematical justification for the research design and the corresponding explanation of the methodologies to be used in the data analysis. (The rigid design of the clinical databaseâ?”the repository of all collected research dataâ?”will be detailed in next monthâ?Ts Clinical Trials Track.) In addition, it is here that the â?orandomization schemeâ?ť is justified; this is the instrument used to assign patients, randomly and blindly, into various arms of the trial. Finally, it is within this statistical review that the expected patient enrollment is shown to be sufficient for providing a statistically meaningful data set.

Ultimately, the goal of a clinical trial is to prove an NCEâ?Ts safety and efficacy. Thus, the goal of the experimental design is to structure a study that can do just that. In addition, it is important to realize that issues of patient safety and health are paramount to the design. Scientists and researchers must be very careful to create clinical trials that do not jeopardize or needlessly complicate a patientâ?Ts health or quality of life. The reasons are obviously ethical and legal; for example, U.S. law forbids the incorporation of a placebo arm in a study that will include patients suffering from life-threatening diseases for which an alternative therapy is available. Another reason, however, goes to the statistical heart of a trial: Patient enrollment may suffer if the chosen clinical assessments or dosing regimens are extreme or complex.

Finally, it is worth noting that protocols are routinely amended even after a trial begins (with investigational review board and FDA approval). Amendments to correct errors in design are obviously a much cheaper approach than discarding an approved study and starting fresh. Of course, spending the time and consideration to develop an effective protocol at the beginning of a study can ensure better, faster, and more accurate and complete results and conclusions, which are critical in achieving FDA approval.


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Sponsorship, Authorship, and Accountability


Sponsorship, Authorship, and Accountability
As editors of general medical journals, we recognize that the publication of clinical-research findings in respected peer-reviewed journals is the ultimate basis for most treatment decisions. Public discourse about this published evidence of efficacy and safety rests on the assumption that clinical-trials data have been gathered and are presented in an objective and dispassionate manner. This discourse is vital to the scientific practice of medicine because it shapes treatment decisions made by physicians and drives public and private health care policy. We are concerned that the current intellectual environment in which some clinical research is conceived, study participants are recruited, and the data analyzed and reported (or not reported) may threaten this precious objectivity.

Clinical trials are powerful tools; like all powerful tools, they must be used with care. They allow investigators to test biologic hypotheses in living patients, and they have the potential to change the standards of care. The secondary economic impact of such changes can be substantial. Well-done trials, published in high-profile journals, may be used to market drugs and medical devices, potentially resulting in substantial financial gain for the sponsor. But powerful tools must be used carefully. Patients participate in clinical trials largely for altruistic reasons–that is, to advance the standard of care. In the light of that truth, the use of clinical trials primarily for marketing, in our view, makes a mockery of clinical investigation and is a misuse of a powerful tool.

Until recently, academic, independent clinical investigators were key players in design, patient recruitment, and data interpretation in clinical trials. The intellectual and working home of these investigators, the academic medical center, has been at the hub of this enterprise, and many institutions have developed complex infrastructures devoted to the design and conduct of clinical trials (1, 2). The academic enterprise has been a critical part of the process that led to the introduction of many new treatments into medical practice and contributed to the quality, intellectual rigor, and impact of such clinical trials. But, as economic pressures mount, this may be a thing of the past.

Many clinical trials are performed to facilitate regulatory approval of a device or drug rather than to test a specific novel scientific hypothesis. As trials have become more sophisticated and the margin of untreated disease harder to reach, there has been a great increase in the size of the trials and consequently the costs of developing new drugs. It is estimated that the average cost of bringing a new drug to market in the United States is about $500 million (3). The pharmaceutical industry has recognized the need to control costs and has discovered that private nonacademic research groups–that is, contract research organizations (CROs)–can do the job for less money and with fewer hassles than academic investigators. Over the past few years, CROs have received the lion’s share of clinical?trial revenues. For example, in 2000 in the United States, CROs received 60% of the research grants from pharmaceutical companies, as compared with only 40% for academic trialists (1).

As CROs and academic medical centers compete head to head for the opportunity to enroll patients in clinical trials, corporate sponsors have been able to dictate the terms of participation in the trial, terms that are not always in the best interests of academic investigators, the study participants, or the advancement of science generally (4). Investigators may have little or no input into trial design, no access to the raw data, and limited participation in data interpretation. These terms are draconian for self-respecting scientists, but many have accepted them because they know that if they do not, the sponsor will find someone else who will. And, unfortunately, even when an investigator has had substantial input into trial design and data interpretation, the results of the finished trial may be buried rather than published if they are unfavorable to the sponsor’s product. Such issues are not theoretical. There have been a number of recent public examples of such problems, and we suspect that many more go unreported (5, 6).

As editors, we strongly oppose contractual agreements that deny investigators the right to examine the data independently or to submit a manuscript for publication without first obtaining the consent of the sponsor. Such arrangements not only erode the fabric of intellectual inquiry that has fostered so much high-quality clinical research but also make medical journals party to potential misrepresentation, since the published manuscript may not reveal the extent to which the authors were powerless to control the conduct of a study that bears their names. Because of our concern, we have recently revised and strengthened the section on publication ethics in the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication,’ a document developed by the International Committee of Medical Journal Editors (ICMJE) and widely used by individual journals as the basis for editorial policy. The revised section follows this editorial. (The entire “Uniform Requirements’ document is undergoing revision; the revised version should be available at the beginning of 2002.) As part of the reporting requirements, we will routinely require authors to disclose details of their own and the sponsor’s role in the study. Many of us will ask the responsible author to sign a statement indicating that he or she accepts full responsibility for the conduct of the trial, had access to the data, and controlled the decision to publish.

We believe that a sponsor should have the right to review a manuscript for a defined period (for example, 30 to 60 days) before publication to allow for the filing of additional patent protection, if required. When the sponsor employs some of the authors, these authors’ contributions and perspective should be reflected in the final paper, as are those of the other authors, but the sponsor must impose no impediment, direct or indirect, on the publication of the study’s full results, including data perceived to be detrimental to the product. Although we most commonly associate this behavior with pharmaceutical sponsors, research sponsored by government or other agencies may also fall victim to this form of censorship, especially if the results of such studies appear to contradict current policy.

Authorship means both accountability and independence. A submitted manuscript is the intellectual property of its authors, not the study sponsor. We will not review or publish articles based on studies that are conducted under conditions that allow the sponsor to have sole control of the data or to withhold publication. We encourage investigators to use the revised ICMJE requirements on publication ethics to guide the negotiation of research contracts. Those contracts should give the researchers a substantial say in trial design, access to the raw data, responsibility for data analysis and interpretation, and the right to publish–the hallmarks of scholarly independence and, ultimately, academic freedom. By enforcing adherence to these revised requirements, we can as editors assure our readers that the authors of an article have had a meaningful and truly independent role in the study that bears their names. The authors can then stand behind the published results, and so can we.

Frank Davidoff, MD
Editor Emeritus, Annals of Internal Medicine

Catherine D. DeAngelis, MD, MPH
Editor, Journal of the American Medical Association

Jeffrey M. Drazen, MD
Editor-in-Chief, The New England Journal of Medicine

The Editors
The New Zealand Medical Journal

John Hoey, MD
Editor, Canadian Medical Association Journal

Liselotte Højgaard, MD, DMSc
Editor-in-Chief, Ugeskrift for Læger
(Journal of the Danish Medical Association)

Richard Horton, FRCP
Editor, The Lancet

Sheldon Kotzin
Executive Editor, MEDLINE/Index Medicus

Magne Nylenna
Editor-in-Chief, Tidsskrift for Den norske laegeforening
(Journal of the Norwegian Medical Association)

A. John P.M. Overbeke, MD, PhD
Executive Editor, Nederlands Tijdschrift voor Geneeskunde
(Dutch Journal of Medicine)

Harold C. Sox, MD
Editor, Annals of Internal Medicine

Martin B. Van Der Weyden, MD, FRACP, FRCPA
Editor, The Medical Journal of Australia

Michael S. Wilkes, MD, PhD
Editor, Western Journal of Medicine

Corresponding Author:
Harold Sox, MD, American College of Physicians-American Society of Internal Medicine, 190 N. Independence Mall West, Philadelphia, PA 19106.


Henderson L.
More AMCs finding growth from reform. Centerwatch. 2000;7:1, 10-13.

Kowalczyk L.
Harvard, other medical schools aim to give drug firms faster pace for trials. Boston Globe. 28 July 2000:C4.

Mathieu MP.
Parexel’s Pharmaceutical R&amp;D Statistical Sourcebook, 1998. Waltham, MA: Parexel International Corp.; 1999.

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Thyroid storm [Editorial]. JAMA. 1997;277:1238?43. [ PMID: 9103350 ]

Kahn JO, Cherng DW, Mayer K, Murray H, Lagakos S.
Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 10(6)/L CD4 cell counts: a randomized controlled trial. JAMA. 2000;284:2193-202. [ PMID: 11056590 ]

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The section on publication ethics from the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication’ follows below. The full revised “Uniform Requirements’ will be published later.

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Control Groups in Pharmacotherapy and Psychotherapy Evaluations


Control Groups in Pharmacotherapy and Psychotherapy Evaluations
Donald F. Klein, MD
Department of Psychiatry, Columbia University
Department of Therapeutics, College of Physicians and Surgeons and the New York State Psychiatric Institute

Whether placebos should be included in evaluative therapeutic research remains controversial. Some argue that placebos should be abandoned on pragmatic and ethical grounds and replaced with comparative trials against known effective agents (Rothman &amp; Michels, 1994). However, placebo controls are essential if causal attribution regarding characteristic features is to be made. This methodology also assures that pragmatic therapeutic goals are met. An algebraic model is presented to demonstrate the critical importance of placebos in controlling for demand characteristics and spontaneous remission. The inherent difficulty in designing psychological placebos by fiat and the inadequacy of wait-list controls are addressed. The model demonstrates that inclusion of a pill-placebo group may be the optimal controlled design in psychotherapy as well as pharmacotherapy research and argues for collaborative psychotherapyâ?”pharmacotherapy research programs.

Supported in part by PHS Grant MH-30906, MHCRC-New York State Psychiatric Institute.

I thank Lauren Smith and Donald Ross for editorial and substantive contributions and Jon Stewart, Michael Liebowitz, and Ned Nunes for comments on early drafts.

Correspondence concerning this article may be sent via email to [email protected]

The relative values of naturalistic, quasi-experimental and experimental methods has led to enormous controversy. Here we focus on a narrower issue: Does a pill-placebo case management group provide a useful pragmatic comparison in the experimental evaluation of psychotherapy? To approach this, some basic issues are reviewed.

Naturalistic studies, until recently, have been the mainstay of therapeutic advance. Ill people were given a treatment, and if it was reported that many became well, the treatment was considered effective. This conclusion actually rests on an implicit historical control: the course of those with the illness who had gone untreated. Because many patients who came to treatment appeared to have a long-standing difficulty, the presumption was understandable that the illness would continue unless effectively treated.

This post hoc ergo propter hoc (after and therefore because of) logical fallacy led to the adoption of many interventions, some pharmacologically useful (e.g., aspirin, quinine, digitalis) and some (particularly those that stemmed from the primitive theories of the day) that were positively harmful (e.g., emetics, cathartics, bleeding, and purging). In fact, most such remedies yielded no pharmacological specific benefit but nevertheless often produced relief, due to the so-called placebo effect. This was demonstrated experimentally by showing that these putative treatments were no more efficacious than pharmacologically inert substances. It also became apparent that many illnesses improved or completely remitted without formal treatment on their own.

Therefore, there were two hypotheses in competition with the hypothesis of efficacy, supported by historical control: (a) the patients got better on their own (spontaneous remission) or (b) the treatment benefits were only equivalent to those produced by any credible treatment approach (placebo effect). This last was often referred to as suggestion.

Much early discussion about psychoanalytic efficacy revolved about whether the patientâ?Ts insights or benefits were due to suggestion. The attempt was made to argue that the objective psychoanalytic method, amplified by the analystâ?Ts own analysis, provided a sufficient safeguard. However, warring psychoanalytic schools, all claiming superior results based on opposing theories, were not reassuring.

Eysenck (1952) provided an even more pointed critique by arguing that spontaneous remission produced as good or better results than psychotherapy and psychoanalysis. This led to extended controversy. The argument revolved about attempts to arrive at firm estimates of spontaneous remission (which are not uniform across patient groups) as well as firm estimates of improvement during treatment, which were of dubious objectivity and reliability and usually did not incorporate into the final accounting those who failed to complete treatment, as this was defined by the therapist in the context of an indefinitely prolonged treatment. It was not possible to distinguish treatment failures from treatment dropouts.

The major logical point of Eysenckâ?Ts critique is that it is a mistake to rely on the assumption that the patient would not have become well in the absence of intervention. An historical control is of value under quite restricted circumstances. Pasteurâ?Ts rabies vaccine did not require a controlled trial because the antecedent was unmistakable (being bitten by a rabid animal) and the disease was invariably fatal. Survival demonstrated the treatmentâ?Ts efficacy because neither placebo effect nor spontaneous remission were reasonable alternative hypotheses.

The development of psychotropic agents in the 1950s met with considerable skepticism. It was argued that apparent benefits could be due to suggestion or spontaneous remission. This led to the rapid adoption of the randomized, placebo-controlled trial. Both treatment groups were, within chance sampling fluctuations, equivalent with regard to placebo effect and spontaneous remission, providing an elegant control. Other alternative hypotheses such as experimenter or patient bias or a confound of patient differences with treatment method were countered, respectively, by double-blinding and randomization.

The remarkable success of this procedure confronted psychotherapy advocates with a dilemma since the alternative hypotheses of suggestion and spontaneous remission could apply to the benefits of psychotherapy. Further, Jerome Frank (1961) compared short-term psychotherapy with pill placebo and found similar symptomatic benefits. However, this was largely ignored or discounted as an inadequate design because a classical control group incorporates all of the putative treatment aspects except for the proposed active ingredient. Frankâ?Ts comparative treatment groups differed in many ways. Thus, his uncomfortable findings were largely ignored. It will be shown below that inappropriate explanatory criteria were used to discount pragmatically useful information.

Instead, comparative psychotherapeutic research focused on so-called wait-list controls, between-treatment comparisons, and contrasts with “psychological placebos.” The problems with these designs are discussed below, but first a model of therapy will be developed. It is intended to clarify the issues and, in particular, address the allowable inferences if a pill-placebo case management group is included in a psychotherapeutic trial.

This particular design problem achieved recent prominence in the controversies over the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (TDCRP). This study was first contemplated in the late 1970s to compare interpersonal psychotherapy and cognitiveâ?”behavioral therapy in the treatment of major depression. However, the NIMH Scientific Advisory Committee to the TDCRP concluded that this simple comparison did not disconfirm the alternative explanatory hypotheses that all benefits were the result of placebo effects or spontaneous remission. Therefore, it was agreed that a standard reference treatment was necessary. Imipramine, which had been confirmed by many placebo-controlled trials, as well as clinical practice, was chosen. Because this treatment was to represent pharmacological care, the provision of medication was embedded in a case management format that eschewed any formal psychotherapeutic intervention. This yielded the opportunity to assess the relative merits, and perhaps the comparative indicators, of these different classes of treatment. This was clearly of public health importance.

However, imipramine had not, in all trials, been uniformly superior to placebo, and it was suspected that patients with atypical depression might be imipramine refractory. Therefore, to establish that the sample was actually imipramine responsive (which allows generalization of psychotherapy effects to the relevant population in which psychotherapy and medication may be fruitfully compared), it was necessary to include a pill-placebo case management treatment arm. This served as an internal calibration demonstrating good medication practices, as well as a medication treatable sample, and thus allowed generalization of the psychotherapy benefits to a medication-appropriate population.

However, there was an immediate conflict as to the legitimacy of comparing psychotherapeutic effects to pill-placebo case management outcome. How could these results be interpreted when it was evident that the treatments differed in multiple ways? Some argued that the only legitimate contrast with the placebo group was the imipramine group and that the placebo versus psychotherapy contrasts were invalidated by multiple confounds.

Explanatory Versus Pragmatic Trials
The role of pill-placebo case management can also be framed in terms of Schwartz and Lellouchâ?Ts (1967) distinction between explanatory and pragmatic trials. The objective of the explanatory trial is to gain knowledge of whether a pharmacological benefit exists and to acquire an estimate of the effect size attributable directly to the active ingredient in this experimental setting. In pragmatic trials, the intent is simply to make a costâ?”benefit decision. This last approach is emphasized in outcomes research. The outcomes approach argues that if complex Treatment A is better (costâ?”benefit) than complex Treatment B in apparently similar groups of patients, why should there be concern about narrow questions of causal allocation? Letâ?Ts use A and discard B.

The term pragmatic has a reassuring, practical quality. Those involved in actually delivering services are continually reminded of the need to be practical, that is, to minimize cost. There are different strategies adoptable in pragmatic interests. For instance, researchers can relentlessly pursue a series of dismantling studies, progressively paring down the expenses of the treatment while investigating whether comparable outcome quality is achieved. This is neither simple nor quick.

A psychotherapeutic comparison with pill placebo in this framework might be considered the most radical sort of dismantling pragmatic trial. It results in the same causal ambiguities, but if the null hypothesis cannot be disconfirmed in a sufficiently powerful trial, then the expensive, lengthy procedures of a series of progressive dismantling trials can be avoided.

It is extraordinarily difficult, in the context of psychotherapy, to develop true explanatory clinical trials. This may be the reason that researchers invested in understanding the mechanisms of inducing psychotherapeutic benefit often pursue so-called process analyses. The intention is to demonstrate, on an individual longitudinal basis, that certain interventions, or attitudes, or interactions regularly precede therapeutic progress. The explanatory goal is to gain causal information with the hope of eventually improving practice. The major problem, of course, is that a heavy investment in understanding process, without an assurance that one is studying a treatment that contains characteristic effective therapeutic ingredients, puts the cart before the horse.

We have the peculiar situation in which the pill-placebo case management control, in the context of a pharmacotherapeutic clinical trial, yields an explanatory test with pragmatic implications. In contrast, the pill-placebo case management control in the context of a psychotherapeutic clinical trial does not allow a simple causal inference but nonetheless is an ultrapragmatic strategy.

Model of Placebo, Characteristic Treatment, and Incidental Variables
Following Basham (1986) and Grunbaum (1986), let E represent the sum of all extraneous factors, balanced across conditions through the use of random assignment, and let T represent the sum of all factors present in the formal treatment. The natural course of the illness, including spontaneous improvement or deterioration, is subsumed in E, so that the absence of treatment equals E. The total effect of treatment equals E + T. D represents the demand characteristics associated with treatment or placement in a control condition. Demand characteristics, as defined by Orne (1962), consist of the patientâ?Ts knowledge, expectations, and intentions regarding an experimental situation and, in this case, the process of psychotherapy. This results in an artifact that does not reflect the efficacy of the hypothesized treatment factors.

Then let us expand the notation to encompass patientsâ?T reaction to being placed in the experimental treatment and wait-list control settings. The deferring of treatment during a wait-list control equals E + DC, where DC represents all demand artifacts (patient reactions and expectancies) resulting from being placed in the wait-list condition. In the active treatment, it is noted that T now includes DT, which represents the analogous treatment condition artifact. Both DC and DT can be either negative or positive. Table 1 provides a summary of the variables used in the model.

Table 1
Summary of Variables Used in Model Notation Variable Definition
E All extraneous factors
T All factors in formal treatment
TS Characteristic-specific treatment factors
TNS Nonspecific treatment factors
D Demand characteristics
DC Wait list
DT Treatment
DP Pill

Basham (1986, p. 89) critiqued the all too common use of the so-called waiting-list control in psychotherapy as follows:

At the start of the study, subjects read and sign a consent form telling them they will be participating in a study and will be randomly assigned to either a delayed or immediate treatment condition. Having thus been informed they are in an experiment, subjects are likely to develop condition-specific expectancies about whether or not they will improve. Most likely, the subjects in the immediate treatment condition develop an increased expectancy of improving, whereas subjects in the waiting-list condition develop a reduced expectancy of improving and may be further demoralized by having received the less preferred condition.

Therefore, DC does not equal DT, and the net effect of these two artifacts is fully confounded with the effects of treatment. If a treatment is superior to wait list, it may simply indicate that DT is superior to DC, as seems very likely.

In the pharmacological situation, DC and DT are equated by the use of pill placebo and double blinding. With double blinding, neither subjects nor evaluators are aware of what is taken, thus equating subjectsâ?T and evaluatorsâ?T expectancies among the various treatments. If the measure is objective (e.g., the number of dollars earned), the need for evaluator blinding decreases. When the evaluator is also the therapist, the blind is often broken. Therefore, independent blinded evaluations and objective measures are extremely desirable in both pharmacotherapy and psychotherapy trials.

In the pharmacological placebo-controlled design, in contrast to the wait-list design, we subdivide T by defining DP as the demand artifact associated with receiving a pill, TNS as the incidental treatment factors, and TS as the sought-for characteristic treatment factor. We then have placebo effect = E + DP + TNS, whereas treatment = E + DP + TNS + TS. Therefore, one can, by subtraction, allocate the treatment effect to TS, which produces the differential outcome, if any.

Psychotherapy Designs
Much of the debate over placebos in psychotherapy research is the result of theoretical and terminological ambiguity. Critelli and Neumann (1984) stated that “placebo” is not clearly defined. Commonly, following pharmacological practice, it is defined as an inert agent, but in the psychotherapeutic context this is misleading. The use of placebos, both pharmacological and psychological, rests on the fact that they are not inert, because they affect subjects’ perceptions, reactions, and expectancies; however, they are also not specific in the sense of requiring a particular component. (One might argue that they are specific in the sense that their efficacy is uniformly due to alleviating a particular antecedent patient characteristic: demoralization.). Critelli and Neumann argued that the concept of placebo is best understood in terms of the common factors associated with various types of therapy, such as expectancy, contact with a therapist, and therapeutic alliance.

Grunbaum (1986) criticized Critelli and Neumann (1984) for their conceptualization of placebo as the common factors in therapy because different therapies can share characteristic causal treatment components (including unrecognized ones). He distinguished characteristic factors, which are the hypothesized effective treatment components, from incidental factors, which include demand characteristics.

The control group in an experimental design is an intentional placebo controlling for demand characteristics and spontaneous worsening or improvement. Two different therapies compared with a placebo (composed of incidental factors) could both prove effective even if active ingredients are common to both therapies. The placebo is crucial in demonstrating that the improvement is not the result of the incidental aspects of treatment. Thus, the claim that placebos are only necessary to delineate particular specific mechanisms is untrue (Horvath, 1988; Wilkins, 1986) because with complex treatments the therapeutic mechanisms often remain obscure.

In psychotherapy research, the psychological placebo equivalent would be a psychological intervention that was inactive with regard to the theoretically defined active ingredients of the treatment (e.g., relaxation for Pavlovian desensitization). Pill placebos and psychological placebos seem to estimate the same effect, but pill placebos have an advantage because psychological placebos are only declared placebos by dubious, theoretical fiat (Horvath, 1988). Further, placebo = E + DP + TNS, but treatment = E + DT + TNS + TS. The difference equals (DT – DP) + TS. Unfortunately, the demand characteristics cannot be equated by double blinding. Therefore, comparison of a psychotherapy with a supposed psychotherapy placebo does not unequivocally estimate a characteristic benefit, despite assumptions to this effect.

The demand characteristics associated with treatment may well differ from the demand characteristics associated with the placebo treatment, especially if the placebo treatment is of poor credibility, thus lowering DP. This confounds the detection of a characteristic treatment effect. Further, there is the lingering suspicion that the constructed psychological placebo may actually include theoretically irrelevant but unrecognized actually beneficial or even toxic components, which cannot be the case with pill placebo. The construction of a psychotherapy placebo (including only incidental factors) is no mean feat. As Adair, Sharp, and Huynh (1990) showed, one can classify different groups of supposed placebos and show a range of effects relative to no treatment. Heimberg and Liebowitz (unpublished data) found that pill placebo appeared more effective on non-self-measures than what was considered a psychological placebo, but the reverse was true from patient self-ratings.

Basham (1986, p. 88) stated that

it is crucial in terms of the experimentâ?Ts internal validity that the treatment factors contained in the placebo group are strictly a subset of the factors in the total treatment. If such a component control condition is not used, the placebo group is no longer a formal control group, and valid statements about the causal role of specific treatment factors can no longer be made.

This is entirely correct with regard to explanatory trials.

Therefore, Basham (1986) recommended moving to comparing (pragmatically) putatively active treatments. This changes the question “Does it work?” to relative questions such as “Which works best?” or “How do they differ?” or “Which should I use?” Including demand artifacts and differentiating nonspecific from specific treatment factors, we have the following: Treatment A = E + DT +TNS +TS(A) and Treatment B = E + DT + TNS + TS(B). This amounts to estimating the relative difference between the two active agents TS(A) and TS(B). However, this assumes, probably incorrectly, equal demand characteristics, that is, DT(A) = DT(B).

Bashamâ?Ts (1986) argument for comparative studies is precisely the argument made by Klein and Rabkin (1984). Given the difficulty in constructing a psychological placebo, one should first find a difference between two credible, putatively active therapies and then pursue dismantling studies in an attempt to arrive at causal mechanisms (or the least costly treatment that yields equivalent benefits).

However, this may be unsatisfactory because for many psychotherapies the entire motor of change may be the common antidemoralizing aspects of therapy (e.g., providing a prestigious ally, a framework for understanding, prescribing what are claimed to be effective activities, and in general raising hope). That is, there is no TS. Therefore, even if several studies show that Treatment A is equivalent to Treatment B, there is still no basis to assert that they are doing anything beyond antidemoralization (E + DT + TNS). Worse, even if Psychotherapy A is better than Psychotherapy B, it may be that in this sample, Psychotherapy B has toxic components (DT(A) is not equal to DT(B)) such as relaxation for panic disorder (Heide &amp; Borkovec, 1984). There is no assurance that the superior Treatment A possesses any specific benefits (TS(A)), although the pragmatist may discard Treatment B.

Comparison of Psychotherapy to Pill Placebo
This brings us back to pill placebo, which has no pharmacological activity, either toxic or beneficial. As before, pill placebo = E + DP + TNS, and Psychotherapy A = E + DT + TNS + TS(A). The difference between psychotherapy and pill placebo equals TS(A) + (DT – DP). If psychotherapy is better than pill placebo, we cannot attribute this difference solely to TS(A) because it might be due to the difference between DT and DP.

In fact, this is exactly the same equation developed for the difference between psychotherapy and a putative psychotherapy placebo. Comparative psychotherapeutic studies are no more causally stringent than comparisons of pill placebo with psychotherapy.

I believe that both logic and concern for the public health suggest that psychotherapeutic evaluations be conducted jointly with pharmacologic evaluations. The advantage is two-fold. First, pill placebo cannot contain any unsuspected active factors (positive or negative). Second, for patients who accept the utility of pharmacotherapy, credibility is assured.

The scientific goal of unequivocal causal attribution is not met, but what about the pragmatic, evaluative goal? It would be reassuring if a psychotherapy is clearly superior to pill placebo because it is unlikely that DT is much superior to DP, which implies a beneficial psychotherapy effect over and above placebo effects.

However, what if psychotherapy proves no better than pill placebo? What can be said then? Again, no unequivocal causal allocation can be made, but if one wants to maintain that TS(A) was actually effective, one would have to unreasonably maintain that DP – DT approximates TS(A). At any rate, who would be comfortable in promulgating a psychotherapy that could not beat pill-placebo case management? Therefore, in the context of comparing pharmacotherapy and psychotherapy, pill-placebo case management provides a useful, pragmatic, understandable benchmark.

Dush (1986) objected to additive models, such as this one, that include main effects for the therapeutic context posited to exist for both placebo and active treatment groups and estimates main effects by taking the difference in group outcomes. Dush argued that treatment Ã- situation interactions, such as a placebo Ã- setting effect, should be included in the model. Because it is impossible to separate treatment main effects from the treatment Ã- situation interactions, one cannot properly analyze the data. (This is not a logical necessity but an ethical problem because the surreptitious administration of medication would eliminate this confound in pharmacotherapy trials.)

However, treatment Ã- situation interactions can be reasonably regarded as part of the treatment effects because the therapeutic situation is a component of the treatment. Crucially, neither the main effects nor the interactions would appear without an active agent. If it can be concluded that the treatment is superior to placebo, what pragmatic or explanatory difference does it make if drug superiority is part main effect and part interaction?

Just as in the case of a two-way analysis of variance with one observation per cell, in which row Ã- column interactions and within-cell error are subsumed under error because they cannot be separated, it seems reasonable to subsume both treatment main effects and interactions under the concept of treatment effects. Therefore, Dushâ?Ts (1986) critique does not invalidate the present model. It does point out that treatment context may be of consequence and is subject to further study. Stratifying for varying treatment contexts may provide useful information.

Simply comparing two psychotherapies does not address the alternative explanatory hypotheses that all apparently equivalent improvement is due to spontaneous remission or placebo effect. This discussion affirms that psychotherapeutic evaluation against a so-called wait-list control is grossly misleading. Further, pragmatic differences between psychotherapies may be due to different demand characteristics rather than differences in characteristic efficacies.

Simply comparing a new treatment to a so-called standard treatment is so vulnerable to sampling definitions and variability that it is quite possible that the sample selected is unsuitable for the standard treatment. If the new putative treatment was equivalent to the “standard” treatment in this sample, it would simply indicate equivalent inefficacy. But this would be untestable in this experimental design. (This is discussed elsewhere; see Klein, 1995; Rothman &amp; Michels, 1994.) Internal placebo calibration is necessary.

The proliferation of psychotherapy studies against wait-list or other incredible controls should be stemmed or at best considered hypothesis generating rather than hypothesis testing. The TDCRP design (psychotherapy, pharmacotherapy, pill-placebo case management) should serve as a minimum contemporary standard for definitive trials in the important area of comparative therapies. It may be amplified by a specified psychotherapy placebo. Deviations from this design require explanation and justification rather than a bland assumption that the alternative hypotheses to characteristic treatment effect have been adequately met. Amplifying this design to include a combination psychotherapy and medication treatment, various sequential treatments, or well described treatments as usually provided in clinical practice would be of great pragmatic value.

Adair, J. G., Sharpe, D., &amp; Huynh, C. L. (1990). The placebo control group: An analysis of its effectiveness in educational research. Journal of Experimental Education, 59, 67â?”86.

Basham, R. B. (1986). Scientific and practical advantages of comparative design in psychotherapy outcome research. Journal of Consulting &amp; Clinical Psychology, 54, 8â?”94.

Critelli, J. W., &amp; Neumann, K. F. (1984). The placebo: Conceptual analysis of a construct in transition. American Psychologist, 39, 32â?”39.

Dush, D. M. (1986). The placebo in psychosocial outcome evaluations. Evaluation &amp; The Health Professions, 9, 421â?”438.

Eysenck, H. J. (1952). The effects of psychotherapy: An evaluation. Journal of Consulting Psychology, 16, 319â?”324.

Frank, J. D. (1961). Persuasion and healing. Baltimore, MD: Johns Hopkins University Press.

Grunbaum, A. (1986). The placebo concept in medicine and psychiatry. Psychological Medicine, 16, 19â?”38.

Heide, F. J., &amp; Borkovec, T. D. (1984). Relaxation-induced anxiety: Mechanisms and theoretical implications. Behaviour Research &amp; Therapy, 22, 1â?”12.

Horvath, P. (1988). Placebos and common factors in two decades of psychotherapy research. Psychological Bulletin, 104, 214â?”225.

Klein, D. F. (1995). Response to Rothman and Michels on placebo-controlled clinical trials. Psychiatric Annals, 25, 401â?”403.

Klein, D. F., &amp; Rabkin, J. G. (1984). Specificity and strategy in psychotherapy research and practice. In J. Williams &amp; R. Spitzer (Eds.), Psychotherapy research: Where are we and where should we go? New York: Guilford Press.

Orne, M. T. (1962). Implications for psychotherapy derived from current research on the nature of hypnosis. American Journal of Psychiatry, 118, 1097â?”1103.

Rothman, K. F., &amp; Michels, K. D. (1994). The continuing unethical use of placebo controls. The New England Journal of Medicine, 331, 394â?”398.

Schwartz, D., &amp; Lellouch, J. (1967). Explanatory and pragmatic attitudes in therapeutical trials. Journal of Chronic Diseases, 20, 637â?”648.

Wilkins, W. (1986). Placebo problems in psychotherapy research: Socialâ?”psychological alternatives to chemotherapy concepts. American Psychologist, 41, 551â?”556.


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Executive strategy reports


Executive strategy reports

Using electronic data capture to improve the outcome of clinical trials
By Colin Spink

Summary Executive overview Business benefits A strategic approach to EDC Conclusion
A strategic approach to EDC 1| 2 | 3 | 4

A Strategic Approach to EDC
Pharmaceutical companies must take a strategic approach to the deployment of EDC to achieve significant, long-term business advantage. This must embrace both a new culture and corporate processes so they can exploit EDC to attain commercial benefit.

A strategic implementation of EDC ensures that it is both implemented in tandem with other corporate objectives and that senior sponsors play a role in instigating the necessary process and organizational change. It also ensures that the EDC technology is integrated into the corporate IT infrastructure to enable rapid access to clinical trials information throughout the company, which drives new business processes. The strategy should also encompass not only today’s technology, but envision how future developments will potentially impact the clinical trial process. Considerations for the future include:
Managing by exception will enable CRAs or DMs to focus only on the areas flagged as problems by the software.
Direct data entry should remove reliance on paper-based records and eliminate the need for Source Data Verification (SDV). There are regulatory issues associated with direct data entry: source data must be kept and archived at site and it must be possible to differentiate the data that has been entered directly and that which has not. Some companies are encouraging direct entry of data — indeed, a recent survey undertaken by Silico Research on behalf of IBM and others revealed that 22 percent of participants were entering data directly into the EDC system.
Pharmaceutical companies must take a strategic approach to the deployment of EDC in order to achieve significant, long-term business advantage.
The use of wireless devices, by physicians or patients themselves, is becoming more prevalent and will have implications for usage patterns.
EDC software also needs to link into Customer Relationship Management (CRM) solutions to ensure the sales force knows when visiting doctors, whether they are participating in trials, so they can leverage the existing commercial relationship.


Implementing the strategy
Once a strategy has been agreed there are four key areas that need to be addressed to ensure a successful wide-scale EDC deployment: Technology, Logistics, Process Change and Organizational Change.

Key success factors include ensuring a high level sponsor and addressing each of these areas in unison, not sequentially. EDC pilots are useful in facilitating user acceptance and enabling processes to be trialled. Companies can choose a limited, low-key pilot study to minimize risk although high profile pilot studies will raise awareness of the technology and ultimately bring greater rewards. Additionally, it is important to collect metrics to demonstrate the benefits of EDC. Ideally these should be collected for both traditional paper-based processes and EDC implementations to measure improvements.

Regulatory compliance — such as Food &amp; Drug Administration (FDA) compliance is essential and will influence each of the four key areas. Under the FDA compliance requirements, implementation of EDC has to meet 21CFR part 11. Both software and Information Technology (IT) infrastructure need to satisfy specific requirements of 21CFR part 11 and all processes should be documented to ensure they can be audited by the FDA.

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Moving into the 21st century


Moving into the 21st century
Digital source documents and casebooks lead the way.
Clinical research in the United States has been conducted more or less the same way for decades. Regardless of the type and phase of the study, the therapeutic area, and the specifics of a trial, the nuts and bolts of human research are well established and rigidly consistent. A clinical research study is conducted according to the following general outline:

An investigative site is chosen to recruit patients into an approved trial.
After patients give their consent, the investigative centers (sites) enroll them into trials.
The sites conduct assessments, evaluations, and laboratory analyses according to the study protocol.
Data are recorded in source documents and transcribed later by a coordinator into the study-specific case report form (CRF).
A monitor compares each data point in the CRF with the source record.
The monitor then ships a paper copy of the CRF to a central data management center (per FDA regulations, the site maintains the original source documents and a copy of the CRF).
For accuracy, data-entry technicians double-enter each data point into a clinical database.
A computerized review of the database then generates queries about data inconsistencies, missing information, and incomplete entries. The monitor resolves the queries with the site.
Data-entry technicians double-enter the resolutions.
Another computerized review occurs, and the reviewâ?”queryâ?”resolution loop continues until the data are â?ocleanâ?ť.
Finally, the database is transferred to the clinical statistician for analysis.
The clinical research process just outlined is slow, tedious, and expensive. As a result, pharmaceutical companies seek ways to reduce the time and expense mandated by research practice. One such attempt involves the use of new, computerized recording and transmitting devices. These technologies are increasingly sophisticated and offer the satisfying possibility of cost and time savings. They also introduce new concerns for research monitors, auditors, and record keepers.

Electronic sources
Source documents can be entered electronically as a result of the advent of inexpensive portable handheld devices. These devices contain simple software that can capture the notes a researcher would normally scribble on paper during a patient examination. Many of them also contain study-specific software to prompt the investigative personnel with fill-in-the-blank style questionnaires.

The advantages of maintaining source documents electronically are obvious: Researchers can immediately review, search, and organize the entered data. Virtual documents also accurately store information about when the data were collected and by whom. (This latter point means that an audit trail is ensured.) Finally, the data can be printed or stored with relative ease.

Unfortunately, the use of portable electronic devices raises two issues of concern about data integrity. The first issue is the possibility of data errors. For example, a researcher is more likely to transpose or mis-enter the numbers in a blood pressure reading when keying into an electronic notebook than when writing onto a paper one. The second integrity issue relates to storage. The FDA requires that each site maintain the original source documents for a study, and so keeping data on a battery-powered device may be problematic.

The solutions to these two problems require a certain level of diligence on the part of the investigative site. Data errors can be caught if the data are reviewed immediately, but patient appointment schedules and other time constraints may make this difficult. Some software programs, however, check for odd entries and query them in real time (e.g., entering a patientâ?Ts date of birth as May 32 would be disallowed).

In terms of record maintenance, the FDA considers a computer hard drive sufficient for â?opermanentâ?ť storage, so researchers must routinely download the patient data from the handheld devices.

Patient input
Many research trials include a patient diary, diary card, or other form of participant-recorded evaluation. Here again, portable handheld devices are a possibilityâ?”although their use is still minimal because of associated costs.

The advantages and disadvantages of giving patients electronic diaries are identical to those related to computerized source documents. Some additional advantages exist, however. Patients are less likely to mis-enter the kind of personal data commonly collected in diaries (e.g., patients may be asked to rateâ?”on a graphical scaleâ?”how they feel each morning immediately before dosing); and errors that result from a coordinator misunderstanding, misinterpreting, or incorrectly transcribing patient responses into the CRF are eliminated.

The digital casebook
The most significant advance in clinical research practice is the use of computerized CRFs. These fall into two categories: stand-alone and Web-based. The former involves entering data into a computer-based casebook that is subsequently collected on disk or transmitted electronically to the data management center for review. The second category involves a virtual CRF, maintained on a secure Web site in which investigative centers enter and submit their data directly. In both cases, copies of the completed CRFs can be maintained as hard copies or electronic files.

Virtual CRFs have significant advantages, and for simplicity and cost-effectiveness, Web-based casebooks are best. In fact, the only real disadvantages involve security and storage issues. But the reasons in favor of using Web-based CRFs are significant and include the following:

Coordinators can receive instant feedback when entries are incomplete, inconsistent with previously recorded data, or do not match the required form of the database (e.g., a year is entered as 98 when the database mandates a four-digit entry). In these cases, instant feedback reduces the number of reviewâ?”queryâ?”resolution loops and eliminates the need for data-entry technicians to double-enter all collected research data.
Computerized CRFs are easily searched, reviewed, and audited.
If electronic source documents are used, then an algorithm that inserts the data into the appropriate places in the CRF can reduce the amount of time a coordinator spends on the project and improve the accuracy of the captured information.
Complex queriesâ?”those generated by human CRF reviewers at the data management centerâ?”can be forwarded electronically to the sites, and the coordinators can resolve them directly. This process avoids the need for data-entry technicians and guarantees that the changes a coordinator makes to the dataset are consistent with the existing database (i.e., changes to the database are reviewed and then queried, if necessary, upon submission).
Virtual CRFs can capture vital accountability information, such as when and by whom an entry is made or changed. Furthermore, new regulations make it possible to submit electronic signatures that guarantee that the FDA-required investigator review and approval process occurs for each dataset.
A monitoring perspective
Monitors, who must travel to the sites to review the CRFs for accuracy and completeness, are big winners in the transition to Web-based clinical trials. In particular, sites that combine electronic devices for patient self-evaluations with computerized source documents and virtual CRFs reduce the need for extensive visits. In addition, the work that a monitor must accomplish during a site visit is dramatically altered; monitors need no longer spend time separating copies of CRFs and shipping them off for analysis. Furthermore, the elimination or reduction of the tedious and time-consuming reviewâ?”queryâ?”resolution loop is a blessing. (Note that even with data collected virtually, travel is still a part of the monitorâ?Ts job because other types of in-person review and site training are necessary.)

Many Web-based trial systems also offer important diagnostic and (rudimentary) statistical data reviews, which can help monitors identify problems before they become significant. For example, knowing the number and type of queries that each site addresses may help monitors assess an individual siteâ?Ts training needs. Furthermore, these diagnostics can help pinpoint research centers that may become targets for FDA audits (e.g., centers with high patient enrollment or significant participant dropout rates).

Most important, having a wealth of summary information available for each site can help identify those that may be engaged in negligent or fraudulent behavior. For example, a warning message may be sent automatically to the monitor of a site if the data submitted by that site are entered at unusual times, such as 2 a.m. on a Sunday morning.

The big picture
Electronic CRFs were first designed roughly ten years ago. Their implementation, however, met with numerous problems: Sites needed to be provided with computer systems that were often costly, security issues were significant, data storage was a concern, and no means of obtaining an electronic signature was legally allowed. Thus, the few companies who made the technological leap were disappointed. They found that new layers of documentation and paperwork were introduced, cost outlays undercut most potential benefits, and time savings were insignificant.

Changes in regulations, coupled with technological advances, however, have dramatically altered the playing field. Today, companies like Phase Forward, eResearch Technology, and Databean offer researchers the beneficial features of electronic information gathering as well as functions such as investigator referrals, patient schedulers, and individualized consulting services. The benefits of electronic systems thus include lower costs, enhanced data quality, and improved research speeds. As companies that specialize in gathering data electronically for clinical trials expand and make deals (e.g., in May 2001, Eli Lilly chose Phase Forward as its standard platform provider for Web-based trials), the future of virtual research is assured.

(For more information on the clinical uses of personal digital assistants (PDAs), see “Rx for PDAs”, Modern Drug Discovery, January 2002.)

Cullen T. Vogelson is a former assistant editor of Modern Drug Discovery. He writes and teaches in northern California. Send your comments or questions regarding this article to [email protected] or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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