Declaration of Helsinki, 2008: Implications for stakeholders in researchKS Puri, KR Suresh, NJ Gogtay, UM Thatte
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, India
The Declaration of Helsinki (DoH) was adopted by the World Medical Association (WMA) in 1964, as a statement of ethical principles, to provide guidance to physicians and other participants in medical research involving human subjects. Having undergone several amendments, the most recent version was approved on 18 October 2008, by the WMA General Assembly at Seoul, South Korea, replacing all previous versions. This version highlights issues such as, participant safety, the need to include participants from otherwise underrepresented groups, clinical trial registration, post-study access, usage of data and human tissues, compensating participants with research-related injury, and usage of placebo.
Keywords: Clinical trial registration, compensation, post-study access, research ethics, revised declaration of Helsinki
The Declaration of Helsinki  (DoH) was adopted by the World Medical Association (WMA) in 1964, as a statement of ethical principles, to provide guidance to physicians and other participants in medical research involving human subjects. The WMA  was established in 1947, after the Second World War, in reaction to the atrocities committed by Nazi physicians and is today a global body with 85 national medical associations (including the Indian Medical Association) representing approximately eight million physicians. 
The DoH is a global ethical standard for medical research and was approved at the WMA General Assembly by a majority vote of 75%, after extensive public debate. Almost all ethical guidelines such as, the Council for International Organizations of Medical Science  (CIOMS); the International Ethical Guidelines for Biomedical Research Involving Human Subjects, 2002; the International Conference on Harmonisation - Good Clinical Practices  (ICH-GCP) Guidelines, 1996; the Amended Schedule Y;  and the Indian Council of Medical Research (ICMR) Ethical Guidelines for Biomedical Research on Human Participants,  have their origins in the principles of the DoH.
Historically, many guidelines have been developed following a public outcry against research atrocities (e.g., the Nuremberg Code following the Nazi tribunal and the Belmont Report following the Tuskegee scandal). Although the DoH may find its origins in the Nazi disaster, it has undergone several modifications over time as research ethics have evolved. Thus, significant additions were made in 1975, followed by minor amendments in 1983, 1989, and 1996. A major revision and reorganization was completed in 2000, at Edinburgh, where the use of placebos was specifically addressed. There were, however, many reactions to paragraph number 29 (regarding placebo). 
The process of revision of the DoH is a laborious one at that time involving many consultations and in this case began in May 2007, guided by a five member workgroup (Brazil, Germany, Japan, South Africa, and Sweden) with three rounds of stakeholder consultations. On 18 October, 2008, the WMA General Assembly meeting at Seoul, South Korea, overwhelmingly voted to adopt a completely new version. 
This new version addresses important points like emphasizing the need for providing access to research to otherwise underrepresented populations, registration of clinical trials, post-study access, and compensating subjects with research-related injuries, which have great implications for all stakeholders in clinical research today.  In this commentary we discuss the major highlights of the 2008 version and consider the ramifications.
Throughout all the versions of the Declaration, emphasis has always been given to the fact that, "it is the duty of the physician to promote and safeguard the health of patients". In the current version, the Declaration clearly specifies that this is also applicable to the "researcher physician". When a medical professional conducts research, his/her primary responsibility as a physician must not be in conflict with his/her scientific curiosity to find research answers, thus, his/her responsibility to safeguard the research participant's health and well-being is significantly enhanced.
The Declaration states that "populations that are underrepresented in medical research should be provided appropriate access to participation in research". This is important, as it clearly indicates the need to perform research among populations that otherwise would always enter the "exclusion criteria". For example, pregnant or lactating women, children, and the elderly, are often left out as they may be vulnerable. However, the absence of research (especially during the drug development process) suggests that it is often difficult to develop "evidence-based treatment guidelines" for these populations. Of course, the need to identify these participants as vulnerable and the necessity to have special protections in place remain as in the previous versions.
The older versions of the Declaration required continued research on current interventions for their effectiveness, efficiency, accessibility, and quality. However, the current version also highlights the need for continued research for their safety. This is relevant especially for drugs and devices, where the number of post-marketing recalls is increasing. The stories of the market recalls of rofecoxib  (recalled following the DSMB requirement to halt a clinical trial of the drug for a new indication due to safety concerns), and more recently rimonabant  (banned because of increased depression and suicidal attempts) illustrate the need for emphasis on safety during the clinical phases of drug development.
A disturbing aspect of the 2008 version of the Declaration is a missing sentence. The line, "the particular needs of the economically and medically disadvantaged must be recognized" has been removed from paragraph 9 (paragraph 8 in the 2004 version). In countries like India, where the reality is that patients often participate in research to get access to health care (in the absence of accessible and affordable health care, especially in therapeutic areas like oncology), recognizing the economically disadvantaged population as vulnerable is the need of the hour. The ICMRs Ethical Guidelines for Biomedical Research on Human Participants have clearly identified "persons who are economically or socially disadvantaged" as vulnerable and research in India should respect these guidelines. 
The need for having a well-defined research protocol has been described in the earlier versions of the Declaration. However, in this version the Declaration clarifies that each protocol must "indicate how the principles in this Declaration have been addressed". Designing a protocol is usually the responsibility of the sponsor/investigator, and a bland statement is often included that the trial will be conducted "in accordance with the Declaration of Helsinki". However, the systems that have been put in place to honor these statements are equally important, as emphasized in the current version.
Additionally, the current version states that a protocol must have "provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study." This is a very important inclusion. It is interesting to note that both the Amended Schedule Y  and ICMR Guidelines  have already described these aspects, and the ICMR in association with the Indian Society for Clinical Research (ISCR) and Forum for Ethics Review Committees in India (FERCI) have published draft guidelines for compensation of participants in case of research-related injuries.  In India, awareness and mechanisms of compensation to participants for research-related injuries  are inadequate and implementation of the guidelines will assist in honoring the DoH statement.
The aspect of post-trial access is often debated. The 2008 version of the DoH clearly states that "the protocol should describe arrangements for post-study access by study subjects to interventions identified as beneficial in the study or access to other appropriate care or benefits". Although this had found mention in the 2004 "Note of Clarification for Para 30", it has been now incorporated into para 14, emphasizing the need for a priori scheme for ensuring access to the intervention. All stakeholders in clinical research (including ethics committees who should consider this aspect while reviewing the proposal, regulators who should consider whether the intervention will be registered for public access in the country, the sponsor, and the investigator) must have a plan before initiating a trial.
Perhaps the strongest statement for transparency in the conduct of clinical trials comes in the form of Para 19, which requires that "every clinical trial must be registered in a publicly accessible database before recruitment of the first subject." As an extension to this point, the DoH in Para 30 goes on to say that "authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports" and that "they should adhere to accepted guidelines for ethical reporting".
Even before the 2008 DoH, the clinical research registration movement was strong, when the ICMJE (International Committee of Medical Journal Editors)  issued a statement that, commencing from July 2005, registration of a trial would be mandatory before it could be considered for publication in any of the 12 member journals. In India, the Clinical Trials Registry - India (CTRI),  the first such initiative in Asia, was launched by the ICMR's National Institute of Medical Statistics (NIMS) on 20 July, 2007. Any researcher who plans to conduct a drug trial on humans is expected to declare the details of the research in this registry, which is jointly funded by the Department of Science and Technology, WHO, and ICMR.
Although, according to the DoH, clinical trial registration is mandatory before recruitment of the first volunteer in a trial in India and elsewhere too; registration remains largely voluntary at present. Interestingly, out of a total of 67426 clinical trials registered at www.clinicaltrials.gov from161 countries, 901 are Indian trials accounting for hardly 1.3% of all registered trials. Of the 901 trials, there are 59 oncology studies. The CTRI has only 13 oncology trials registered. Obviously, the concept of registration is still nascent and there is a need for all stakeholders including sponsors, Ethics Committees, and investigators to consider implementing the DoH requirement of clinical trial registration.  As a step to increase transparency, 12 Indian medical journals (including the Journal of Post Graduate Medicine) have issued a policy that from January 2010, results of a clinical trial will be accepted for publication only if the trial has been registered at CTRI (or any other equivalent registry), if started in or after June 2008. 
The issue of obtaining voluntary informed consent from a potential research participant has been mentioned in the ethics guidelines right from the Nuremberg Code.  Earlier versions of the DoH have also mentioned that participation in research should be voluntary and informed. The current version, however, goes one step further, making a clear statement about the need to honor the autonomy of the participant. If, as said in Para 22 of the guidelines, the participant is competent to give consent (legally or medically), he/she should not be included without his/her (informed and voluntary) consent. Although not disallowing family or community consultation, the guideline clearly requires that the individual's autonomy be respected. The implementation of this guideline extends not only in the design of the consent forms, but also to the ethics committees, which must review and approve the consent procedure from this point of view, and more importantly, at the time of actual consenting.
Para 24 demands that special attention be given to the fact that the specific information needs of a participant are conveyed in an understandable manner. Although this was not present in the earlier versions, both Schedule Y and ICMR Guidelines have already anticipated this guideline, in that, translations in the vernacular are required to make the information understandable in the local context.
Para 25 is an entirely new and topically relevant feature. It applies to "medical research using identifiable human material or data" and clarifies clearly that "researchers must seek consent for collection, analysis, storage, and/or reuse of data". Whenever a consent waiver is sought, the DoH states that this may be done only after the research is reviewed and approved by a research ethics committee. The ICMR Guidelines have also very succinctly described the conditions when a consent waiver may be given and Ethics Committees and Investigators should honor this guideline in both word and spirit.
The new DoH (Para 31) allows a physician to also be a researcher only if he is convinced of the potential benefit and that participation in the study will not adversely affect the health of the patients who serve as research subjects. This emphasis on the safety of the participant increases the responsibility of the investigator as well as that of the ethics committees.
The issue of placebo controlled trials continues to remain hotly debated,  with convincing arguments run by both "sides" of the deliberations. Historically the DoH was against the usage of placebo, but in 2002, in Washington, the usage of placebo was explained in a note of clarification. 
The current guideline clearly states that a placebo may be used only where no current proven intervention exists or where there are compelling and scientifically sound methodological reasons. There are two important riders on this statement: one that the patients who receive placebo or no treatment should not be subject to risk of serious or irreversible harm, and two, extreme care must be taken to avoid abuse of this option. The role of the ethics committees in ensuring implementation of these two points needs to be realised. The EC members need adequate expertise to review the justification put forth for the use of placebo and also to oversee that the participant is not at risk.
The last point that is worth noting in the revised DoH is Para 33, which states that "research participants are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits". We have already discussed that the DoH mentions the need for defining post-trial access in the protocol itself, before initiating the study. Informing participants of research results is possible through the registry. However, this statement does raise ethical problems when it comes to genetic research. 
The process of development of guidelines that influence research is as important as the guideline itself. In the case of the DoH, it is evident that as much attention has been paid to the process as to the final product itself. With contributions from many stakeholders, and genuine public debate, the 2008 version is another important contribution from the WMA. It is essential for everyone involved in research on humans, an ethics committee member, researcher, author, editor or reviewer, to read and internalize the principles laid down in the DoH, and this article has highlighted some of the major new aspects included, which may require revision by the Standard Operating Procedures (SOP), for planning, conduct, and reporting of clinical research.