The Impact of the Declaration of Helsinki
Eva Nilsson Bagenholm MD & Bev Holt MD
Session chaired by: Francis P Crawley
Reporter: Rachael Winter RICR
Keywords
Declaration of Helsinki, Moral responsibility, Research ethics, World Medical Association (WMA)
Francis Crawley opened this session by introducing the speakers. Dr Eva Nilsson Bagenholm, chair of the World Medical Association (WMA) ethics committee that produced the 2008 revision of the Declaration of Helsinki (DoH) and President of the Swedish Medical Association, would discuss the changes made to the DoH in the 2008 revision and their intended impact. Dr Bev Holt, of Quintiles would then speak about the relevance of the Declaration of Helsinki in today’s regulatory climate.
Francis then repeated the interesting, and perhaps surprising, result of voting that had taken place in an earlier plenary session. The audience was asked whether they agreed with the statement that the 2008 revisions to the Declaration of Helsinki would have a significant impact on clinical trials; 1% strongly agreed, 4% agreed, 14% neither agreed nor disagreed, 61% disagreed and 20% strongly disagreed.
Details of the 2008 revision
Dr Nilsson Bagenholm is a registered nurse and licensed physician specialising in internal medicine and is a council member and chairperson of the ethics committee of the WMA. She began by stating that she would discuss the DoH and the revision process that had taken place in the past two years, the revisions being approved in October 2008. Dr Nilsson Bagenholm stated that the DoH is a set of ethical principles for medical research involving human subjects and, as it will never be a set of guidelines, it should not be more detailed. The DoH was originally written by physicians for physicians, since it was this group that carried out most clinical research at that time. The 2008 revision encourages other professionals and organisations to adopt these principles.
Physicians should consider national and international ethical, legal and regulatory standards for research, but the protection of research subjects as set forth in the DoH should never be reduced or compromised by compliance with any of these standards.
Dr Nilsson Bagenholm then gave a brief history of the DoH, why it was developed shortly after World War II and why it was first adopted in 1964. Every 6-8 years since then the DoH has been revised to reflect current practices. Dr Nilsson Bagenholm therefore expects the next revision to be in 2015.
The 2008 revisions are classed as ‘minor’ revisions (although Francis Crawley would later contend that they are far more significant) and came about because the WMA noticed demand for greater transparency and stronger protection of research subjects. The WMA decided that they needed to identify gaps in the DoH, update specific areas, integrate the 2002 and 2004 notes of clarification (which have caused some confusion since their introduction) and finally to promote the DoH to increase awareness and discussion, particularly to ensure that the most current version is used.
The following specific areas of the DoH were then highlighted as the ones that had undergone revisions:
Duty of the physician & Research protocol
The duty of the physician in research is to protect the life, health, dignity, integrity, right to self-determination, privacy and confidentiality of personal information of the research subject. One issue discussed during the revision process was the importance of the research protocol. There is now a separate paragraph stating what the protocol must contain (paragraph 14). The protocol should state the ethical considerations involved and state how the principles in the DoH have been addressed. There must also be information regarding funding, affiliations and conflicts of interest, and the post-study arrangements should be documented, as these should be approved by the ethics committee.
Research Ethics Committee
The role of the ethics committee is clarified in this revision. The ethics committee should be independent of the researcher and the sponsor (and any other influence). The ethics committee should consider the protocol before the study begins (this is common practice but the WMA committee felt that this should be written in the DoH). Laws and regulations in the country or countries where the research is to be performed should be considered during ethical review. Finally, the ethics committee, not just the physicians and sponsors, must consider the DoH and the ethics committee must monitor ongoing studies.
Trial register
There is a new paragraph, which is an expansion of the previous text, which states that every clinical trial must be registered in a publicly accessible database before recruitment of the first subject. Dr Nilsson Bagenholm stated that this has been very controversial but she thinks it is very important in the protection of research subjects and to increase transparency in research.
Researcher
Dr Nilsson Bagenholm stated that that term ‘researcher’ is now used in addition to physician, as the WMA appreciates that there are many other professionals conducting research, not just doctors. Research on patients or healthy volunteers does, however, require the overall supervision of a qualified physician that is responsible for their care and protection. One clarification is that physicians must immediately stop a study if the risks are found to outweigh the benefits.
Subjects
All participation must be voluntary and privacy and confidentiality must be protected. Subjects must be fully informed of all benefits and risks and be free to withdraw at any time without reprisal. Informed consent must be freely given. Dr Nilsson Bagenholm stated that many of these points seem self-evident and are common sense, but they do need to be documented so that they can be followed.
Human material or data
There is a new paragraph on human material or data in the 2008 revision. The WMA thinks this is particularly important for epidemiological research, but also for other research.
Consent should be sought for medical research using identifiable human material or data (ie, collection, analysis, storage and reuse). The WMA recognises that obtaining such consent might sometimes be impossible or impractical, and such cases should be considered for approval by an ethics committee.
Publication
This paragraph has been reworded for clarity and emphasis. Authors, editors and publishers all have ethical obligations with regard to the publication of research results and authors have a duty to make research results publicly available and to ensure that such results are accurate and true. All conflicts of interest must be declared in publications.
Finally, Dr Nilsson Bagenholm stated that the following two paragraphs were the most controversial in the DoH:
Placebo
The WMA has incorporated the 2002 note of clarification but no change to the requirements have been made. The WMA hope that this is now very clear, but as this is the most controversial issue in the revisions and a separate vote was conducted at the council as to whether to include this paragraph or not, as it has been a contentious subject. The WMA has assigned a new working group to look at this subject to ensure that everyone understands what the DoH is stating.
Post-study arrangements
The 2004 note of clarification has been incorporated, and this section states that patients are entitled to be informed of the outcomes of the research and to share any benefits that come from the study (ie, beneficial interventions or other appropriate care or benefits). There must be arrangements for patients to benefit from the research (eg, continuing to receive a successful study drug) after the end of the study, but the DoH does not state who should fund this. Such arrangements must be stated in the protocol and reviewed by an ethics committee. If post-study arrangements are not considered adequate by the ethics committee, the study should not be approved and should not proceed.
Continuing relevance of the Declaration?
Dr Bev Holt of Quintiles was then introduced. Dr Holt began by posing the question of why does the DoH state what it does? He spoke about the Nuremberg code and the Nuremberg trials. Dr Holt stated that nothing much happened for about 10 years after the Nuremberg code and that doctors were continuing to do research on humans for their own reasons and without any form of consent. Doctors felt that they knew best and that patients should go along with their research because of this.
Shortly after, guidelines were produced by Royal College of Physicians, the UK Ministry of Health and the original Declaration of Helsinki was adopted. Then there was a gap and ethics committees were not formally required but drug companies were requesting ethics review, and journals were only willing to publish research that had received ethics approval. This eventually led to a formal requirement for ethics committees and national regulations such as the UK Medicines for Human Use Clinical Trials Regulations of 2004.
Then and now
Dr Holt then stated that since it was the 30th anniversary of the ICR conference, he would like to describe what a research study 30 years ago may have been like. There was no ethics review, no statistical input, the protocol would be written on one side of A4 paper. There was no case report form, school exercise books were used and mistakes were torn out or obscured under correction fluid! Negative findings were never reported or published and there was no monitoring, GP contact or patient follow up. Dr Holt stated that everything was the responsibility of the investigator and nothing much went wrong!
Today, moral responsibility has been transferred from the investigator to the ethics committee and the regulatory authority. There is a strong feeling that the Declaration is not relevant in today’s climate, as demonstrated by the voting earlier in the day. Legal requirements are numerous and include compliance with GCP, MHRA approval, ethics approval and so on. The investigator’s responsibilities are therefore much decreased and the main one is that they must look after the subjects. Dr Holt said he once heard an investigator say that he did not need to know how a drug worked because that was the responsibility of the ethics committee and the MHRA! He stated that this is obviously totally wrong, but highlights why we need to understand responsibilities so that nothing ‘falls into a gap’ because having multiple organisations in control can cause problems due to over-regulation and confusion. Dr Holt thinks that although the MHRA and ethics committees do an excellent job, the system may be at fault.
Dr Holt stated that above all of the legal and ethical requirements we must think about the patient. There is an enormous amount of bureaucracy and this can cause the system to fall down. Dr Holt quoted a letter to the Times published in January 2009, which stated that clinical trials in the UK have a huge regulatory burden which is destroying research in this county and that safety is not always increased by these regulations, as demonstrated by the Northwick Park incident. This incident came about due to multiple authorities not knowing quite who was doing what, leading to things being missed when one department thought another was covering aspects that they turned out not to be.
The future
So where do we go from here? More trials are being outsourced to Africa and Asia where people know that there is not so much regulation. Dr Holt suggests that the only way to protect the research subjects and yourself is to abide by the DoH. He thinks it has immense relevance and that the Northwick Park incident shows that regulations and laws cannot always be relied upon.
Dr Holt closed with the statement that “no amount of regulation, auditing or public accountability can detract from the fact that people are morally responsible for their own actions.”
Discussion
The floor was then opened for questions. One questioner asked whether the speakers felt that ICH GCP covered the same principles as the DoH, and so could be one document rather than two separate ones. Dr Nilsson Bagenholm stated that legal regulations and ethical principles should be two separate things. The DoH binds only the physician and some regulations do not like to refer to the DoH because of this so there is a need for both and there should be no controversy. They should be two separate documents that are used in conjunction. A point was then raised that agreed with Dr Nilsson Bagenholm, that since much research in the UK are not ‘clinical trials’ and so are not bound by the legal regulations, the Declaration of Helsinki is an important document to refer to.
Dr Eva Nilsson Bagenholm is President of the Swedish Medical Association and Chair of the World Medical Association ethics committee.
Dr Bev Holt is Consultant Research Physician and Principal Investigator at GDRU, Quintiles.
Francis P Crawley is Executive Director of the Good Clinical Practice Alliance.
Rachael Winter RICR is a CRA with Smith & Nephew Medical Ltd.
