Skipton House 80 London Road London SE1 6LH T: 020 797 22545 W: www.hra.nhs.uk

The Health Research Authority Response to the WMA Declaration of Helsinki Working Group Draft revised text for public consultation, 15 April – 15 June 2013 1. Introduction

1.1 The Health Research Authority (HRA) was established in December 2011 in England to promote and protect the interests of patients and the public in health research. We strive, with partners, to make sure the UK is a great place for health research. Recognising that many members of the public want the opportunity to participate in research, we aim to ensure that health research involving them is ethically reviewed and approved, that they are provided with the information that they need to help them decide whether they wish to take part, and that their opportunity to do so is maximised by simplifying the processes by which high quality research is assessed. In doing this, we will help to build both public confidence and participation in health research, and so improve the nation’s health. 1.2 In preparing this response the HRA has sought comments and advice from the National Research Ethics Advisors’ Panel (NREAP)1. The panel is comprised of 7 members including individuals with expertise in moral philosophy, research ethics committees (RECs), patient and public involvement and clinical research. The panel is independent but hosted within the HRA and is a resource available to all RECs, funded by the UK Health Departments, within England and the devolved nations. The panel’s primary role is to help research ethics committees deliver robust, consistent and fair decisions through and consultation with all stakeholders, including RECs.

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http://www.nres.nhs.uk/about-the-national-research-ethics-service/nrea/

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2. General Comments on Proposed Revisions to the Declaration

2.1 The Health Research Authority welcomes the opportunity to comment on the revision of the Declaration of Helsinki. The HRA are broadly supportive of the stated aims of this revision i.e.:     

Better readability by reorganising and restructuring the document with sub headings More protection for vulnerable groups More protection for participants by including the issue of compensation for the first time More precise and specific requirements for post-study arrangements A more systematic approach to the use of placebos, but no weakening of the ethics of placebo use

2.2 However, the HRA have a number of comments regarding the proposed changes: 

More protection for vulnerable groups:

2.3 Para 19: It is not clear, nor sufficiently justified, why there is reason to believe that some vulnerable populations would have an increased likelihood of “incurring additional and greater harm”. Such populations may have an increased likelihood of the same harm as a nonvulnerable population, but it does not follow that they would also have an increased likelihood of “additional and greater harm”. 2.4 Para 20: The phrase “Consideration should also be given to ensuring that the community receives a fair level of additional benefits” would benefit from clarification. This section would also benefit from further clarification of the terms “fair level” and “additional benefits”, which are currently not defined. 

More protection for participants by including the issue of compensation for the first time:

2.5 Paragraph 15 appears to introduce a global requirement for “no fault” compensation to be available for all medical research. Whilst the HRA are fully supportive of the provision of adequate compensation and treatment for subjects who are harmed as a consequence of their participation in research we do not understand this in terms of a comprehensive “no fault” compensation requirement. Rather, the HRA would expect a proportionate and appropriate view to be taken by research ethics committees of the remedies available to participants in the event that they suffer any harm during the conduct of the medical research, of which “no fault” compensation could be an appropriate solution.

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

More precise and specific requirements for post-study arrangements:

2.6 Post-trial access should always be an aspiration but there are often good reasons why it cannot or should not happen in practice. For example, the study drug may no longer be available, or it may not be possible to tell at the end of the patient’s treatment if the intervention is beneficial. The HRA believes that the provision of post-trial access following the completion of a study should be examined on a case-bycase basis, particularly in the light of the health care systems in operation within the relevant country in which the research is taking place. As the development of an intervention moves towards being licensed then the issue of post-trial access becomes less controversial as the efficacy of the product and risks associated with its use become better known. The HRA has issued guidance on this issue that illustrates the complexity of this issue: ‘Care after research’2. 

A more systematic approach to the use of placebos, but no weakening of the ethics of placebo use:

2.7 The statement that “…patients who receive any intervention less effective than the best proven one, placebo or no treatment will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention” is problematic. Any treatment less effective than the best proven treatment must, by definition, subject the patient to an additional risk that may result in serious or even irreversible harm. 2.8 Whilst we understand that the current wording (October 2008) on the use of placebo has prompted debate around whether the term "best current" should be understood globally or locally it is noted that the proposed new wording ("best proven") is necessarily global. However, this new wording creates two new problems: 1) Firstly, is it to be decided that something is "proven" or, more problematically, "best proven”? At what level in the hierarchy of evidence are we talking of ‘proof’? 2) Secondly, many treatments are only strictly understood as "proven" in very restricted populations, but nonetheless are used for much wider populations e.g. children, women and the elderly. Furthermore, some current treatments have been in use for so long that they have never, in any strict sense, been proven to be effective. If this change is introduced it would raise a whole new set of questions for research ethics committees to grapple with.

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“Care After Research: A Framework for NHS RECs” (19 December 2012). Available from http://www.nres.nhs.uk/applications/guidance/guidance-and-goodpractice/?1307152_entryid62=148568 HRA Response to the ‘WMA Declaration of Helsinki Working Group - Draft revised text for public consultation, 15 April – 15 June 2013’ – v1.0 June 2013

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

Paragraph 10:

2.9 The HRA prefer that the original wording contained in the Declaration i.e. “should” is retained rather than the use of the word “must”. 2.10 The stipulation that physicians "must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards” is welcome but this revision increases the existing tension between the Declaration (which requires that “No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration”) and existing national provisions for the ethical review of research, particularly in the absence of a clear definition of “medical research”. 2.11 The claim that the principles contained within the Declaration have primacy over all national and international laws and regulatory norms and standards is insufficiently justified. This claim creates practical difficulties where national legal and regulatory instruments do not require certain categories of research to be the subject of an application to a research ethics committee. This is made more problematic where national and international legal instruments incorporate specific reference to the Declaration of Helsinki. 

Paragraph 23: Research Ethics Committees:

2.12 It is unclear what the term “duly qualified” means when applied to ethics committees. If taken to apply to individual members then what would constitute a “duly qualified” lay member? Does it refer to the academic qualifications simply that members be qualified through their experience? If it refers to academic qualifications then does it apply to the committee as a whole (i.e. the committee should encompass sufficient qualifications among its members) or should every individual member have appropriate qualifications? 2.13 In the UK the competence of research ethics committee members is assured through an accreditation process3 undertaken every 3 years. This accreditation process includes an audit of REC members’ attendance and training to ensure that membership reflects the requirements of the Governance Arrangements for Research Ethics Committees (GAfREC)4. GAfREC requires that there is a broad range of experience and expertise, so that the scientific, clinical and methodological aspects of a research proposal can be reconciled with the welfare of research participants. GAfREC further requires that research ethics committees should contain a “mixture of people who reflect the currency of public opinion (‘lay’ members), as well as people who have relevant formal qualifications or professional experience that can help the REC understand particular aspects of research proposals (‘expert’ members)”. 2.14 3 4

The HRA, therefore, suggest the following wording for para 23:

HRA Accreditation Scheme for the audit and continuing assessment of NRES RECS and REC Centres (May 2010) https://www.gov.uk/government/publications/health-research-ethics-committees-governance-arrangements

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‘This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must contain a mixture of people who reflect the currency of public opinion, as well as people who have relevant formal qualifications or professional experience that can help the REC understand particular aspects of research proposals’. 

Paragraph 37: Unproven Interventions:

2.15 This paragraph now implies that doctors who use an unproven intervention (with consent) in the treatment of patients where other options may have been exhausted would then obliged to embark upon a research project to formally test that intervention. The HRA consider this to be unduly onerous as many doctors will not have the time, resources, or training in order to undertake such research to an appropriate standard. The original wording (“where possible”) is preferred. 3. General Comments on the Existing Declaration Text

3.1 The HRA would like to take this opportunity to also comment on sections in the current proposed text that have not been revised: 

Definitions/Terminology:

3.2 The term “medical research” remains undefined in the revised declaration and would benefit from clarification. 3.3 The terms ‘human subjects, ‘research subjects’ and ‘patients’ are used interchangeably throughout and would benefit from definition and consistency of terminology. 

General Principles/Risks, Burdens and Benefits: Paragraph 8 &16:

3.4 The proposed changes do not remove the acknowledged inconsistency between paragraph 8 and paragraph 16. If the ‘well-being’ of the individual research subject absolutely, and without qualification, takes precedence over all other interests then, it may well make much, otherwise reasonable and ethical, research impossible to conduct. We suggest that para 16 should be revised to state that research should only be undertaken in circumstances where the burden imposed upon the subject is not disproportionate to the potential societal benefit.

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

Research Ethics Committees: Paragraph 23

3.5 The use of the term “must” in the context of RECs is unnecessarily strict and the HRA prefer the word “should”. RECs (in the UK and elsewhere) are not necessarily constituted to be expert or knowledgeable with regards to applicable “laws and regulations” nor are required to be so given that they are required to give an ethical opinion and not a legal one (with the exception in the UK of ethics committees explicitly needing to take into account the research provisions of the Mental Capacity Act and Human Tissue Act). 3.6 The requirement that researchers “must provide monitoring information to the committee, especially information about any serious adverse events” may create a tension with the forthcoming EU Clinical Trials Regulation as under the currently proposed version adverse events are to be reported to the Member State (and not directly to the REC). It is for the Member State to decide by whom such information is to be reviewed. 3.7 With regards to the statement that ‘No change to the protocol may be made without consideration and approval by the committee’. In the U.K. where changes are made to a research study that the sponsor considers ‘minor’ rather than ‘substantial’ amendments, there is no requirement to obtain an ethical opinion from a REC5. The current wording used in the Declaration could be understood as requiring that the correction of typographical errors and other non-substantial changes should be submitted to RECs. The HRA suggest that in deciding whether a change to the protocol should be submitted for ethical review that consideration needs to be given to whether the proposed changes have any implications for the safety or welfare of participants, and/or the information that participants might require to give informed consent to continue to participate in the research as amended.

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p5.37 ‘Notification of minor amendments’ - NRES Standard Operating Procedures for Research Ethics Committees in the United Kingdom v5.1 (Published March 2012) (http://www.nres.nhs.uk/EasySiteWeb/GatewayLink.aspx?alId=141304) HRA Response to the ‘WMA Declaration of Helsinki Working Group - Draft revised text for public consultation, 15 April – 15 June 2013’ – v1.0 June 2013

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4. Detailed Comments on the Draft Revised Declaration

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Subjects Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008

WMA Declaration of Helsinki Working Group Draft revised text for public consultation, 15 April – 15 June 2013 Annotated version Comments Preamble

HRA Comments Key: Comments on Proposed Revisions Comments on the Existing Text

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The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.

Old paragraph 1. No changes.

 The term “medical research” remains undefined in the declaration and would benefit from clarification.  The terms ‘human subjects, ‘research subjects’ and ‘patients’ seem to be used interchangeably throughout and would benefit from definition and consistency of terminology.

The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied without consideration of all other relevant paragraphs. 2

Although Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians,. Tthe WMA encourages other of all other relevant paragraphs. participants in medical research involving human subjects to adopt these principles.

Old paragraph 2. Clarifies why the Declaration is addressed primarily to physicians.

No comment

General Principles 3

The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient's best interest when providing medical care.”

No comment Old paragraph 4. No changes.

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It is the duty of the physician to promote and Old paragraph 3. safeguard the health and well-being of patients, including those who are involved in medical Expands the duty of physicians. research. The physician's knowledge and conscience are dedicated to the fulfilment of this duty.

5

Medical progress is based on research that ultimately must include studies involving human subjects.

Old paragraph 5 separated into two No comment parts; this is the first part. The second part is in paragraph 13.

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The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best current proven interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality. Medical research is subject to ethical standards that promote respect for all human subjects and protect their health and rights.

Old paragraph 7.

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Change made for terminological consistency with rest of document. Old paragraph 9, divided into 2 parts; this is the first part. The second part of old paragraph 9 is now in paragraph 19

No comment

The proposed change makes the statement in the second half of this paragraph untrue, if "proven" is taken literally. If the term ‘evaluated’ is taken to refer to ‘research’ then it is not logically correct to state that "Even the best proven interventions must be evaluated continually...."

No comment

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8

In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests.

Old paragraph 6. There is an acknowledged internal inconsistency in the document but this paragraph is intended to be aspirational.

The proposed revision does not remove the acknowledged inconsistency. If the ‘well-being’ of the individual research subject absolutely, and without qualification, takes precedence over all other interests then, it may well make much, otherwise reasonable and ethical, research impossible to conduct. It is suggested that this paragraph be removed and para 16 amended so as to introduce the concept of proportionality (see comments below)

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It is the duty of physicians who participate in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality o f personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent.

First sentence is old paragraph 11. No comment

Last sentence moved up from the last part of old paragraph 16. First part of old paragraph 16 is now paragraph 12.

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10 Physicians should must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration.

Old paragraph 10. “Should” changed to “must” to strengthen the wording of the paragraph.

The stipulation that physicians "must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards” is welcome but this revision increases the existing tension between the Declaration (which requires that “No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration”) and existing national provisions for the ethical review of research, particularly In the absence of a clear definition of “medical research”. The HRA believe that the claim that the principles contained within the Declaration have primacy over all national and international laws and regulatory norms and standards is insufficiently justified. This claim creates practical difficulties where national legal and regulatory instruments do not require certain categories of research to be the subject of an application to a research ethics committee. This is made more problematic where national and international legal instruments incorporate specific reference to the Declaration of Helsinki. The HRA prefer that the original wording contained in the Declaration i.e. “should” is retained rather than “must”. For example, under the UK Governance Arrangements for Research Ethics Committees (GAfREC)6 research involving NHS or social care staff recruited as research participants by virtue of their professional role does not require ethical review. Adherence to the national regulatory norms and standards might (depending on how “medical research” is to be understood) then be in breach of the Declaration and the researchers will have difficulty in publishing the study results.

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Available from: www.gov.uk/government/publications/health-research-ethics-committees-governance-arrangements

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11 Appropriate caution must be exercised in the conduct of medical research that may harm the environment.

Old paragraph 13. No changes.

No comment

12 Medical research involving human subjects must be conducted only by individuals with the appropriate scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional.

First part of old paragraph 16 with the addition of “education”.

Without a clear definition of what ‘medical research’ is the requirement that physicians or other health care professionals must supervise medical research involving patients or healthy volunteers is either unnecessarily restrictive (e.g. why should an education specialist not be able to undertake research on patient data in the context of clinical care) or circular (‘medical research’ is research only undertaken by ‘medics’ i.e. physicians and health care professionals).

13 Populations that are underrepresented in medical research should be provided appropriate access to participation in research.

From old paragraph 5, second sentence. No changes. First part of old paragraph 5 is now the new paragraph 5.

No comment

14 The physician may combine medical research with medical care only to the extent that the research is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.

Old paragraph 31. No changes.

No comment

New paragraph. It reflects the obligation to ensure that subjects who are harmed will receive compensation and

Paragraph 15 might appear to introduce a global requirement for “no fault” compensation to be available for all medical research. Whilst the HRA are fully supportive of the provision of adequate compensation

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Adequate compensation and treatment for subjects who are harmed as a result of participating in the research must be ensured.

Second part of old paragraph 16 is moved to paragraph 9.

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treatment.

and treatment for subjects who are harmed as a consequence of their participation in research we do not understand this in terms of a comprehensive “no fault” compensation requirement. Rather, the HRA would expect a proportionate and appropriate view to be taken by research ethics committees of the remedies available to participants in the event that they suffer any harm during the conduct of the medical research, of which “no fault” compensation could be an appropriate solution.

Risks, Burdens and Benefits 16

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In medical practice and in medical research, Combines two previous most interventions involve risks and burdens. paragraphs (old paragraphs 8 Medical research involving human subjects may and 21). No changes. only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects.

Every medical research study involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and communities involved in the research in comparison with foreseeable benefits to them and to other individuals or communities affected by the condition under investigation. Measures to minimise the risks must be implemented. The risks must always be monitored by the

Old paragraph 18. No changes.

As noted above (Para 8): This paragraph is in conflict with para 8. It is suggested that this paragraph be amended so as to introduce the concept of proportionality. We suggest that the text should be revised to state that research should only be undertaken in circumstances where the burden imposed upon the subject is not disproportionate to the potential societal benefit. No comment

Second part is new. Addresses the issue of risk minimization and monitoring during the trial.

researcher throughout the trial.

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Physicians may not participate in a research Old paragraph 20. No changes. study involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians must immediately stop a study when the risks are found to outweigh the potential benefits or when there is conclusive proof of positive and beneficial results.

No comment

Vulnerable Populations 19

Some research populations are particularly vulnerable and need special protection have an increased likelihood of incurring additional and greater harm.

Second part of old paragraph 9. First part of old paragraph 9 is now part of paragraph 7.

It is not clear, nor sufficiently justified, why there is reason to believe that some vulnerable populations would have an increased likelihood of “incurring additional and greater harm”. Such populations may have an increased likelihood of the same harm as a nonvulnerable population, but it does not follow that they would also have an increased likelihood of “additional and greater harm”.

Old paragraph 17.

The phrase “Consideration should also be given to ensuring that the community receives a fair level of additional benefits” would benefit from clarification. This section would also benefit from further clarification of the terms “fair level” and “additional benefits”, which are currently not defined.

These include those who cannot give or refuse consent for themselves and those who may be vulnerable to coercion or undue influence. All vulnerable groups need specifically considered protection. 20

Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the health needs and priorities of this population or community and the research cannot be carried out in a non-vulnerable population. In addition, and if there is a reasonable likelihood that this population or community should stands to benefit from the knowledge, practices or interventions that result from the results of the research.

Combines fair benefit and reasonable benefits approaches. Captures several important principles with respect to vulnerable populations.

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Consideration should also be given to ensuring that the community receives a fair level of additional benefits.

Scientific Requirements and Research Protocols 21

Medical research involving human subjects Old paragraph 12. No changes. must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

No comment

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The design and performance of each research study involving human subjects must be clearly described in a research protocol. The research protocol should discuss and justify the chosen study design. The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest, incentives for subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study. The protocol should must describe arrangements for poststudy access by study subjects to interventions identified as beneficial in the study or access to other appropriate care or benefits.

No comment

Old paragraph 14.

Editorial clarification

Clarifies obligation to include this information in the study protocol.

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Research Ethics Committees 23

The research protocol must be submitted for consideration, comment, guidance and approval to a research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No change to the protocol may be made without consideration and approval by the committee. At the end of the study, the investigators must submit a final report to the committee containing a summary of the study’s findings and conclusions.

Old paragraph 15.



Adds the issue of transparency of REC’s. The issue of qualification of the REC and its members is now addressed, recommended by several commentators. Clarifies what should occur at the end of the study.

It is unclear what the term “duly qualified” means when applied to ethics committees. If taken to apply to individual members then what would constitute a “duly qualified” lay member? Does it refer to the academic qualifications simply that members be qualified through their experience? If it refers to academic qualifications then does it apply to the committee as a whole (i.e. the committee should encompass sufficient qualifications among its members) or should every individual member have appropriate qualifications. The following wording is suggested: ‘This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must contain a mixture of people who reflect the currency of public opinion, as well as people who have relevant formal qualifications or professional experience that can help the REC understand particular aspects of research proposals’.



The use of the term “must” in the context of RECs is unnecessarily strict. RECs (in the UK and elsewhere) are not necessarily constituted to be expert or knowledgeable with regards to applicable “laws and regulations” nor are required to be so given that they are required to give an ethical opinion and not a legal one (with the exception in the UK of ethics committees explicitly needing to take into account the research provisions of the Mental Capacity Act and Human Tissue Act)



The requirement that researchers “must provide monitoring information to the committee, especially

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information about any serious adverse events” may create a tension with the forthcoming EU Clinical Trials Regulation as under the currently proposed version adverse events are to be reported to the Member State (and not directly to the REC). It is for the Member State to decide by whom such information is to be reviewed. 

With regards to the statement that ‘No change to the protocol may be made without consideration and approval by the committee’. In the U.K. where changes are made to a research study that the sponsor considers ‘minor’ rather than ‘substantial’ amendments, there is no requirement to obtain an ethical opinion from a REC. The current wording used in the Declaration could be understood as requiring that the correction of typographical errors and other non-substantial changes should be submitted to RECs. The HRA suggest that in deciding whether a change to the protocol should be submitted for ethical review that consideration needs to be given to whether the proposed changes have any implications for the safety or welfare of participants, and/or the information that participants might require to give informed consent to continue to participate in the research as amended.

Privacy and Confidentiality 24

Every precaution must be taken to protect the Old paragraph 23. No changes. privacy of research subjects and the confidentiality of their personal information and to minimize the impact of the

No comment

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study on their physical, mental and social integrity. Informed Consent Old paragraph 22. No changes. 25 Participation by competent individuals as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no competent individual may be enrolled in a research study unless he or she freely agrees. 26 In medical research involving competent human Old paragraph 24. subjects, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-trial access and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information. After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject’s freelygiven informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally

No comment

No comment

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documented and witnessed. 27 When seeking informed consent for participation Old paragraph 26. No changes. in a research study the physician should be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations the informed consent should be sought by an appropriately qualified individual who is completely independent of this relationship.

No comment

Old paragraph 27. No changes. 28 For a potential research subject who is incompetent, the physician must seek informed consent from the legally authorized representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the population represented by the potential subject, the research cannot instead be performed with competent persons, and the research entails only minimal risk and minimal burden. Old paragraph 28. No changes. 29 When a potential research subject who is deemed incompetent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorized representative. The potential subject’s dissent should be respected.

No comment

No comment

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Old paragraph 29. No changes. 30 Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research population. In such circumstances the physician should seek informed consent from the legally authorized representative. If no such representative is available and if the research cannot be delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to remain in the research should be obtained as soon as possible from the subject or a legally authorized representative. 31 The physician must fully inform the patient which Old paragraph 34. No changes. aspects of the care are related to the research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never interfere with the patientphysician relationship. 32 For medical research using identifiable human Old paragraph 25. material or data, such as research on material or data contained in biobanks or similar repositories, physicians must normally seek consent for the its collection, analysis, storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable impractical to obtain for such research or would pose a threat

No comment

No comment

Some countries have specific bodies that consider the use of identifiable human material/data (e.g. In the UK access to patient information without consent may require review by the HRA’s Confidentiality Advisory Group) The following additional wording is suggested following the phrase “…may be done only after consideration and approval of a research ethics committee.”:

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to the validity of the research. In such situations the research may be done only after consideration and approval of a research ethics committee.

“…and any relevant national body that has the duty to consider such research”.

Use of Placebo 33

The benefits, risks, burdens and effectiveness Old paragraph 32. of a new intervention must be tested against those of the best current proven intervention(s), except in the following circumstances: The use of placebo, or no treatmentintervention is acceptable in studies where no current proven intervention exists; or Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, placebo or no treatment is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo or no treatment will not be subject to any additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.

The statement that “…patients who receive any intervention less effective than the best proven one, placebo or no treatment will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention” is problematic. Any treatment less effective than the best proven treatment must, by definition, subject the patient to an additional risk that may result in serious or even irreversible harm. Whilst we understand that the current wording (October 2008) on the use of placebo has prompted debate around whether the term "best current" should be understood globally or locally it is noted that the proposed new wording ("best proven") is necessarily global. However, this new wording creates two new problems: 1) Firstly, is it to be decided that something is "proven" or, more problematically, "best proven”? At what level in the hierarchy of evidence are we talking of ‘proof’? 2) Secondly, many treatments are only strictly understood as "proven" in very restricted populations, but nonetheless are used for much wider populations e.g. children, women and the elderly. Furthermore, some current treatments have been in use for so long that they

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have never, in any strict sense, been proven to be effective. If this change is introduced it would raise a whole new set of questions for research ethics committees to grapple with Post-Trial Access 34 In advance of a clinical trial, sponsors, Old paragraph 33.  researchers and host country governments should make provisions for post-trial access Clarifies and strengthens post-trial for all participants who still need an access issue. intervention identified as beneficial in the study. This information should also be disclosed to participants during the informed consent process. All study participants should be informed about the outcome of the study. At the conclusion of the study, patients entered into the study 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.

Post-trial access should always be an aspiration but there are often good reasons why it cannot or should not happen in practice. For example, the study drug may no longer be available, or it may not be possible to tell at the end of the patient’s treatment if the intervention is beneficial. The HRA believes that the provision of post-trial access following the completion of a study should be examined on a case-by-case basis, particularly in the light of the health care systems in operation within the relevant country in which the research is taking place. As the development of an intervention moves towards being licensed then the issue of post-trial access becomes less controversial as the efficacy of the product and risks associated with its use become better known.



The phrase ‘an intervention identified as beneficial in the study’ raises the question of whether this refers to an intervention identified as being beneficial to the study population or to an individual.



It is uncontroversial to state that all study participants who wish to be informed about the outcome of a study should be. However, the stated wish of a participant NOT to be informed should always be respected.

Trial Registration and Publication of Results

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35 Every clinical trial must be registered in a publicly Old paragraph 19. No changes. accessible database before recruitment of the first subject. 36

Researchers, Aauthors, sponsors, editors and publishers all have ethical obligations with regard to the publication of the results of research. 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. They should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

Old paragraph 30.

No comment

The Declaration might usefully include a statement regarding the sharing of raw data.

The HRA would like to draw attention to its’ recent publication regarding transparency entitled “The HRA Adds researchers and sponsors to interest in good research conduct: Transparent those who have ethical Research” (May 2013) which is available here as well as obligations. the recent House of Commons Science &Technology committee discussion on ‘Clinical Trials and Disclosure of Data’ to which the HRA Chief Executive Officer (Dr. Janet Wisely) recently gave evidence. See: http://www.parliament.uk/business/committees/committe es-a-z/commons-select/science-and-technologycommittee/inquiries/parliament-2010/clinical-trials/

Unproven Interventions

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37

In the treatment of an individual patient, where proven interventions do not exist or have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician's judgement it offers hope of saving life, reestablishing health or alleviating suffering. Where possible, tThis intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information should be recorded and, where appropriate, made publicly available.

Old paragraph 35.

This paragraph now implies that doctors who use an unproven intervention (with consent) in the treatment of Intended to clarify the intent of this patients where other options may have been exhausted paragraph. would then obliged to embark upon a research project to formally test that intervention. The HRA consider this to Strengthens requirement to make be unduly onerous as many doctors will not have the the intervention the object of time, resources, or training in order to undertake such subsequent research. research to an appropriate standard. The original wording (“where possible”) is preferred.

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