HHS_Comments_on_DOH_for_Cape_Town_Conference_12-5-7-2012

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U.S. Department of Health and Human Services
Perspectives on the Revision of the Declaration of Helsinki
World Medical Association Expert Conference
December 5-7, 2012
The Declaration of Helsinki (DOH) has been an important source of ethical guidance in the
conduct of clinical research throughout the world for nearly half a century. The DOH is highly
regarded and respected for its reflection of fundamental principles and widely-held values. As
the process to revise the 2008 version of the Declaration of Helsinki begins, we wish to
commend the World Medical Association (WMA) for the integrity and transparency of its
consultative and deliberative processes and for giving due consideration to the perspectives of all
stakeholders and interested parties.
DOH’s strength and influence lies in its articulation of basic ethical guidance for the conduct of
clinical research. While ethical principles are enduring, clinical research is a dynamic enterprise.
New frontiers of clinical science and new opportunities to address human diseases and advance
human health can raise ethical questions. We support efforts to augment the DOH where new
ethical challenges arise and to adjust current content to reflect new research practices and
directions. At the same time, it is important to resist calls to add procedural specifics to the
DOH. Prescribing specific procedural steps leads to conflicts between the DOH and the
mandatory procedures that countries have in place to protect human research participants. Such
conflicts weaken DOH’s influence and diminish its value as a source of fundamental ethical
guidance.
We appreciate the opportunity to provide our perspectives on the specific topics being discussed
at this Expert Conference, to raise several issues with regard to the content and structure of the
current document, and to listen to the thoughtful perspectives of other participants. We also look
forward to providing further input during the next phases of the revision process when specific
revisions to the current version will be considered.
Discussion Topics
Vulnerable Groups
In the current DOH, attention is given to the ethical issue of vulnerability in two separate
paragraphs, 9 and 17. Taking note of the definition provided in Paragraph 9, we would
recommend that the reference to disadvantaged populations in Paragraph 17 be dropped. Its
inclusion effectively and, in our view, inappropriately characterizes every disadvantaged
population or community as incapable of giving or refusing consent for themselves or as
vulnerable to coercion or undue influence. In addition, the second “if” clause currently makes no
reference to the fact that research participation in itself can be beneficial to a population or
community. We would suggest that this issue be addressed by dropping the phrase “results of
the.”
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Post-Study Arrangements
The current DOH approach to post-trial arrangements, expressed in Paragraphs 33 and 14,
warrants reconsideration and revision, particularly Paragraph 33. The expectation in Paragraph
33 that investigators will provide access to interventions identified as beneficial or to other
appropriate care or benefits is a standard that most investigators cannot meet. Especially
troubling is the statement that study participants “are entitled” to share in the benefits that result
from the study. Investigators may face any number of challenges and impediments to providing
access to such benefits, including lack of funding, insufficient supplies, the country’s health care
situation and its national regulations and health care policies. Moreover, requiring post-study
access may restrict the number of countries where research involving potentially beneficial
interventions can be conducted and could have profoundly adverse consequences across the
globe on the ability of the public and private sectors to carry out research on investigational
therapies, diagnostics, and preventive measures.
Certainly, researchers must be attentive to the ongoing health needs of research participants, but
establishing a standard that is largely impossible to achieve does not advance the ethical conduct
of research. We urge WMA to consider a more reasonable articulation of the investigator’s
obligations to the future well-being of the participants enrolled in their studies. In our view, the
WMA should adopt a more measured ethical approach that would call upon researchers to
consider the issue of post-trial access in the context of local needs, the local healthcare
infrastructure, national regulations and health care policies, and the availability of effective
treatments and, where such access is possible, to describe arrangements for access to
interventions identified as beneficial in the study, such as continued therapy with an
investigational intervention or other appropriate care or benefits.
For reasons we will describe later, the concepts in Paragraph 33 should be moved to Part B.
Biobanks
Biobanks raise many important ethical issues, and they will likely play a role of growing
importance in the world of research. The debate with regard to the ethical issues surrounding
biobanks is ongoing, and there is as yet no consensus. It is premature to establish ethical
requirements in areas where a consensus on the appropriate ethical course to take has not been
established.
Ethics Committees
One important element regarding the composition and role of ethics review committees is
missing from Paragraph 15. Language should be added to specify that Ethics Review
Committees should be comprised of members with the appropriate expertise to review the
research protocols that are submitted to them. Addressing this gap would strengthen the DOH.
Enhancement
HHS does not see a need for the DOH to address the ethical issues related to physical or
cognitive enhancement research. To the extent that such research involves the same ethical
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issues that apply to other types of research, the DOH already provides guidance. If there are
unique ethical issues with enhancement research, those issues have not yet been identified or
resolved. As such, it would be premature to attempt to articulate specific ethical guidance.
General Consultation Topics
HHS looks forward to learning more about the specific aspects of the four consultation topics
that may be under consideration for inclusion into the DOH. As the thinking advances and the
intentions become clearer, we will likely have more specific comments. Below are some of our
preliminary thoughts.
Insurance/Compensation/Protection
We agree that clinical researchers have an ethical obligation to provide for treatment of
individuals who experience adverse events or injuries as a result of their participation in
research. Compensation for harms or costs of long-term care is a much more complex issue. In
this regard, the U.S. Presidential Commission on the Study of Bioethics Issues addressed the
issue in a recent report, which is currently under consideration by HHS. Articulating the ethical
principle that research participants should not bear the cost of unforeseen harms related to their
study participation may be an appropriate addition to the DOH. However, given the different
approaches that nations take in addressing this issue, it would be counterproductive to go farther
by attempting to identify a specific implementation mechanism.
Use of Unproven Interventions/Off-label Use
HHS does not see a need to modify or expand on the current text in the DOH that addresses
unproven interventions. Paragraph 35 speaks to the issues that should guide a physician’s
decision-making when considering the use of an unproven intervention. Moreover, existing
national regulations and guidance provide more detailed explanation of requirements for the use
of unproven interventions with therapeutic intent for an individual patient. More detailed text on
this topic is likely to conflict with national regulations that vary in their requirements for dealing
with the use of investigational drugs for therapeutic purposes.
Also, we advise against addressing the topic of off-label use of approved products. It is a
medical practice, rather than a research, matter. Moreover, attempting to address the issue of
off-label use in the DOH is likely to lead to conflicts with national regulations that vary in their
policies or requirements.
Broad Consent
The ethical acceptability of the use of broad consent in certain types of research is an important
and timely issue. HHS is currently considering regulatory changes to allow the use of broad
consent for research involving biospecimens and data. Such a change will facilitate important
research and, if properly designed and implemented, would be in keeping with applicable ethical
principles.
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Medical Research Involving Children
Specific ethical guidance on research involving children need not be added to the DOH. The
principles outlined in the DOH generally apply to research with children and, together with the
principle outlined in Paragraph 17 that covers vulnerable populations, the DOH provides
sufficient ethical guidance for studies involving pediatric populations. Articulating detailed
standards for pediatric research would require a significant expansion of the DOH. However,
such an expansion would be inappropriate because adding specific details in this area to the
DOH may conflict with specific and comprehensive regulations for pediatric studies already in
place for many countries.
Other Issues with the 2008 Version of the DOH
Deference to National Human Subjects Protections Requirements on Specific Details
While much of the DOH appropriately remains at the level of broad principles, there are
provisions that detail specific requirements. Some of these are, moreover, at odds with national
laws and/or regulatory requirements. Excessive specificity undermines the value of DOH as a
source of basic ethical guidance and leads to unnecessary conflicts with national approaches that
are based on the same fundamental ethical principles. This problem is exacerbated because of
language in the DOH that claims moral supremacy over national requirements and standards.
We urge WMA to modify Paragraphs 10 and 15. Both Paragraphs include statements that
inappropriately call on researchers to disregard their obligations to follow their national laws and
regulations when they conflict with the provisions of the DOH. Paragraph 10’s statement 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 the similar
statement in Paragraph 15 should be deleted.
Clarifying the Intent of Paragraph 6
Paragraphs 6 conflates medical research with medical care and, in so doing, incorrectly creates a
standard for the well-being of the subject that is akin to that which applies to patients in clinical
care. That standard is not the one that is currently being applied in the research setting, for if it
were, much of the research conducted today would be in violation of the standard. Paragraph 6
should be revised and combined with paragraph 21, which more closely reflects the applicable
standard.
Registration of Clinical Trials
HHS agrees with the importance of the goals of transparency and accountability articulated in
Paragraph 19 and that information about clinical trials should be available through registration in
a publicly accessible database. However, specifying a timeframe for registration does not relate
to an ethical principle, i.e., whether the registration occurs before recruitment or sometime after
recruitment begins is not important for the protection of the study participants. Moreover, there
is no international consensus on best practices about the scope and timing of registration.
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Accordingly, Paragraph 19 should be revised to become a statement of principle that “Every
clinical trial should be registered in a publicly accessible database as early as possible in order to
facilitate transparency and accountability.”
Artificial Distinction between Medical Research (Section B) and Medical Research
Combined with Medical Care (Section C)
The distinction that the DOH is drawing between “medical research” and “medical research
combined with medical care” is confusing. In fact, there do not appear to be conceptual
differences that would warrant separate ethical guidance sections. As such, we recommend
deleting Part C “Additional Principles for Medical Research Combined with Medical Care,” and
incorporating sections of Paragraphs 31-35 into sections A and/or B, as follows.
 Paragraph 31 repeats concepts already covered in Paragraphs 3, 6, and 16 and can be
deleted altogether.
 Paragraph 32 addresses the use of placebos and should be moved to follow Paragraph 16.
 Paragraph 33 should be deleted. An exhortation to inform participants of the outcome of
the study should become part of Paragraph 14 (this should not be worded as an
entitlement since it may not always be possible). For reasons discussed above in Post-
study Arrangements, the second part of Paragraph 33 that reads “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” should be deleted.
 The second sentence in Paragraph 34 regarding refusal to consent and withdrawal repeats
concepts in Paragraphs 4 and 9 and should be deleted. The concept in the first sentence
that care and treatment should be distinguished should be addressed in Paragraph 24.
 The guidance regarding the use of unproven interventions in Paragraph 35 should be
moved to follow Paragraph 18.
Enhancing DOH’s Readability
The paragraphs in Section B should be reorganized so that related issues are presented together
and in a logical order. It would be helpful to add descriptive topic headings as well. Currently,
related items are scattered throughout Section B. A restructuring would help readers navigate
the document more easily, enhance its readability, and facilitate adherence to ethical guidance in
the DOH. For example, the information in Paragraphs15, 25 and 29 concerning the
responsibilities of Research Ethics Committees could be grouped together under the topic
heading “Research Ethics Committees.”
Exceptions to Requirements for Informed Consent
Paragraph 22 should allow for the fact that, in certain limited circumstances, some research
involving competent subjects can ethically be conducted without consent. Specifically,
Paragraph 22 should be expanded to state that the requirement for informed consent may be
waived or altered in situations where risk to research subjects is no more than minimal and
consent would be impossible or impractical to obtain for such research or would pose a threat to
the validity of the research.
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Emergency Research
Changes should be made to clarify Paragraph 29. Although the text applies to pre-planned
emergency research situations, its focus is not evident until midway through the paragraph. Pre-
planned emergency research includes, for example, studies to evaluate the effectiveness of
automated defibrillators in reducing mortality in out-of-hospital cardiac arrest. Since people who
have suffered cardiac arrest are incapable of providing consent for themselves and the urgent
need for the intervention does not, in most instances, permit additional time to seek consent from
a legally authorized representative, the research cannot be carried out without a waiver of
consent. Specifically, Paragraph 29 should be reorganized and revised to make clear that it
pertains to the waiver of consent in pre-planned emergency research situations and not to an
individual emergency situation. These revisions, which are shown below, will also distinguish it
from Paragraph 35 which addresses consent from the patient or a legally authorized
representative for administering an unproven intervention to an individual in an emergency
situation.
“29. The requirement for informed consent may be waived in certain emergency
research situations. These waivers of consent are justified when all the following
conditions are met: research involves subjects in life-threatening situations where
there are no proven or effective treatments and the initiation of the experimental
intervention cannot be delayed; research involvinges subjects who are physically or
mentally incapable of giving consent due to the life-threatening situation; 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. Participation in the research
holds out the prospect of direct benefit for the subjects; If no such legally
authorized representative is available to provide informed consent; and if the
research cannot be delayed, the study may proceed without informed consent
provided that the research cannot practicably be carried out without a waiver of
consent; and 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.
Placebo Controls in Clinical Research
Although the use of placebo controls in clinical trials was the subject of much discussion and
debate in the past, we are pleased with the consensus wording achieved in 2008. The 2008
version appropriately outlines the ethical criteria that justify the use of placebos when a proven
intervention exists, including that the study has scientific merit and clinical value and that it does
not pose risks of serious or irreversible harm. Paragraph 32 thus offers appropriate ethical
guidance as currently written, and the WMA should resist calls for substantive changes.
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Conclusion
We appreciate the opportunity to present HHS perspectives on the DOH and the additional topics
under discussion and to hear thoughtful perspectives from colleagues around the world. We
stand ready, during the next phase of the revision process, to provide additional perspectives as
well as more specific comments regarding revisions to the 2008 DOH.