Thursday, September 10, 2015

Thank you for visiting PRIM&R's blog, Ampersand.  It has a new home, and a new look, but remains an important resource for those working in the field of research protections and those committed to the ethical conduct of research.

Check out the new Ampersand.

Friday, September 4, 2015

Research Ethics Roundup: The Reproducibility of Psychology Studies, the Effect of Clinical Trial Registration, and More

Two recent studies have generated debate within the research community. We explore those studies, as well as other recent stories about research in the popular media, in this week’s Research Ethics Roundup.

Has US Biomedical Research on Chimpanzees Come to an End?: In June, the US Fish and Wildlife Service announced its plans to classify captive chimpanzees, including those used for research purposes, as endangered animals under the Endangered Species Act. In this article for Science, David Grimm explores the effect of that decision.

Review: ‘Informed Consent’ Tests the Ethics of Genetic Research:  “Informed Consent,” a new off-Broadway play, brings to life the story of the Havasupai, a Native American tribe who sued Arizona State University over the misuse of their blood samples for genetic research. Charles Isherwood reviews the play in this piece for The New York Times.

Many Psychology Findings Not as Strong as Claimed, Study Says: Following an evaluation of 100 psychology studies that were published in leading journals, researchers concluded that many of the original findings were not reproducible. Benedict Carey reports on the researchers’ findings in this article for The New York Times.

Biohackers Gear Up for Genome Editing: In this article for Nature, Heidi Ledford reports on how amateur biologists are exploring and using CRISPR, a new technology that can be used to edit DNA. 

Registered Clinical Trials Make Positive Findings Vanish: A new study published in PLoS One found that reports of positive clinical trial findings declined significantly following the enactment of a law that required the registration of clinical trials in 2000. Chris Woolston explores the recent study in this article for Nature.

Thursday, September 3, 2015

DHHS Releases Long-awaited Proposed Changes to the Common Rule

On Wednesday, the Office of the Federal Register made available a pre-publication version of a much-anticipated Notice of Proposed Rulemaking (NPRM) that proposes changes to the Federal Policy for the Protection of Human Subjects, or the “Common Rule.”

The release of the NPRM comes four years after the publication of an Advance Notice of Proposed Rulemaking (ANPRM), which first put forward proposals to modernize the regulations governing human subjects research in the United States. The NPRM, which was issued by the Department of Health and Human Services (DHHS), as well as fifteen other Federal agencies, is the next step in the process leading to a final rule. Its contents have been influenced by ongoing dialogue and debate in the years since the release of the ANPRM, as well as by recent policy proposals, including the Office for Human Research Protections’ “Draft Guidance on Disclosing Reasonable Foreseeable Risks in Research Evaluating Standards of Care” and the National Institutes of Health’s “Draft Policy on the Use of a Single IRB for Multi-Site Research.”

The NPRM, which is 519 pages long, puts forward eight major proposals that address improving the informed consent process; strengthening consent requirements for the research use of stored biospecimens; adding categories of activities that are not subject to regulation under the Common Rule; calibrating the level of review to the level of risk involved in research; limiting the use of waivers or alterations of consent for research involving biospecimens; mandating the use of a single IRB for cooperative research; modifying requirements for continuing review; and extending the scope of the Federal Policy for the Protection of Human Subjects.

For each proposed change, DHHS outlines the goal of the change, the current rule, the discussion generated by the ANPRM proposal on that topic (if applicable), and the NPRM proposal. The document also puts forward a number of questions for public comment. The comment period for the NPRM will be 90 days, and the official deadline for comments will be made available once the NPRM is published in the Federal Register, which is scheduled to happen on Tuesday, September 8.

Over the next several weeks, PRIM&R will be synthesizing, analyzing, and digesting the proposed changes for our community. We will post a descriptive chart comparing the current regulations with the proposals in the NPRM next week. We will also be featuring a series of blog posts closely examining the proposals contained in the NPRM here on Ampersand.

PRIM&R’s Public Policy Committee, which oversees the development of written comments on policy items relevant to PRIM&R's mission, will also be considering the proposed rule. The Public Policy Committee invites and encourages PRIM&R members to be involved in this process by sharing your input on the proposed changes. Feedback shared with PRIM&R by September 29, 2015 will be provided to PRIM&R’s Public Policy Committee for review, and all comments will be considered as the Committee prepares its response.

We will also be hosting several events aimed at fostering understanding of the proposed changes. On September 15, Heather H. Pierce, JD, MPH, senior director for science policy and regulatory counsel in scientific affairs at the Association of American Medical Colleges, and P. Pearl O’Rourke, MD, PRIM&R board member and director of human research affairs at Partners HealthCare Systems, Inc., will facilitate a webinar aimed at helping all those involved with human subjects protections understand the proposals put forward by DHHS. The webinar will be free to PRIM&R members. And in November, the issues and questions raised by the NPRM will be highlighted throughout the 2015 Social, Behavioral, and Educational Research Conference and the 2015 Advancing Ethical Research Conference, which are being held November 12-15 in Boston, MA. We encourage you to join us for these exciting events as we explore the future of human subjects research.

Tuesday, September 1, 2015

From the Director: Informed Consent, Fair Transaction, and Fond Remembrance

by Elisa A. Hurley, PhD, executive director

I recently had occasion to think fondly of a member of our PRIM&R community whom we lost in April: Alan Wertheimer, PhD. Alan was a senior research scholar in the Department of Bioethics at the National Institutes of Health, professor emeritus of political science at the University of Vermont, and a long-time PRIM&R faculty and conference planning committee member. He was also a cherished friend and mentor to me. He passed away on April 10.

Ever the scholar and truth-seeker, Alan never hesitated to let me know—collegially, of course—if he disagreed with something I said. For instance, he wrote me a note about my Ampersand post on informed consent last year, and in it, reminded me that it’s actually a matter of controversy within the bioethics community whether lack of comprehension on the part of a potential research subject invalidates that person’s informed consent. At the time, I had considered including that dimension of the debate around consent in my post, but ultimately decided not to, in the service of keeping the post brief and focused on the central point of not using consent as a transitive verb.

But as I was reflecting on this exchange recently, I went back and re-read the Kennedy Institute of Ethics Journal article Alan and his colleague Frank Miller wrote in 2011, in which they argued for a model of consent (which they called the “Fair Transaction” model) that does not make comprehension a requirement for valid consent. It’s a brilliant paper—though in the end, I’m not sure I agree with their view (more on that later)—and when reading it, I was reminded just how significant are Alan’s contributions to research ethics scholarship. So I thought I’d use this post to both pay tribute to Alan, whom I miss very much, and shed some light on this controversy, by taking a brief look at Alan and Frank’s conception of informed consent.

According to the traditional model of informed consent (often called the autonomous authorization (AA) model), substantial comprehension on the part of a subject is a requirement for valid informed consent. But that model, the most comprehensive account of which can be found in Ruth Faden and Tom Beauchamp’s seminal book, A History and Theory of Informed Consent (Oxford University Press, 1986), runs into a real problem, namely, the Therapeutic Misconception (TM). TM is the phenomenon whereby clinical research subjects fail to understand the difference between research and ordinary treatment (including, for example, that research follows a fixed protocol which precludes making personalized decisions about care), and therefore mistakenly attribute therapeutic intent to research procedures (Lidz C. and Appelbaum, P. “The Therapeutic Misconception: problems and solutions.” Medical Care, 2002). There is evidence that a substantial percentage of clinical research subjects manifest TM (see Appelbaum, P. and Lidz, C. “The Therapeutic Misconception,” Oxford Textbook of Clinical Research Ethics, Oxford University Press, 2008).

Since TM constitutes a lack of substantial understanding, on the AA model, it would seem to follow that if a subject consents to research participation while under the TM, his or her consent is invalid and the research unethical. In their paper, Miller and Wertheimer point out that most people who subscribe to the traditional view of consent nevertheless reject that conclusion in practice—that is, they don’t acknowledge that TM invalidates informed consent or that a considerable portion of current clinical research is unethical. According to Miller and Wertheimer, this inconsistency between what the model entails and what people who subscribe to the model are in practice willing to conclude suggests a flaw in the AA model of consent. So they suggest an alternative.

According to Miller and Wertheimer, requiring substantial comprehension for valid consent in all cases can actually be a failure of respect for persons. To show this, they ask us to consider two cases: first, a case where subjects are randomized in a trial comparing two standard treatments for depression that are expected to offer similar risks and benefits, and where there has been clear disclosure by investigators about the nature of the research, but some of the subjects fail to appreciate that they will be randomized to one of the two interventions, believing instead that the doctor will select the intervention that is best for them. They argue, “Despite the subjects’ defective comprehension, it seems disrespectful not to recognize the validity of their less than autonomous consent, given their choice to participate after receiving adequate information about the trial and given the personally favorable risk-benefit ratio of trial participation” (207). In other words, Miller and Wertheimer suggest that though these subjects’ consent may not be fully autonomous (because it is given without full comprehension), it is nevertheless freely given, and to discount such freely given consent by saying they nevertheless cannot participate in the trial seems disrespectful. Furthermore, they argue, it seems unfair not to let these subjects participate, in light of the prospect of benefit and lack of predictable harm from participation.

If, on the other hand, we are talking about a placebo-controlled trial of an experimental anti-depressant in the same population, then things look very different. In this second case, Miller and Wertheimer argue, the experimental intervention involves much greater uncertainty about risks and benefits, and randomization to placebo means that some subjects will get something that departs dramatically from standard treatment for depression. (I leave aside, as they do, the fact that some would argue that conducting a placebo-controlled trials in such a case is unethical). Manifesting a TM in this case, Miller and Wertheimer argue, does invalidate consent, because subjects would be failing to appreciate the significant possible disadvantage to them of not receiving active treatment by being randomized to placebo. That is, here the failure to understand the difference between research and treatment constitutes a failure to understand the much less favorable risk-benefit profile of the research, and, in particular, that there is a “known potential for disadvantage” if randomized to placebo (210).

Miller and Wertheimer thus suggest that by placing comprehension above all else, the traditional model of consent is inappropriately insensitive to other considerations that are relevant to respecting persons and their well-being, such as advancing their interests and values, and respecting their preferences—including, for instance, preferences not to be excluded from research that has a personally favorable risk-benefit ratio. The model is thus unfair to subjects. Miller and Wertheimer argue that determining what level of understanding is required for informed consent to be valid should be sensitive to the risk-benefit profile of the research in question. For low-risk research, there is nothing ethically wrong in accepting as valid a subject’s less-than-fully-autonomous consent, though there should always be good faith efforts to communicate information about the research in language the potential subject can understand, and other regulatory safeguards and research protections mechanisms, such as regular ethics review of risks and benefits, must, of course be in place.

Interestingly, Miller and Wertheimer also suggest that the traditional model of consent is unfair to investigators. “The lengths to which investigators should be expected to go in assessing the quality of informed consent should be reasonable in view of the risk-benefit profiles of different studies” (210). While they agree that, in general, investigators should assess the capacity of subjects to consent and enroll subjects only when they are “reasonably confident that they have adequate comprehension,” they think that insisting on rigorous testing of comprehension in low-risk studies is unnecessarily costly and unreasonable, and thus unfair to researchers.

And so, Miller and Wertheimer propose instead a Fair Transaction model of consent, which does not require substantial comprehension in all cases of valid research consent, as the AA model does, but is instead, sensitive to context. What fairness requires, with respect to comprehension, will vary depending on the risk-benefit profiles of the research in question. They write, “It is fair to both subjects and to investigators to require more stringent efforts to promote and to test comprehension when the negative consequences to subjects from trial participation are potentially more significant as compared with standard medical care,” but unreasonable to require “exacting scrutiny of consent to low-risk, life-saving treatment.” And with respect to the TM, specifically, they argue that there need be only minimal concern about correcting it in trials that compare similar treatments in conditions that are like standard practice (i.e., pragmatic trials), and more concern in trials that pose potentially important disadvantages to subjects (212).

Thus, according to Miller and Wertheimer, and contrary to much standard thinking, “Autonomy is not the decisive consideration in the validity of consent” (212). Rather, consent is valid “when subjects are treated fairly in making decisions about research participation consistent with their preferences and values” (217).

So what to make of Miller and Wertheimer’s critique of the traditional view of informed consent, and of their alternative? Though I find their arguments thought-provoking, I wonder whether their account misses some of the point of seeking informed consent for participation in research by focusing so much on the relevance of the risk-benefit profile of the research in question. That is, I’m not convinced that the level of risk subjects are about to undertake in entering a research study should be the arbiter of how much concern we have about whether they understand the difference between research and clinical care. Rather, respect for research subjects would seem to require that we always be concerned that people who are about to enroll in research understand what it means to participate in research—an enterprise whose goal is the creation of generalizable knowledge rather than achieving a personalized benefit, and whose procedures are therefore governed by a standard protocol, rather than personalized decisions about care. That is not to say that the informed consent process need look exactly the same in high and low risk cases. But what seems objectionable to me is the idea that if the risks are low enough, we need not be too worried whether people understand that they are research subjects, with all that that entails.

What do you think?

Friday, August 28, 2015

Modernizing Biomedical Innovation: Understanding the 21st Century Cures Act

by Avery Avrakotos, education and policy consultant

On July 10, 2015, the US House of Representatives passed H.R. 6, the 21st Century Cures Act, with a vote of 344-77. The passage of the bill, which many have hailed as a noteworthy example of bipartisan collaboration, is the result of more than a year of congressional hearings, roundtable discussions, whitepapers, and political debate. First introduced in April 2014 by Fred Upton (R-MI), chairman of the US House of Representatives’ Energy and Commerce Committee, and Representative Diana DeGette (D-CO), the 21st Century Cures initiative seeks to “accelerate the pace of cures in America.”

The legislative phase of the 21st Century Cures initiative began in January 2015, with the release of the first discussion draft of the bill. This version proposed major changes to the drug and device development process and touched on issues related to human subjects protections, the sharing of clinical trial data, expanded access, adaptive clinical trial designs, orphan drugs, and much more. The reaction to the discussion draft was varied, with supporters hailing the collaborative and transparent nature of the bill’s development, and critics voicing concerns over provisions that they believed would negatively affect patient safety.

Over the next several months, additional discussion drafts were released and the 21st Century Cures Act was further refined, with later versions representing “a less aggressive streamlining of the drug approval process.” Nonetheless, the version of the 21st Century Cures Act that was passed by the House on July 10 proposes significant changes and has prompted debate among scientists, academics, industry representatives, patient advocacy groups, and regulators.

One element of the 21st Century Cures Act that has been met with a mixed reception are provisions that would broaden the evidence base that can be used to demonstrate the safety and efficacy of drugs and devices. Some have praised the changes for their ability to expedite the drug and device approval process, while others have expressed concern that the proposed changes will lower safety standards. In an opinion piece for The New England Journal of Medicine, Jerry Avorn, MD, and Aaron S. Kesselheim, MD, JD, MPH, raised concerns that the bill would take the United States back in time in terms of drug and device approval. They write, “Embedded in the language of the 21st Century Cures Act are some good ideas that could streamline the development and evaluation of new drugs and devices; its call for increased NIH funding may prove to be its most useful component. But political forces have also introduced other provisions that could lead to the approval of drugs and devices that are less safe or effective than existing criteria would permit.”

Tucked within the lengthy 21st Century Cures Act are a number of provisions that apply directly to the clinical trials process and human subjects protections. Early versions of the draft legislation called on the Secretary of the Department of Health and Human Services (DHHS) to make modifications to the existing regulations for the protection of human subjects so as “to ensure that human subject research that is subject to the Federal Food, Drug, and Cosmetic Act or to section 351 of this Act, and is therefore subject to parts 50, 56, 312, and 812 of title 21, Code of Federal Regulations (or any successor regulations), is not subject to subpart A of part 46 of title 45, Code of Federal Regulations (or any successor regulations).” However, in the version that was ultimately approved by the House, that language, which raised concerns among some in the research protections community, was removed.

The legislation now focuses more broadly on directing the Secretary of DHHS to make modifications to existing regulations governing the protection of human subjects in order to: harmonize FDA and DHHS requirements to the extent possible; modernize the provisions for multi-site and collaborative research projects; “reduce regulatory duplication and unnecessary delays;” and “incorporate local considerations, community values, and mechanisms to protect vulnerable populations.” The legislation also calls on the Secretary of DHHS to ensure that federally funded research can use joint or shared review and to provide further guidance on such arrangements. The use of central IRBs for the review of multi-site research is further supported later in the bill by a provision that requires Section 520 of the Federal, Food, Drug, and Cosmetic Act be amended to remove the term “local.” This change will allow for centralized review of FDA-regulated studies involving a device.

Another noteworthy provision would amend the Federal Food, Drug, and Cosmetic Act in order to allow for waivers of informed consent for drug and device research in situations where “the proposed clinical testing poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of the human subject.” This change would eliminate one of the significant differences between the FDA and DHHS regulations governing the protection of human subjects.

The 21st Century Cures Act also proposes a number of changes that would allow for easier access to health data for use in research. Specifically, the 21st Century Cures Act calls for amendments to the HIPAA Privacy Rule “to allow: (1) use of protected information for research purposes to be treated as use for health care operations, (2) remote access to information by researchers, and (3) individuals to authorize future use of their information for research.” In addition to the specific provisions outlined above, the bill also addresses the need to include patient perspectives in the drug development process, the promotion of pediatric research, the inclusion of under-represented communities in clinical trials, and the issue of reducing administrative burden for researchers.

With the passage of the 21st Century Cures Act by the House, attention has turned to the Senate, which is working on a parallel bill under the leadership of Lamar Alexander (R-TN), chairman of the Committee on Health, Education, Labor, and Pensions (HELP); and Patty Murray (D-WA), ranking minority member of HELP. Over the past several months, HELP has held a number of congressional hearings and is gathering information as they work to develop their own legislation aimed at fostering biomedical innovation. Most recently, Senator Alexander informed a National Academies panel charged with “develop[ing] a new framework for Federal regulation of research universities in the 21st century” that he welcomes their input and encourages the group to provide preliminary recommendations by the end of the summer, so that their work can be incorporated into the Senate’s efforts.

Earlier this year, Upton and DeGette, who moved the 21st Century Cures Act quickly through the House, shared that they hope to have a final bill signed into law by year’s end. Ultimately, however, the feasibility of that goal is dependent on the Senate, which appears to be moving at a slower pace than the House did.

Portions of this post were adapted from an article titled 21st Century Cures Looks to Modernize Clinical Trials which appeared in the May 2015 edition of the PRIM&R Member Newsletter. The PRIM&R Member Newsletter is distributed once a month to PRIM&R members. To learn more about the PRIM&R Member Newsletter, as well as other member benefits, please visit our website