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


Thursday, August 27, 2015

#TBT - An August to Remember: Celebrating the Animal Welfare Act

By Angela Craig, DVM, lab animal veterinarian and institutional animal care and use committee (IACUC) member at the University of Minnesota

If you were to reflect on important events that occurred in 1966, a legal decision handed down that year had such impact as to influence the conduct of our society every day thereafter. History buffs may think I’m referring to the Supreme Court decision in the case of Miranda v. Arizona which protected the rights of the accused, and introduced the Miranda warning. While this was undeniably monumental and provided necessary protections within the criminal justice system, it was not the only important safeguard measure enacted that year. For animals, the critically significant Public Law 89-544 was signed into existence on August 24, 1966. It is more familiar to us as the Animal Welfare Act (AWA).

This original AWA responded to societal concerns about the treatment of animals, specifically defining how dogs, cats, and certain other animals would be procured, transported, and used for research, among other things. To this day, the AWA is the only federal law describing the requirements for how animals are to be treated in the United States of America; its enforcement falls to the United States Department of Agriculture. Given its critical importance in providing direction and protection for animals, it is no surprise that the AWA has changed over time to remain current with societal standards and to address new concerns as they arise.

The AWA has been amended seven times since 1966, with each change providing greater clarity of expectations and expansion of coverage. In 1985, the Improved Standards for Laboratory Animals Act amendment (also called the Food Security Act) provided additional direction on standards for sanitation, housing, and ventilation for lab animals. Exercise requirements for dogs and the promotion of psychological well-being in nonhuman primates were other key changes. The Institutional Animal Care and Use Committee (IACUC) was introduced and described, and so many things considered standard practices of IACUCs today—such as the minimization of pain and distress, and the consideration of alternatives to painful procedures—were written into law in this amendment.

The AWA has been criticized by some who focus on its limitations. For instance, it does not cover birds, rats of the genus Rattus, and mice of the genus Mus—animals common to research. However, many other policies and guidance documents provide standards and expectations to supplement those found in the AWA and cover additional species. These include the Guide for the Care and Use of Laboratory Animals, the Public Health Service Policy on Humane Care and Use of Laboratory Animals, the Guide for the Care and Use of Agricultural Animals in Research and Teaching, and the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training.

Another criticism is that the AWA “only” describes the minimum expected standards for facilities, husbandry, transport, and veterinary care. One can argue, convincingly, that laws are not the sole motivation that drives animal care and use professionals to make appropriate decisions about animal care and well-being. The AWA ensures action will be taken against those who do not meet minimum standards. Yet, many individuals and institutions exceed the Act’s expectations each day in their conduct and care. They strive to surpass the idea of ‘minimally acceptable’ and exemplify what is infinitely possible with continued refinement and dedication to best practices in every aspect of their work with animals. Their choices have nothing to do with legality and everything to do with an enduring commitment to animal welfare.

When we look back years from now, we’ll know the outcomes of current discussions related to the Animal Welfare Act. Rather than exercise our right to remain silent, the AWA reminds us of our duty to be vocal about how we can best provide high quality care to our animals while furthering improvements in human and animal health.  The two are not mutually exclusive. New standards will be based on the changing values of society, and as knowledgeable members of that group, we must listen closely and contribute to the conversation to keep the Animal Welfare Act robust and applicable for decades to come.

Wednesday, August 26, 2015

PRIM&R’s Comments in Response to Framework for NIH-wide Strategic Plan

by Avery Avrakotos, Education and Policy Consultant
On July 22, the National Institutes of Health (NIH) announced it was seeking comment on a framework for a five-year, NIH-wide Strategic Plan. The plan, which will ultimately be submitted to Congress and is being generated with input from senior leadership and staff across NIH, is intended to “outline a set of unifying principles to guide NIH in pursuit of its mission” and “highlight major trans-NIH themes” in order to help advance the biomedical research enterprise.

In the framework, NIH identifies three areas of opportunity that apply across biomedicine: (1) the promotion of fundamental science, (2) the improvement of health promotion and disease prevention, and (3) the advancement of treatment and cures. In addition to the crosscutting areas of research, NIH identifies two unifying principles: (1) set NIH priorities, and (2) enhance stewardship. Notably absent from the areas of opportunity and unifying principles identified is an explicit discussion of NIH’s role in promoting the ethical conduct of research.

Recently, PRIM&R’s Public Policy Committee, which is composed of experts from a range of disciplines and institutional settings, responded to NIH’s request with a brief letter. In this response, PRIM&R acknowledges the role that NIH has played in promoting human subjects protections, the ethical conduct of science, and scientific integrity, and asks the Institutes to build on that history and ensure that the centrality of ethics in the research enterprise is reflected in its forthcoming strategic plan.

Specifically, PRIM&R encourages NIH to add the following as a unifying principle in its strategic plan:
Integrate Ethics—NIH integrates ethics, including principles for the ethical conduct of science, robust human and animal subject protections, and scientific integrity, by ensuring that ethics is an integral component of scientific design, the training of scientists, grant and contract review, the sharing, dissemination, and assimilation of research results, and public education.

PRIM&R goes on to note that the success of NIH’s crosscutting objectives “rests on a scientific enterprise that is and appears to be based on ethical principles, including transparency and independence from financial and other outside interests” and that “explicit inclusion of ethics as a unifying principle of the framework will serve as a strong affirmation to the community of scientists that attending to research ethics is not a wasteful ‘burden’ but a means to better and more sustainable research.”

Take a moment to read PRIM&R’s complete response to NIH and to share your thoughts about PRIM&R’s comments or the framework for the NIH-wide Strategic Plan in the comments below.

Friday, August 21, 2015

Research Ethics Roundup: Exploring Research Misconduct, Alternatives to Animal Models, and More

New techniques and technologies are changing the way we think about research. This week’s Research Ethics Roundup explores some of those developments, including the growing use of randomized trials to evaluate social programs and continued efforts to create alternatives to animal models.

 A Scientific Look at Bad Science: In this piece for The Atlantic, Bourree Lam reviews recent literature in an effort to answer the question: “are retractions increasing because errors and other misdeeds are becoming more common, or because research is now scrutinized more closely?”

Can We Eliminate Animals from Medical Research?: Teal Burrell reports on efforts to develop alternatives to animal models, including the work of Donald Ingber, MD, PhD, who developed a lung-on-a-chip, in this piece for NOVA Next.

Can Randomized Trials Eliminate Global Poverty? : Economists are increasingly turning to randomized trials in order to generate empirical data on the effectiveness of social programs. In this article for Nature, Jeff Tollefson explores this trend, as well as its history and potential future growth.

How to Know Whether to Believe a Health Study: In this piece for The New York Times, Austin Frakt explains some common elements of clinical trial design in an effort to increase understanding and help the public become “savvy consumer[s] of research.”

Registered Clinical Trials Make Positive Findings Vanish: A new study published in PLoS One suggests that the number of studies reporting positive trial results has declined significantly since 2000, when requirements for the registration of clinical trials were enacted. Chris Woolston provides insight into the study, as well as the public reaction, in this article for Nature.