Category: Human Subjects Research

Weighing Risks in a Pediatric Anthrax Vaccine Clinical Trial

The Petrie-Flom Center Staff 1 Comment

by Brendan Abel, JD

Countless regulations have been enacted over the past 35 years to protect children from unnecessary clinical testing. Federal regulations, the Belmont Report, and professional guidelines all state that children should be enrolled in clinical trials only when the research is a high imperative. Federal research regulations insist that absent a potential for direct benefit to the participating child, research should take place only if there is “minimal risk” or “minor increase over minimal risk.”

Thus, it was surprising that one year ago, the National Biodefense Science Board (NBSB), an advisory panel to the Secretary of Health and Human Services, recommended that HHS develop and implement a study of pre-exposure anthrax vaccine in pediatric populations. Such a vaccine would subject children to risks with little potential for therapeutic benefit. The matter is now in front of the President’s Commission for the Study of Bioethical Issues, at the request of Secretary Kathleen Sebelius, who in May visited the Commission to ask for advice regarding the ethical issues raised by this potential study. The  Commission’s recommendation is expected early next year.

Much of the controversy surrounding anthrax-vaccine testing in the pediatric population relates to the issue of timing. Since the vaccine can be used either prophylactically or as a post-exposure treatment, the government is considering whether children should be tested now to determine safety, efficacy, and dosing levels in a structured, controlled environment, or whether it is best to avoid subjecting children to the risks of the testing and to face an (unlikely) anthrax attack without the knowledge that would be gained from such a study.

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Reporting Information about Clinical Trial Data: Passing the Torch from HHS to the FDA

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By Leslie Francis

In 2007, motivated by concerns that pharmaceutical companies were not sharing negative data about what had been learned in clinical trials, Congress established enhanced reporting requirements.

A series of articles published in January 2012 in the British Medical Journal demonstrates that data reporting remains deeply problematic, especially for industry-sponsored trials. (The articles can be found here and are very much worth reading).

A posting Sept. 26 in the Federal Register indicates that the Secretary of HHS has delegated authority to to oversee the reporting process to the FDA.  Whether this signals improved monitoring of clinical trial data submissions remains to be seen.  One can only hope.

PCSBI: Privacy and Progress in Whole Genome Sequencing

Holly Fernandez Lynch Leave a comment

Yesterday, President Obama’s Commission for the Study of Bioethical Issues released its fifth report: Privacy and Progress in Whole Genome Sequencing.  I haven’t had a chance to digest it yet, but for now, just wanted to call it to everyone’s attention.  The gist seems to be privacy, privacy, privacy.

Here are the major recommendations, straight from the Commission’s “mouth”:

Recommendation 1.1
Funders of whole genome sequencing research; managers of research, clinical, and commercial databases; and policy makers should maintain or establish clear policies defining acceptable access to and permissible uses of whole genome sequence data. These policies should promote opportunities for models of data sharing by individuals who want to share their whole genome sequence data with clinicians, researchers, or others.

Recommendation 1.2
The Commission urges federal and state governments to ensure a consistent floor of privacy protections covering whole genome sequence data regardless of how they were obtained. These policies should protect individual privacy by prohibiting unauthorized whole genome sequencing without the consent of the individual from whom the sample came.

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FDA Drug Amendments: Still a good fit at fifty?

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Fifty years ago on Wednesday, President Kennedy signed into law the US Food and Drug Amendments. The amendments radically overhauled the way in which manufacturers brought drugs to market. Most importantly, the amendments instituted the four-phase review process and the requirement that manufacturers get informed consent from people receiving experimental drugs. If the past fifty years is any indication, though, its unlikely that FDA’s current regulations are well suited to deal with the changing context of medicine, including clinical trials of stem-cell therapies forecasted with the Nobel Prize Committee’s awarding of their prize in Physiology or Medicine earlier this week.

The amendments’ supporters had good intentions and the regulations have had positive effects overall. Yet the US government is still trying to redress many of their negative consequences. The rules have proven to be outmoded for new circumstances that policymakers did not have in mind when they created the amendments five decades ago.

The four-phase review process requires that manufacturers apply to the FDA and submit drugs for agency review three times—at least. One consequence of the four-phase review system is that it extended the time until consumers could access new therapies. This can seem a small price to pay to assure that drugs are safe and effective, a phrase that has become the slogan for the Amendments. People with new, fast-moving diseases, however, have seen the delay as a death sentence. For example, sociologist Steven Epstein has written extensively and carefully about the response to drug delays in the 1980s and 1990s among the HIV/AIDS activist community. The FDA has responded with changes, such as a fast-track approval system, but these shifts tend to come only in response to dire crises.

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Upcoming Event – Frank Miller on Placebo-Controlled Trials Before Informed Consent

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What were they thinking? Placebo-controlled trials before informed consent

Franklin G. Miller, Ph.D., Department of Bioethics, National Institutes of Health

October 25, 2012 – 4pm

Shapiro Clinical Center JCRT 5A (East Campus), Beth Israel Deaconess Medical Center, Boston, MA

Sponsored by the Program in Placebo Studies and the Therapeutic Encounter; Martinos Center for Biomedical Imaging; MGH; BIDMC Division of General Medicine and Primary Care; HMS Department of Global Health and Social Medicine

For more information call 617-945-7827

Why Consent Is a Requirement for Ethical Research

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by Jonathan J. Darrow

In a Petrie-Flom Center event last month, Dr. Alan Wertheimer raised the question of why consent is needed in ethical research.  Without commenting on his answer to the question (attendees were asked not to do so), I would like to offer two principal lenses through which an answer can be understood: one by analogy to contract, and one by analogy to tort.

First, informed consent is needed to ensure that there is a “meeting of the minds” between the researcher and the research subject.  The concept of a meeting of the minds will be familiar to all first-year law students who have taken a course on contracts, and relates to the need for each party to assent to the essential elements or terms of the contract.  See 17A Am. Jur. 2d Contracts § 30.  In lay terms, a meeting of the minds is needed in order to protect the reasonable expectations of each party.  Just as each party to a contract desires to know, in advance, what must be given and what can be expected to be received, so too must each party to a research subject agreement know what is expected of him or her and what benefits are likely to accrue.  (Because of information asymmetries, with the researcher normally knowing far more than the subject about the nature of the proposed relationship, consent need only be required of the subject).

Second, consent is needed to avoid what essentially amounts to misappropriation or conversion.  Without an understanding of what the researcher will gain from the research, the subject may feel that what was taken from him or her was wrongfully converted to the benefit of the researcher.  The feeling that one’s property has been converted to the benefit of someone else, without appropriate disclosure or compensation, seems to have been a primary motivation to bring suit in the famous case of Moore v. Regents, 793 P.2d 479 (Cal. 1990), where cells extracted from a patient became potentially valuable to the researcher. While the analogy of this second lens is to tort law, rather than contract, the underlying motivation is the same: to protect the reasonable expectations of the subject, and thereby allow the subject to make a choice that he or she is less likely to later regret.

Innovative Approaches to Pharmaceutical Innovation: Alternative R&D Mechanisms

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by Adriana Lee Benedict

Earlier this year, the World Health Organization’s Consultative Expert Working Group on Research and Development: Financing and Coordination (CEWG) issued a report calling for, inter alia, increased support for innovative pharmaceutical R&D funding mechanisms.  Although lack of financing has posed a challenge to implementation of alternative approaches to R&D, the increasing pace of pharmaceutical innovation has certainly spurred significant innovation in this realm.  These approaches can be broadly categorized into “push” and “pull” incentive mechanisms.

“Pull” mechanisms–such as advance market commitments, prize funds, and expedited regulatory review—reward R&D outcomes by facilitating translation of innovation to marketable products.  Several “pull” mechanisms have yet to be tested.  For instance, pay-for-performance mechanisms, such as those contemplated by the proposed Health Impact Fund, would use government and donor financing pay for performance in lieu of normal profits gained from market exclusivity.  Other untested ideas include patent buy-outs, transferable IP rights and market exclusivity, reduction of patent length, and “optimal hedging to smooth public health expenditures”.

“Push” mechanisms, on the other hand, fund R&D at earlier stages. Patent pools, for instance, bring patents into a collectively owned and managed pool that can issue voluntary licenses to generic companies for product development. Other “push” mechanisms that have seen some success include targeted disease-specific funding, health innovation networks for the “Global South”, capacity-building and technology transfer initiatives, open-source and crowd-sourced R&D for neglected and rare diseases, and private-public product development partnerships.  “Push” mechanisms that have been proposed but not yet tested include taxes on patents; proportional, tiered or stage-specific partial prizes; and making undisclosed clinical trial data an international public good. Innovative financial proposals that de-link R&D investment from profits include linking donor funding to technology transfer commitments, cost sharing for clinical trials, for-profit investment partnerships, neglected disease and global health tax credits, and additional fees on patent applications (called “Green IP”).

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Social Inequality in Clinical Research

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by Suzanne M. Rivera, PhD

For a variety of reasons, racial and ethnic minorities in the US do not participate in clinical research in numbers proportionate to their representation in the population.  Although legitimate mistrust by minorities of the healthcare system is one reason, institutional barriers and discrimination also contribute to the problem.  The equitable inclusion of minorities in research is important, both so that they receive an equal share of the benefits of research and to ensure that they do not bear a disproportionate burden.

Under-representation is not just a question of fairness in the distribution of research risks.  It also creates burdens for minorities because it leads to poorer healthcare.  Since participation in clinical trials provides extra consultation, more frequent monitoring, and access to state-of-the-art care, study participation can represent a significant advantage over standard medicine.  To the extent that participation in research may offer direct therapeutic value to study subjects, under-representation of minorities denies them, in a systematic way, the opportunity to benefit medically.

For many years, our system for drug development has operated under the assumption that that we can test materials in one kind of prototypical human body and then extrapolate the data about safety and efficacy to all people.  That’s a mistake; the more we learn about how drugs metabolize differently based on genetics and environmental factors, the more important it becomes to account for sub-group safety and efficacy outcomes.  More recently, greater emphasis has been placed on community-based participatory research.  This movement toward sharing decision-making power between the observer and the observed is a critical step for addressing both the subject and researcher sides of the inequality equation.

Research Exceptionalism Diminishes Individual Autonomy

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by Suzanne M. Rivera, Ph.D.

One of the peculiar legacies of unethical human experimentation is an impulse to protect people from perceived research risks, even when that means interfering with the ability of potential participants to exercise their own wills.  Fears about the possibility of exploitation and other harms have resulted in a system of research oversight that in some cases prevents people from even having the option to enroll in certain studies because the research appears inherently risky.

Despite the fact that one of the central (some would say, the most important) principles of ethical human research is “respect for persons,” (shorthand: autonomy), our current regulations– and the institutions that enforce them– paradoxically promote an approach to research gate-keeping which emphasizes the prevention of potential harm at the expense of individual freedom.  As a result, research activities often are treated as perils from which unsuspecting recruits should be shielded, either because the recruits themselves are perceived as too vulnerable to make reasoned choices about participation, or based on the premise that no person of sound mind should want to do whatever is proposed.

One example of such liberty-diminishing overprotection is the notion that study participants should not be paid very much for their time or discomfort because to provide ample compensation might constitute undue inducement. Although there is no explicit regulatory prohibition against compensating research participants for their service, The Common Rule requires researchers to “seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.”  This has been interpreted by many to mean that payment for study participation cannot be offered in amounts greater than a symbolic thank you gesture and bus fare. Read More

When Do Doctors Discount Clinical Trial Results?

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by Jonathan J. Darrow

A research study reported today in the New England Journal of Medicine found that physicians are able to discriminate between clinical trials with high levels of rigor versus those with low levels of rigor, as well as between clinical trials that are funded by industry and those that are funded by the government.

The randomized study analyzed the responses of 269 physicians who were presented with hypothetical abstracts of clinical trial findings for three hypothetical drugs.  Abstracts were deliberately crafted to reflect three levels of clinical trial rigor (low, medium, and high), and three types of funding disclosure (no disclosure, National Institutes of Health funding, and pharmaceutical industry funding), yielding 27 abstract types.

The major finding of the study was that physicians are less willing “to believe and act on trial findings, independent of the trial’s quality,” if the trial is funded by industry.  That industry funding led to a decrease in perceived credibility, even for large and well-designed trials, concerned the study authors, who felt that “[t]he methodologic rigor of a trial, not its funding disclosure, should be a primary determinant of its credibility.”

The full article citation is: Aaron S. Kesselheim et al., A Randomized Study of How Physicians Interpret Research Funding Disclosures, 367(12) New Eng. J. Med. 1119 (Sept. 20, 2012). Available here.

[Editorial Note: And within the et al. is Chris Robertson, a former Petrie-Flom Academic Fellow, current prof at University of Arizona, and future guest blogger here at Bill of Health!]