The Common Rule: Human Samples, Ethics, and the Future of Biomarker Research

The Common Rule is the regulation governing research involving human subjects (subpart A of 45 Code of Federal Regulation part 46).  The original Common Rule was adopted in 1991 at a time when research was predominantly conducted at universities, colleges, and medical institutions, and each study generally took place at only a single site.  The evolution of research involving human subjects over the past two decades has revealed ambiguities in the original regulations and has led to questions regarding the effectiveness of the current regulatory framework to meet the needs of the researchers and research subjects.  On July 22 2011, the department of Health and Human Services (HHS) released an Advanced Notice of Proposed Rulemaking (ANPRM) for Revisions of the Common Rule.  This noticed was officially published in the Federal Register on July 25^th 2011 under the title:”Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators“.  Over the past 90 days, HHS has sought comment on seven key issues (link):

1. Revising the existing risk-based framework to more accurately calibrate the level of review to the level of risk.
2. Using a single Institutional Review Board review for all domestic sites of multi-site studies.
3. Updating the forms and processes used for informed consent.
4. Establishing mandatory data security and information protection standards for all studies involving identifiable or potentially identifiable data.
5. Implementing a systematic approach to the collection and analysis of data on unanticipated problems and adverse events across all trials to harmonize the complicated array of definitions and reporting requirements, and to make the collection of data more efficient.
6. Extending federal regulatory protections to apply to all research conducted at U.S. institutions receiving funding from the Common Rule agencies.
7. Providing uniform guidance on federal regulations.

As of October 26^th 2011, the 90-day period for public comment has been closed.

In the October 20^th 2011 of Nature (link), Krishanu Saha and J. Benjamin Hurlbut discuss these proposed changes to the Common Rule in the context of biobanking. The authors argue that the revision to the regulations does little, or even worsens, the current disconnect between research subjects and researchers.  Indeed, the proposed changes to the Common Rule encourage the use of blanket informed consent that in effect, ask donors to authorize all possible future research unless they opt out of specific research categories (see also previous post:  Enabling Retrospective Biomarker Studies: Resolving the Conflict between Short and Long Term Goals).  While this evolution of the informed consent removes the ambiguity associated with the original Common Rule (which resulted in legal disputes), according to the authors, it poses the risk of reducing the involvement of the public in sample donation by further distancing the research subjects from the research performed on their samples.  As a solution, the authors advocate for a model in which the research subjects are actively involved.  For example, disease advocacy groups have succeeded in mobilizing research subjects by making them active players in the prioritization of research activities.  Companies like PatientsLikeMe and 23andMe attract research subjects by providing feedback about and control over the research conducted with volunteer samples.

The idea of offering dynamic feedback about and control over research activities to research subjects using for example, interactive web portals seems attractive at first glance.  Research subject could decide in real-time to opt in or out of certain research activities.  Researchers could easily gather supplemental information about research subjects.  However, under this model, the rules of research subject anonymity imposed by the Health Insurance Portability and Accountability Act (HIPAA) would be substantially more difficult to maintain and would require considerably stronger security measures to prevent accidental and/or malicious identification of subjects.  Also, the possibility of providing to research subjects feedback about research activities would open the door to the thorny issue of revealing unverified medical finding to the subjects.  Even if such communication were to occur via the subject’s physician, the exploratory nature of the research precludes the use of those findings for medical decision making.  Actually, the company 23andMe has been under increased scrutiny from the FDA Center for Devices and Radiological Health (CDRH) for providing research-grade genetic information to their customers (see earlier post: Genetic biomarker: the power and risk of knowing), even though the company claims that this information is not for medical decision making.

The proposed changes the Common Rule provide a welcome clarification of the regulations governing the collection and use of samples from human subjects.  While one can argue that these changes are not ideal, it is also true that the original version of the Common Rule exposed researchers and research subjects to a significant level of ambiguity.  Ultimately, the changes to the Common Rule are designed serve the greater good for society by facilitating medical research while preserving the right of research subjects.  


Thierry Sornasse for Integrated Biomarker Strategy
(The views expressed in this post are my own and are not meant to reflect the opinion of any other party)

Enabling Retrospective Biomarker Studies: Resolving the Conflict between Short and Long Term Goals

In the field of clinical biomarker research, it is common to need to explore new hypotheses after the conclusion of a clinical study (i.e. retrospective studies).  However, if the proper samples are not available, even the best ideas are no more than fantasies.  While this statement might seem trivial, it is surprising to discover that many bio / pharmaceutical companies struggle to implement the proper strategic and tactical steps to enable retrospective biomarker studies. 

In my experience, the most common strategic issue facing bio / pharmaceutical companies in this area is in resolving the conflict between short term and long term corporate goals.  Specifically, in the context of the conduct of clinical studies, the need to meet recruitment quotas and deadlines often clashes with the proposal to acquire supplementary samples that, at the time, have only theoretical value (i.e. potential use in retrospective studies).  Indeed, there is a general consensus among the teams responsible for running clinical trials (i.e. clinical operation) that adding sample collection procedures can complicate approval of protocols by the Institutional Review Boards (responsible for clinical study protocol approval on behalf of the institution and their patients) and can impede patient recruitment.  Therefore, unless there is a strong concrete justification for collecting certain samples, additional sample collections tend to be excluded from clinical protocols.  The solution to this apparent conflict resides in a strong corporate policy in support of biomarker research in general and retrospective biomarker research in particular.  Without the assurance that the logistical constrains imposed by sample acquisition for biomarker research will be fully acknowledged as a factor affecting the conduct of clinical studies, clinical operation will favor the bottom line (i.e. completion of studies in the shortest possible time).

Beyond a biomarker-friendly corporate attitude, the scientists and clinicians responsible for biomarker research need to have a sound understanding of the logistical impact of additional sample collection on clinical studies.  Biomarker researchers need to be able to negotiate intelligently with their colleagues in clinical operation.  Reciprocally, clinical operation staff needs to be with the scientific questions explored by the biomarker researchers.  Therefore, cross-training of biomarker researchers and clinical operation staff is one of the key aspects of a successful clinical biomarker research program.

In some cases, clinical samples that were collected for one purpose (e.g. pharmacokinetics) can be repurposed for biomarker research.  However, if the proper informed consent was not put in place at the time of sample collection, using these samples for retrospective biomarker studies is not acceptable.  Indeed, current ethical and legal standards mandate that all individuals enrolled in a clinical study be fully informed about the use of the biological samples collected in course of the study.  The issue of drafting informed consent forms that adequately inform the patients about future biomarker research can be quite tricky.  While it is impossible to describe all potential future use of clinical samples for biomarker research, it is important to define the overall intent and the limit of this research.  Also, it is often desirable to draft the informed consent form with the option for the patient of opting in (or out) of future biomarker research. 

Finally, assuming that clinical samples exist and are properly consented, efficient retrospective biomarker research requires a solid sample management system.  Beyond the physical inventory of samples, such as system ideally needs to seamlessly integrate anonymized patient medical information, clinical study specific information, consent status (whether patient opted in or out of biomarker research), and prior data obtained from these samples.  Hence, an efficient patient sample management is as much about inventory management as it is about information management.

Thierry Sornasse for Integrated Biomarker Strategy