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 

Overhaul of the FDA Medical Device Pre-Market Approval Program: What Does It Means for Diagnostics

On October 19^th, the FDA Center for Devices and Radiation Health (CDRH) released its Medical Device Pre-Market Programs: An Overview of FDA Actions (link).  This document presents the center’s review of the processes of pre-market approval of all medical devices, and articulates solutions to the problems identified in this review.

First, CDRH wants to dispel the misperception that safety/effectiveness and innovation are incompatible.  Their solution is not to focus on whether more or less regulations are needed but rather to focus on smart regulation: effectively achieve both aspects of the center’s mission as a regulator and facilitator.

Second, the number one problem identified from discussions with key stakeholders (i.e. industry, academia, and payers) is insufficient predictability in the pre-market program.  This lack of clarity has resulted in inefficiencies, increased cost for both the industry and the FDA, and delays in bringing safe and effective innovative products to the market.  At the root of these problems, CDRH identified excessive staff turnover, insufficient training (FDA and industry), rapidly increasing workload associated with the growing complexity and number of submissions, inconsistent data requirements, insufficient guidance for the industry, and poor quality of industry submissions.

To address these issues, CDRH is proposing a set actions centered on three areas of emphasis:

1. Create a culture change toward greater transparency, interaction, collaboration, and the appropriate balancing of benefits and risks
1. Better engagement with industry
1. Improve Interactive Review (informal call to the submitter) to accelerate review time
2. Improve pre-submission meetings to specify consistent and stable submission expectations
2. Greater use of external experts
3. Implementing flexible, risk-based policies that appropriately balance benefits and risks and apply a more patient-centric approach
4. Establishing new ways of doing business that add value
1. Create an innovation pathway (an entirely novel approach) to enable the timely review of ground-breaking technologies
5. Setting clear expectations for CDRH staff
2. Assure predictable and consistent recommendations, decision making, and application of the least burdensome principle
1. Providing adequate management oversight and staffing
2. Enhancing training
3. Improving internal processes
4. Adopting smarter policies and issuing more guidance
5. Developing new communication tools
3. Implement efficient processes and use of resources
1. Making existing processes more efficient
2. Using our resources more effectively
3. Improving our ability to rely on data from outside the U.S. and actions by regulatory bodies of other countries

For regulatory purposes, diagnostics are medical devices.  Therefore, the changes proposed by CDRH will affect the submission and approval of novel diagnostics.  Specifically, the development and approval of diagnostics will most likely benefit from the improved review process with greater predictability and transparency.  The commitment of CDRH to actively interact with the sponsors will most likely provide greater efficiency and reduced review time.  The call for enrolling experts in the relevant fields should streamline the process of defining the requirements for successful submissions.

While these improvements are promising, CDRH makes no secret that a significant number of these solutions will require additional funding.  The ongoing negotiations of the reauthorization of user fees will therefore most likely result in higher cost for the sponsors.  In keeping with this move, CDRH emphasizes the concept of shared responsibilities by stating: “We must fully embrace the paradigm that assuring the safety and effectiveness of devices is everyone’s job and the responsibility resides as much with industry, practitioners and patients as with the Agency”.

The specific aspect of review of approval of companion diagnostics is not specifically addressed in this report.  The sometime chaotic relationship between CDRH and its drug reviewing counterpart CDER would certainly benefit from a similar review.

Thierry Sornasse for Integrated Biomarker Strategy

Volumetric MRI and Neuropathology in the Elderly: a Key Bridging Study

In the October 17^th issue of PLoS One, Robert Dawe and colleagues, from the Illinois Institute of Technology and the Rush Alzheimer’s Disease Center, present the results of a key bridging study of volumetric MRI correlation with normal aging, Alzheimer’s disease (AD), and additional neuropathologies frequently associated with aging (link).

As mentioned in an earlier post (Biomarker Qualification Consortia: The ADNI Success Story), in vivo volumetric MRI of specific region of the brain (i.e. medial temporal lobe à hippocampus) has been shown to be a valuable biomarker of disease progression in AD and mild cognitive impairment (MCI).  While the correlation between reduction in hippocampal volume and histopathologically confirmed AD has been conclusively demonstrated, the effect of other neuropathologies generally associated with aging on hippocampal volume remained ill-defined.

In order to address this gap in knowledge, the authors combined antemortem imaging studies, antemortem cognitive testing, postmortem MRI on isolated brain hemisphere, and histopathology on the brains of 100 elderly subjects from the Rush Memory and Aging Project, and the Religious Order Study (two longitudinal clinical-pathologic studies of aging).  The authors confirmed the strong association between reduced hippocampal volume and the diagnostic of AD (determined prior to death based on cognition test and determined postmortem based on histopathology).  In addition, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory.  Other pathologies such as Lewy bodies, moderate amyloid angiopathy, gross infarcts, and micro infarcts were not significantly associated with reduced hippocampal volume.  In contrast, hippocampal sclerosis (HS) was strongly associated with significant reduction in hippocampal volume independently of the presence or absence of co-occurring AD pathology (of 13 individuals with HS, 9 had also AD pathology and 4 had not other pathology).  In fact, the association of HS and reduced hippocampal volume was more pronounced than that observed in AD.  Shape analysis of the hippocampal surface confirmed prior knowledge namely that hippocampal volume reduction in AD is more pronounced in the head and tail of the hippocampus, and that these changes tend to be more homogeneously distributed in HS.  The authors did not discuss whether shape analysis of the hippocampal surface could be used to distinguish between AD and HS.

Despite some minor limitations: the postmortem MRI performed on isolated brain hemispheres precluded the measurement of cranial volume, this study provides a highly valuable bridge between in vivo volumetric MRI measurements and underlying neuropathology.  


Thierry Sornasse for Integrated Biomarker Strategy

Magnetic Resonance Spectroscopy to Monitor Tumor Metabolism: Not a Biomarker Yet But a Promising Concept

In the October 12^th issue of PLos One, Alessia Lodi and Sabrina Ronen from UCSF published the results of their work on the use of Magnetic Resonance Spectroscopy (MRS) to monitor the metabolic activity of tumor cells (link).  Although this work was entirely conducted in vitro on cell lines, the concept presented in this paper offer a glimpse at a possible new approach to monitor drug effect early during treatment.  Indeed, there is ample evidence that anti-cancer drugs alter the metabolic profile of cancer cells before producing detectable effects on tumor size (detectable by CT scan or MRI) or even overall metabolic activity (detectable by FDG-PET).

The utility of MRS to monitor early metabolic changes induced by drugs in cancer cells has been demonstrated before.  However, these earlier studies focused on single metabolites which limited their observations to the specific drug – cell combination studied.  In this work, the authors expanded on earlier work MRS use for the monitoring of cancer cell metabolism by used an unbiased 1H MRS-based metabolomics approach to investigate the overall metabolic consequences of treatment with the phosphoinositide 3-kinase inhibitor LY294002 and the heat shock protein 90 inhibitor 17AAG in prostate and breast cancer cell lines.

Obviously, translating this concept to human patients, in which complexity will be several orders of magnitude greater, will not be easy but one can speculate that as MRS technology further progresses, tracking multiple metabolites in vivo will become trivial. 


Thierry Sornasse for Integrated Biomarker Strategy

An Old Diagnostic Gets the Boot: PSA Testing in Healthy Men is No Longer Recommended

This week, the United States Preventive Services Task Force is due to release its draft recommendation on the use of the Prostate-Specific Antigen (PSA) test in healthy men of all ages.  The PSA test has been a standard tool in urology to assist in the diagnosis of prostate cancer.

Essentially, this recommendation states that the PSA test in healthy men has no clinical benefit, does not save lives, and actually may lead to unnecessary follow up tests and procedures that can have deleterious effects on the patient’s health (see The New York Times article).

These conclusions are based on the results of five well-controlled clinical studies which confirm the general empirical consensus about the PSA test: its lack of specificity and sensitivity result in unacceptable numbers of false positive and false negative tests, respectively.  In particular, false positive tests are particularly troublesome since a positive test will usually lead to a biopsy and treatment that can lead to impotence and/or incontinence.  While those risks of complications are somewhat acceptable for actual prostate cancer patients, they are unacceptable for individual who have misdiagnosed.

This recommendation by the United States Preventive Services Task Force is already producing strong reactions from prostate cancer survivors and advocacy groups.  The idea of shelving the PSA test is unacceptable to those who feel that this diagnostic saved their live.  The truth is that neither the PSA test nor other currently available tests are particularly useful in detecting prostate cancer.  Hence, there is an urgent need to develop, clinically validate, and deploy effective tools for the early detection of prostate cancer in apparently healthy men.  Ironically, the dominance of the PSA test on the market has probably a substantial obstacle to the development of new diagnostic in this field.  Indeed, the protectionism from a segment of the diagnostic industry with financial interest in PSA testing, as well as the difficulty to change medical practices among physicians have probably contributed to the lack of alternative prostate cancer diagnostics.  One can speculate that the new recommendation about PSA testing will open a breach for innovative tools that will actually save lives.


Thierry Sornasse for Integrated Biomarker Strategy

A New RNA Biomarker for Huntington’s Disease: Going Beyond Nerve Pathology (bis)

In the early online issue of the Proceedings of the National Academy of Sciences of October 3^rd (link), Hu and colleagues reports on a new biomarker of disease activity for Huntington’s disease (HD) based on the differential expression level of the transcript for H2AFY gene in peripheral blood mononuclear cells (PBMC).  HD is an autosomal recessive genetic disorder in which nerve cells in certain parts of the brain waste away, or degenerate.

Similarly to the recent work on ALS biomarkers published in PLoS One this month (see earlier post: New Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology), Hu et al. hypothesized that the key pathobiology affecting neurons in HD would be detectable in other cell types than neurons.  Indeed, the huntingtin protein, which has been shown to be at the center of HD pathobiology, is expressed in most tissues, including PBMC.

Using a standard transcriptomics approach, the authors surveyed the entire genome for differential RNA expression between the PBMC of HD patients, healthy controls, and other neurological disorders (Parkinson’s disease, Alzheimer’s disease, corticobasal degeneration, essential tremor, progressive supranuclear palsy, and multiple system atrophy).  Using stringent statistical criteria and pathobiological knowledge, the team selected the transcriptional modulator H2A histone family member Y (H2AFY) as the most relevant biomarker for HD.  This initial discovery was confirmed by two independent studies.  First, a cross-sectional case controlled study of an additional 36 HD patients, 9 carriers of the HD mutation with no clinical symptoms (the HD mutation has 100% penetrance and therefore all carriers will eventually develop the disease), 50 healthy controls, and one individual with spinocerebellar ataxia.  Second, a longitudinal case-control study where 25 HD patients and 21 healthy controls were followed for at least 2 years (37 subjects were followed for 3 years).

In order to link the transcriptional difference observed in PBMC of HD patients to the pathobiology of the disease, the authors analyzed the expression of the H2AFY-encoded protein MacroH2A1 in the frontal cortex of postmortem brains obtained from 12 HD patients.  While the expression of MacroH2A1 was clearly elevated in the brain of patients with grade 2 or 3 disease, this trend was not maintained in grade 4 patients.  This was most likely due to the fact that MacroH2A1 is expressed at high level in neurons and that this stage of the disease is characterized by a substantial loss of these cells.  Finally, the authors assessed the translational value of the H2AFY / MacroH2A1 biomarker in a mouse model of HD (knock-in of exon 1 fragment of the human huntingtin gene).  There again, the progression of the disease was associated with an elevation of the MacroH2A1 protein in relevant brain substructures and treatment with the experimental HDAC inhibitor sodium phenylbutyrate resulted in a decrease in the biomarker signal.

Altogether, if these observations are further confirmed, the availability of a disease progression and a disease modification biomarker for HD should constitute a major advance in the field.  Indeed, the development of drugs for the treatment of HD has been hampered by the lack of sensitivity and precision of standard clinical end points.  Similarly to other neurodegenerative diseases such Alzheimer’s and Parkinson’s disease, clinical progression in HD is slow, erratic, and relatively unpredictable at the individual level.

Beyond the direct impact of this work, the approach used by Hu and colleagues seems to signal a new trend in biomarker research: instead of limiting the scope of biomarker research to the specific anatomical compartment primarily affected by the disease, which in the case of the central nervous system is essentially inaccessible, the field may significantly benefit from considering accessible peripheral tissues which may display secondary pathobiology similar to that affecting the primary tissues.  Indeed, a similar approach was used by Nardo and colleagues to identify a potential new protein biomarker for Amyotrophic Lateral Sclerosis (PloS One October 5^th; see earlier post: New Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology)


Thierry Sornasse for Integrated Biomarker Strategy