October 27, 2011 - ASM Comments on OHRP Human Subjects Research Protection Proposed Rulemaking

Jerry A. Menikoff, M.D., J.D.
Office for Human Research Protections
1101 Wootton Parkway, Suite 200
Rockville, MD 20852

Dear Dr. Menikoff:

The American Society for Microbiology (ASM) wishes to comment upon specific aspects of the Advance Notice of Proposed Rulemaking for 45 CFR Parts 46, 160, and 164 and 21 CFR Parts 50 and 56 “Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators” (docket ID number HHS-OPHS-2011-0005) published in the Federal Register, Volume 76, Number 143, July 26, 2011 (referred to as the ANPRM).

The ASM is the largest educational, professional, and scientific society dedicated to the advancement of the microbiological sciences and their application for the common good. The Society represents more than 38,000 microbiologists, including scientists and science administrators working in a variety of areas. Areas of interest include biomedical, environmental, and clinical laboratory medicine. Many of ASM’s members are individuals responsible for directing clinical microbiology, clinical immunology and molecular diagnostic laboratories, individuals licensed or accredited to perform such testing, industry representatives marketing products for use, and researchers involved in developing and evaluating the performance of new technologies.  In all settings, members are held accountable for compliance with patient protection afforded by The Common Rule as codified at 45 CFR Part 46 as well as compliance with regulations established for patient privacy by The Health Insurance Portability and Accountability Act (HIPAA). Thus, ASM members have a strong interest in proposed changes to the regulations in the Common Rule.

In particular, we wish to comment on proposed additional regulatory requirements for informed consent for research involving biological specimen repositories. The ASM has previously raised concerns regarding the apparent conflict between the Food and Drug Administration (FDA) regulations codified at 21 CFR requiring informed consent for evaluation of In Vitro Diagnostic (IVD) devices and the categorization of studies using existing data, documents, records, pathological specimens, or diagnostic specimens if the patient sources are de-identified as exempt or qualifying for a waiver of consent as codified in 45 CFR. These concerns were addressed by the issuance of a 2006 FDA guidance document, “Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable.” This document allowed enforcement discretion under certain circumstances with regard to informed consent for IVD device investigations. Studies that qualified for enforcement discretion for informed consent were clearly defined and included de-identified “leftover specimens” such as those maintained in biospecimen repositories. Unfortunately, the issuance of revised FDA regulations for informed consent in 21 CFR 50.23(e) has contributed to renewed confusion among Institutional Review Boards (IRBs) and investigators with regard to IVD device evaluations. Industry-sponsored IVD device evaluations and investigator-initiated evaluations often use the same pool of clinical biospecimens and would be approached similarly by an IRB.

Please note that biospecimen repositories may include both patient specimens and collections of microorganisms derived from patient specimens. Our concerns apply to use of either type in studies with the exception of use of specimens for human genetic studies. We defer to scientists in the human genetics field to make recommendations on application of the proposed Common Rule changes in human genetic studies.

ASM continues to hold the position that use of de-identified “leftover” biological specimens in IVD device evaluations should not require informed consent and are subject to “enforcement discretion.” Further, use of remnant samples strictly in a CLIA-certified, HIPAA-compliant clinical laboratory should not require informed consent, and for purposes other than research, use should not require “de-identification.”  The revision to the Common Rule described in Section II, item 5, page 44515 of the ANPRM is of significant concern. Specifically, the general rule that “a person needs to give consent, in writing, for research use of their biospecimens, though that consent need not be study specific, and could cover open-ended future research” is believed to present an unnecessary obstacle to key investigative processes in the laboratory.

Our position is based on the following opinions:

  1. Remnant biospecimens represent excess material that holds no further value to the patient and would otherwise be discarded.
  2. Such biospecimens provide an essential and readily available source of material for procedure evaluations.
  3. Biospecimen repositories allow procedural investigations to proceed at minimal additional cost to the institution or to a device manufacturer.
  4. A requirement to obtain required consent would place an unnecessary administrative, technical, and financial burden on already financially strained clinical laboratories.
  5. The acquisition of a “general consent form” offers no advantage to patient protection in a clinical laboratory setting already operating under stringent HIPAA privacy and security regulations.

Our responses to specific questions raised in the ANPRM are as follows:

Question 23: Under what circumstances should it be permissible to waive consent for research involving the collection and study of existing data and biospecimens?

Response to question 23: Waiver of informed consent should apply to any remnant biospecimens that would otherwise be discarded that are being used solely in a CLIA-certified laboratory operating in compliance with HIPAA regulations. For IVD device trials, samples should continue to be de-identified. In addition, the following conditions should apply:

  1. Studies are conducted under an IRB-reviewed protocol if appropriate.
  2. Laboratory investigators are bound by existing HIPAA regulations.
  3. Samples are remnant (“leftover”) from routine clinical testing and do not represent additional samples collected for study purposes.
  4. Samples are de-identified if appropriate by personnel who normally have access to patient samples for clinical testing and who do not participate in the study.
  5. Linkage to the study sample is secured and destroyed upon study completion if appropriate.
  6. Study investigators and sponsor if applicable do not have access to Protected Health Information (PHI) or to linkage information.
  7. Results from study samples are not made available to the patient or treating medical staff thereby having no impact on routine patient management.

Question 24: How should the Common Rule be changed to clarify whether or not oversight of quality improvement program evaluation studies or public health activities are covered?

Response to Question 24: Any activity that represents an expected activity under CLIA regulations and conforms to HIPAA regulations should be considered as excluded from the regulatory requirements of the Common Rule. These activities include:

  1. Development, verification, and validation of new laboratory tests being considered for clinical use.
  2. Use of biospecimens for quality control.
  3. Use of biospecimens for patient correlation studies.
  4. Use of biospecimens for establishment of normal ranges in specified populations.
  5. Use of biospecimens for training and competency assessment of technical personnel.

Further, use of any existing biospecimen for submission to a recognized governmental public health entity as a component of a mandatory requirement or investigational protocol should not be subject to Common Rule regulatory requirements by the submitting institution.

Question 47: Should there be a change to the current practice of allowing research on biospecimens that have been collected outside of a research study (i.e. “left-over” tissue following surgery) without consent, as long as the subject’s identity is never disclosed to the investigator?

Response to Question 47: The ASM strongly recommends that this practice continue as long as the conditions previously described in our response to Question 23 are met.

Question 59 (part 2): Would the administrative burden of applying the rule to all data and biospecimens be substantially greater than applying it only to newly collected information and biospecimens?

Response to Question 59 (part 2): The requirement to obtain informed consent for use of existing biospecimens currently in repositories cannot be realistically met. As a result, important and irreplaceable sources of material for quality improvement and investigational studies will be lost. In addition, the requirement to obtain a “general” informed consent for use of ANY biospecimen, existing or prospectively collected is overly burdensome and does not afford any patient protection benefit over that assured by HIPAA in a clinical setting or through the use of an effective de-identification process.

Question 72: To what extent do the differences in guidance on research protections from different agencies either strengthen or weaken protections for human subjects?

Response to Question 72: The use of biospecimens in repositories is essential in order to conduct acceptable, reasonable, and cost-efficient clinical studies, in either FDA overseen IVD device trials or in clinical laboratory initiated studies of new procedures. There is a need for the FDA and HHS to harmonize requirements for clinical studies to avoid confusion in the IRB oversight of human subject protections. In particular, guidance on use of existing “leftover” biospecimens in studies of new methods should be harmonized.

In conclusion, the ASM strongly recommends that the substantial change in the Common Rule put forth in this ANPRM requiring universal written general consent for research use of data or biospecimens be given careful reconsideration prior to implementation. The use of biospecimen repositories provides an essential framework for the expedient and cost effective clinical verification of new procedures as well as a source of materials for quality improvement. A requirement to obtain a general informed consent to cover any potential use of a specimen is overly burdensome to clinical laboratories and healthcare institutions, and does not serve to assure any patient protection not already afforded by other regulations (e.g. CLIA and HIPAA). The requirement appears to be in conflict with the Presidential Executive Order to streamline regulatory requirements to be more effective and less burdensome. In addition, the excess costs passed on to the IVD device industry in clinical trials could result in additional costs to the end-user and ultimately to patients; this could stifle innovation in the IVD device industry.

Thank you for the opportunity to provide comments on this proposal. Any questions may be directed to Kimberly Walker, ASM Public Affairs.


The Professional Affairs Committee
The Laboratory Practices Committee