On July 25, 2011, the Department of Health and Human Services (HHS) and Office of Science and Technology Policy (OSTP) published an Advance Notice of Proposed Rulemaking (ANPRM) regarding updates and changes to regulations for the protection of human research participants. The document, titled Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay and Ambiguity for Investigators, puts forth significant modifications with the intent of better aligning our regulatory framework to the current contexts in which clinical research occurs. HHS and OSTP will accept comments through September 26, 2011.

The ANPRM lists seven domains where enhancements to the regulations would ideally streamline review and approval processes, reduce bureaucratic inconsistencies, appropriately include new research technologies and categories of human subjects research, and expand protections for human research participants. The domains under consideration are:

  1. Risk-based regulatory framework
  2. Single IRB of record for domestic multi-site research
  3. Consent forms and processes
  4. Mandatory data security and information standards
  5. Systematic approaches to collection and analysis of unanticipated problems and adverse events data
  6. Application of Federal regulations for the protection of human research participants to all research at institutions which receive federal funding
  7. Harmonization of guidance on federal regulations

Risk-Based Regulatory Framework

The ANPRM seeks comment in this area as there are concerns that the concept of "minimal risk" is misunderstood and inappropriately applied by IRBs. The proposal states that, "the concern is that IRBs spend too much time reviewing minimal risk research… and over estimate (the) magnitude and probability of foreseeable risks." The suggested changes in this domain include:

  1. Eliminate continuing review for minimal risk research which received expedited review
  2. Revise and regularly update the expedited review categories to expand the types of minimal risk research which can undergo expedited review
  3. Revise regulations and the concept of exempt research to:

a.require that researchers register their exempt studies, and allow the research to commence immediately after registration (rather than IRB review for exempt status)

b.clarify that routine review by an IRB staff member or some other person of such minimal risk exempt studies is neither required nor even recommended

c.expand the current category 2 exemption to include all studies involving educational tests, surveys, interviews, and similar procedures so long as the subjects are competent adults, without the de-identification conditions

d.add a new category of minimal risk behavioral and social science research that goes beyond using only survey methodology (like watching videos or solving puzzles)

e.expand the current category 4 exemption to include all secondary research use of identifiable data and biospecimens collected for purposes other than the currently proposed research. The expanded category exemption would apply even if such data or biospecimens have not yet been collected at the time of the research proposal, and even if identifiers are retained by the researcher.

[This expansion would require the reconsideration of the concept of exempt research. Included in this proposed change is the requirement for signed participant consent for any future research use of specimens. Thus, the writers suggest that this research be regarded as ‘excused’ or ‘registered,’ as some, but not all, regulations may apply.]

f.require random, retrospective audits to assess whether exempt status was appropriately applied

The suggested changes to the risk-based regulatory framework would impact the education of IRB members and investigators particularly with regard to the concepts of minimal-risk and non-medical based human subjects research. There potentially would be a reduction in the work-load for continuing reviews, as expedited studies would no longer be of issue. IRB submission processes will need modification as expedited and exempt studies may not need to be submitted per se, but there will need to be a mechanism for registration and consideration of consent documents. Also, concepts of de-identification will need reconsideration, as participants could potentially withdraw their consent on the use of their specimens, which necessitates a mechanism for linking specimens to the donors.

Single IRB of Record for Multi-Site Research

The ANPRM acknowledges growth in utilization of multiple sites to conduct human subjects research. For this domain, the suggestion is a mandate that all domestic sites in multi-site research studies rely upon a single IRB as the IRB of record. The hope is to reduce work-loads and start-up times for research and minimize conflicts of interest by eliminating the need to submit for local review and approval. The proposed mandate also would include changes to enforcement procedures that will hold external IRBs accountable for regulatory compliance related to the conduct of the approved research. There are, however, significant items of note:

  1. Local IRBs would still have accountability for the protection of human subjects at their institutions.
  2. FDA regulated device studies would still need local IRB review in accordance with FDA requirements.
  3. The suggested mandate would only apply to domestic multi-site human subjects research.

Consent Forms and Processes

The ANPRM highlights the fact that although there have been few changes to human research protections regulations, informed consent documents have constantly evolved, and in ways that do not always put the protection of research participants first. According to the ANPRM, "While the regulations have changed in only relatively modest ways since 1974, the average length of consent forms has been increasing since then, and the forms have become excessively long and legalistic, even for relatively routine and low risk research studies." To address the issues of length and purpose of informed consent forms, HHS and OSTP propose six modifications:

  1. prescribing highly specific content that must be included in consent forms
  2. restricting content that would be inappropriate to include in consent forms
  3. limiting the acceptable length of various sections of a consent form
  4. prescribing how information should be presented in consent forms by, for example, stating what information should be included at the beginning or in appendices versus the main body of the consent document
  5. reducing institutional "boilerplate" language which is oftentimes intended primarily to protect institutions from lawsuits
  6. making available standardized consent form templates, which could satisfy applicable regulatory provisions

The ANPRM discusses two issues related to waiver of informed consent or documentation of consent – the vagueness and non-standard interpretation of criteria for waivers, and the rationale for requiring signed consent for the research use of specimens. The ANPRM does not list any recommendations for waiver of consent/documentation criteria at this time. However, in its contemplation of use of consent for biospecimens, HHS and OSTP highlight that current HHS interpretation of HIPAA is that authorization is study specific, and it is inappropriate to permit global authorizations for unspecified future research uses of health information. The consent requirement would harmonize the Common Rule (the federal policy for the protection of human subjects or 45 CFR Part 46 Subpart A)1 with HIPAA in this area and allow participants the ability to object to the use of their biospecimens in research. However, the ANPRM notes the real concern of investigators regarding the logistical difficulties of obtaining consent for each specimen study, and the potentially negative impacts (on conducting specimen research and validity of data) if significant numbers of participants refuse consent.

Mandatory Data Security and Information Standards

The proposed rule lists concerns related to informational risks (breach or exposure of private information), and the reality that de-identified data is always potentially identifiable data due to advances in technology. To address these issues, the ANPRM suggests revising privacy provisions of the regulations to incorporate HIPAA provisions regarding what constitutes individually identifiable information, a limited data set, and de-identified information. This mandate would extend the data privacy and security elements of HIPAA to non-covered entities and acknowledges the potential for DNA to identify biospecimens. However, the authors also acknowledge that the IRB may not be the best mechanism for the protection against informational risks, and suggests periodic random audits. If these suggestions are implemented, privacy officers will have to increase their monitoring efforts to include all research conducted in their institutions.

Systematic Approaches to the Collection and Analysis of Unanticipated Problems and Adverse Event Data

Currently, there are varying requirements and standards for reporting unanticipated problems and adverse events. This creates additional compliance burden for researchers and institutions to ensure that they are in accordance with all relevant regulations, policies and practices. To address this, the ANPRM suggests "innovations":

  1. use of a standardized yet flexible, streamlined set of data elements to enable customized safety reporting and compliance with Federal agency reporting requirements
  2. implementation of a web-based, Federalwide portal that would build on these data elements, allow electronic submission of certain pre- and post-market safety data and have such data automatically delivered to appropriate agencies and oversight bodies
  3. harmonization of safety reporting guidance and terminology across all federal agencies, and clarification of the scope and timing of such reports

It is important to note however, that the ANPRM does not suggest what entity within HHS would be responsible for the creation, oversight and maintenance of these innovations.

Application of Federal Regulations for the Protection of Human Research Participants to All Research at Institutions Which Receive Federal Funding

The current Office of Human Research Protections (OHRP) Federalwide Assurance (FWA) allows institutions to voluntarily commit to apply federal regulations to non-federally funded research by "checking the box" on the FWA application. However, this creates a compliance loophole for human subjects research which is not federally funded and not under the authority of the FDA (like surgical procedures and some social/behavioral studies). The ANPRM suggests requiring that domestic institutions which receive any funding from Common Rule agencies extend Common Rule protections to all of their human subjects research. Institutions would have to create processes to ensure that all of their research, regardless of funding source, is in compliance with these regulations. No human subjects research would be outside the scope of the regulation.

Harmonization of Guidance on Federal Regulations.

The ANPRM notes that guidance documents created to clarify similar regulations and policies may vary depending on which federal agency issues the guidance. This creates multiple compliance requirements and additional complexity which, the authors note, "causes frustration". The discussion notes various efforts to harmonize guidance documents. However, there are no specific recommendations on how agencies should work together or on what department would issue final guidance documents.

References

The following is a link to Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators: http://www.ofr.gov/OFRUpload/OFRData/2011-18792_PI.pdf