The US Food and Drug Administration (FDA) has announced the publication of a new guidance document intended to guide institutional review boards (IRBs), clinical investigators and sponsors of clinical trials on whether clinical sites are compliant with regulations and whether an investigational application must be submitted to FDA.
Clinical research is at the heart of FDA's regulatory oversight capacity. Good review decisions rely on good clinical data-robust, adequately controlled, well-designed, and ethically sound-and that data relies heavily on the quality and qualifications of the institutions and employees that gather it from patients.
As such, FDA has for decades extensively regulated the practice of clinical trials under various sections of Chapter 21 of the Code of Federal Regulations (CFR). For example, 21 CFR 56 details the circumstances in which an IRBs review of a trial requires (56.103), exemptions and waivers from IRB review (56.104/5), the requirements for IRBs (56.106), IRB functions and operations (56.108-14), record-keeping requirements (56.115) and the consequences of non-compliance (56.120-4).
FDA's Warning Letters regularly reference this section of the CFR, including failure to keep adequate records, report adverse events, or even review research as required.
So if the principles of effective regulatory oversight have already been enshrined in practice for decades, why the need for new guidance?
In an email to industry, FDA sought to answer this question, noting that while "many of the recommendations in [the] guidance have appeared in other FDA guidance documents," the newly issued guidance represents a cohesive, easy-to-reference compilation of recommendations on how IRBs and other entities involved in the regulation of clinical trials can fulfill their responsibilities.
"To enhance protection of human subjects and reduce regulatory burden, the Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and FDA have been actively working to harmonize the agencies' regulatory requirements and guidance for human subject research," FDA added in the email. "This guidance document was developed as a part of these efforts and in consultation with OHRP and is now available."
The guidance itself differs from others published by the agency in that it is set up with something of a conversational question-and-answer format focused on four questions:
- Must an IRB review the qualifications of clinical investigators who conduct FDA-regulated research?
- Is any information publicly available from FDA about a clinical investigator's inspectional history?
- Must an IRB review the adequacy of the research site?
- What are the IRB's responsibilities with respect to verifying the determination of whether an IND or IDE is required for an FDA-regulated investigation?
For regulatory professionals already familiar with the IRB process, the guidance has little in the way of new information, and topics are generally addressed as higher-level discussion matters. For example, FDA notes that 21 CFR 56.111 requires information about the qualifications (educational, professional, etc.) to ensure the safety of patients. The guidance does not, however, discuss specific minimum requirements, instead referring to common methods of obtaining evidence from an investigator, reviewing and verifying the investigator's curriculum vitae, and conducting an assessment of how that investigator's qualifications match the needs of the study.
Elsewhere in the guidance, FDA explains how companies unfamiliar with a research site can investigate it to assure its adequacy and ability to properly execute the clinical protocol requirements.
And, in response to the fourth question, FDA also lays out when IRBs should consider if a study needs to be conducted under an investigational new drug (IND) or investigational device exemption (IDE) application. If the IRB and sponsor are unable to agree on the need for such an application, FDA said the IRB should "follow its procedures for resolving controverted issues" by notifying the clinical investigator in writing of the IRB's concerns and delay approval of the study.
The guidance is now in its final form, and is available on FDA's website.
Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed