You and your colleagues studied all applicable FDA CDRH guidances and competitor summary documents. You decided the best regulatory strategy, then prepared and executed the performance characteristic validation protocols consistent with guidance recommendations and precedence. The application was finally submitted for FDA review and soon a request for additional information comes. CDRH informs you that the agency has changed or added expectations relating to the data submitted as part of your IDE, 510 (k), PMA or HDE.
Despite having read every relevant regulation, validation guidance, compliance policy warning letter, and any other precedence documents you could get your hands on, unbeknownst to you, a more current expectation had become the de facto standard. So now you are facing one of your worst nightmares….. generating more data under FDA time clock constraints.
This scenario demonstrates the current norm where a manufacturer learns of CDRH implemented changes regarding what data or how to gather specific data in support of a particular product submission at the time of or soon after engagement with the agency and often not until after the submission is under review. Complying with requests for additional information and/or studies under constraints of FDA’s review clock can prove expensive and stressful for manufacturers who have already invested considerable time and money into preparing a submission they believed to be consistent with current FDA requirements.
Not to blame FDA. We operate in a dynamic industry where technology is rapidly changing and requirements can be built up with experience and exposure to products. The review process and other sources of product feedback to FDA, including complaints and recalls, can identify scientific information and risks not previously known. This new information may suggest that the currently used test methods or clinical trial designs are inadequate to demonstrate safety and effectiveness or substantial equivalence. Once new information leads to a change in requirements, the process to get a guidance document, regulation, or compliance policy published for industry consumption is long and arduous and may be released years after a requirement was first recognized and put into effect at the review level.
FDA admits this is a precarious situation; understands that rapid communication with industry about changes in premarket regulatory expectations is important to minimize any disruptions in the product development process; and has responded to the complaints received about this perceived lack of transparency.
Have you ever heard of “Immediately in Effect (IIE)” guidance documents? Thanks to a new SOP issued by CDRH, you may soon see these on a regular basis.
The foundation was set a number of years ago. The Food and Drug Administration Modernization Act of 1997, authorized FDA to issue guidance documents without public comment in certain circumstances. The “Act” states that guidance documents “setting forth initial interpretations of a statute or regulation, changes in interpretation or policy that are of more than a minor nature, complex scientific issues, or highly controversial issues” must have prior public participation before implementation “unless the Secretary determines that such prior public participation is not feasible or appropriate.” Regulations finalized in 2000 allow for prior public participation to be “not feasible or appropriate” if: “(1) there are public health reasons for immediate implementation of the guidance document; (2) there is a statutory requirement, executive order, or court order that requires immediate implementation; or (3) the guidance document presents a less burdensome policy that is consistent with public health.”
Now 14 years later, FDA will use “Level 1, Immediately in Effect Guidance Documents on Premarket Data Issues” to more quickly inform stakeholders when CDRH needs to clarify or has changed its expectations relating to data submitted as part of an IDE or pre-market submission in those instances where there are public health reasons for the immediate implementation of new regulatory expectations that outweigh the need for pre-implementation feedback from affected stakeholders. A Federal Register Notice of Availability will announce the guidance, the IIE guidance will be posted on FDA’s website, and FDA may also contemporaneously issue another communication to the affected industry stakeholders summarizing the information in the IIE guidance.
CDRH finalized their SOP effective March 26, 2014 facilitating issuance of these guidance documents. The SOP proposes a three-pronged assessment to determine if an IIE Guidance Document should be developed: (1) is there new scientific information which raises new, important safety risks or calls into question the adequacy of currently used test methods or clinical trial design to demonstrate safety, effectiveness, and/or substantial equivalence of a device type? (2) as a result of such new information, does CDRH need to change its regulatory expectations with respect to IDEs and premarket submissions? (3) is prior public participation appropriate or feasible?
The initiating FDA staff and management will prepare a briefing summary and consult the Center Science Council (CSC) with all the “what” (new scientific information and proposed changed regulatory policy), the “why” (how the risk/benefit profile of the device is changing) and the “who” (affected stakeholders and regulatory documents). The
CSC is charged with determining whether the new scientific information warrants a change in the premarket regulatory expectations, whether the change should be communicated through a traditional guidance document issued in draft and finalized after the appropriate comment period, or whether a Premarket IIE Guidance Document should be issued. The CSC’s recommendations will be reviewed by senior CDRH leadership to ensure they meet applicable regulatory and legal standards. Once it is decreed that an IIE Guidance Document should be issued, the guidance will be drafted.
While the IIE guidance takes effect immediately, the SOP does provide some tradition in that FDA will still accept comments and decide whether any revisions are needed. The comment period will be for 60 days following issuance. Within 90 days following close of the comment period, CDRH will review the comments and revise the document, if necessary.
Providing public notice of dynamically changed regulatory requirements and expectations should alleviate frustrations and costs for most manufacturers and avoid unexpected review delays. However, in the not so rare event when the proposed changes apply to premarket submissions already under review, CDRH should resolve how the new issues can be considered by the sponsors so that they are not unfairly disadvantaged by the change in regulatory expectations. And still, we will all need to continue to keep track of the status quo framework for current premarket data requirements.