Regulatory Pathways

The FDA Regulatory Readiness and Drug/Device Development Tool (DDT/MDDT)


Update: TED and TRACK-TBI Investigators Respond to FDA's Request for Information on Identifying Potential Biomarkers

In a collaborative effort, TED and TRACK-TBI Investigators drafted two responses to the FDA's Request for Information on Identifying Potential Biomarkers for Qualification and Describing Contexts of Use to Address Areas Important to Drug Development. Responses on the potential of blood-based and MRI biomarkers in TBI were submitted.

To read the response on Blood-Based Biomarkers, click here.

To read the response on MRI Biomarkers, click here

Qualification Pathways

Fig. 1. FDA roadmap to patient-focused measurement in clinical trials

The TED Initiative was developed as a response to the myriad challenges that face developers of new medical products; significant costs are compounded by high rates of unsuccessful attempts at regulatory qualification. As noted, TBI trials to date have failed to produce a single drug therapy or identify a biomarker that could enrich our strategy for identifying patients likely to suffer disease progression, or appropriately select and stratify subjects for treatment trials. TBI classification approaches are blunt and have not changed in more than three decades. TBI patients are divided into the crude categories of mild, moderate, and severe, typically using the Glasgow Coma Scale (GCS) ; outcomes after TBI are measured using the equally non-discerning Glasgow Outcome Scale-Extended (GOS-E). These tools do not permit selection of patients with injury mechanisms that may preferentially respond to targeted therapies. In collaboration with our PPPs, The TED Initiative begins its work with validation of Clinical Outcome Assessments (COAs) and biomarkers that meet, but more importantly, refine the current standards (e.g., GCS and GOS-E) to establish these COA’s or biomarker’s direct or indirect evidence of diagnostic or treatment benefit. With early and substantive FDA collaboration, these validated measures could advance innovative approaches for TBI clinical trials, as has been demonstrated in early Alzheimer’s disease, and support submission for the creation of FDA Guidances or DDT qualification.


FDA Guidance

Fig. 2. Categories of Biomarkers for DDTs

In 2004, FDA released a white paper entitled, “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” and launched the Critical Path Initiative (CPI). CPI has created processes to leverage scientific advances as tools to accelerate drug and device development, and to aid regulatory evaluation. These pre-competitive standards and approaches, termed “drug development tools” (DDTs) by FDA, follow an established process for qualification of their validity for a given context of use (COU) and within specific concept(s) of interest (COI) for meaningful diagnostic or treatment benefit to subgroups of patients (Fig. 1).

DDTs include, but are not limited to, clinical outcome assessments (COAs) and biomarkers. COAs, by the FDA’s definition, “…measure a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions.” Biomarkers are defined by FDA as a “characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention.” FDA describes qualification as “a conclusion that within the stated COU, the DDT can be relied on to have a specific interpretation and application in drug development and regulatory review.”

On the FDA website, you can read more about the Guidance that manages the Clinical Outcome Assessment Qualification Program, another that manages the Biomarker Qualification Program, and a similar process is utilized for validation of medical devices.

Qualification has widespread implications for candidate therapies; it may confer broad applicability across multiple drug candidates, independent of the mechanism of action of the drug or of the contributing sponsor as well as across multiple clinical disorders, drugs, or drug classes. As well, qualified DDTs become open standards for the scientific community. Published recommendations describe the type and quality of data that must be submitted as part of CDER’s formal DDT qualification process.

Fig. 3. COAs and Domains for Diagnostic and Therapeutic Trials

Biomarkers may be diagnostic, prognostic, predictive, or pharmacodynamic, or a combination (Fig. 2). Validation relies on objective measures to establish the etiology of, susceptibility to, activity of, or progress of a disease. COA validation may be established according to performance outcome (PerfO), clinician-reported outcome (ClinRO), observer-reported outcome (ObsRO), and/or patient-reported outcome (PRO) to assess disease severity/progression in clinical settings and to measure treatment response in controlled clinical trials. COAs measure a variety of outcome domains (Fig. 3).


Center for Drug Evaluation and Research Organization (CDER) Critical Path Innovation Meeting (CPIM)

The Critical Path Innovation Meeting (CPIM) is an additional portal to FDA collaboration on the regulatory pathway. CPIM was introduced by CDER in fall 2014 “to address issues in drug development identified in the 2004 FDA publication, Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products Challenges and Opportunities Report.” As articulated by CDER:

The CPIM mechanism encourages communication and engagement between CDER and investigators across the private-public spectrum to improve efficiency and success in drug development. Among the topics a CPIM might include are discussion of a methodology or technology proposed by the meeting requester and CDER’s general advice on how this methodology or technology might enhance drug development.

FDA Letter of Support

Another area of engagement in the pre-qualification stage of the drug development process is CDER’s Letter of Support, which may be issued following submission of preliminary evidence by a drug development tool proponent that briefly describes CDER’s observations as to the potential value of a biomarker and encourages further evaluation. As CDER notes, “This letter does not connote qualification of a biomarker. It is meant to enhance the visibility of the biomarker, encourage data sharing, and stimulate additional studies.”