INTRODUCTION

The US FDA has established three Drug Development Tool (DDT) Qualification Programs to support drug developers. The overall objectives of the DDT Qualification Programs are to provide a framework for early engagement and collaboration with FDA to facilitate development of DDTs, to encourage development of DDTs for use with unmet needs, and to encourage innovation in drug development.

The three DDT Qualification Programs are:

• The CDER Biomarker Qualification Program (BQP) supports the development of biomarkers for use in drug development.

• The Animal Model Qualification Program (AMQP) support the development of animal models used for product approval under the Animal Rule.

• The CDER Clinical Outcome Assessment (COA) Qualification Program supports the development of COAs for use in clinical trials.

Qualification of DDTs (section 507) was added to the Federal Food, Drug, and Cosmetic Act (FD&C Act) under the 21st Century Cures Act in 2016. Section 507 includes transparency provisions that apply to submissions and FDA’s formal written determinations in response to such submissions.

In each case, qualification is a conclusion that within the stated context of use, the DDT can be relied upon to have a specific interpretation and application in drug development and regulatory review. Once qualified, DDTs will be publicly available to be used in any drug development program for the qualified context of use. Additionally, the qualified DDT generally can be included in IND, NDA, or BLA submissions without needing FDA to reconsider and reconfirm its suitability. As of 1 June 2020, there are 123 DDP Qualification Program projects in development. The FDA has published several guidance documents to assist developers of DDTs, summarised the procedure, timelines and documentation requirements. 

This article will provide an overview of the CDER Biomarker Qualification Program, with the other Qualification Programs to be covered in future papers.

ELIGIBILITY

A biomarker  is defined by the  Biomarkers, Endpoints and other Tools (BEST) glossary  as “a  characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions”. BEST defines seven biomarker categories: susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety. A full biomarker description includes the biomarker name, the source/matrix, the measurable characteristic(s), and the analytic method used to measure the biomarker. 

A biomarker will be qualified for a specific context of use (COU), which is a concise description of the biomarker’s specified use in drug development. The COU includes two components: 

1. the BEST biomarker category and...

2. the biomarker’s intended use in drug development.

Please refer to Figure 1. Examples of intended use are defining inclusion/exclusion criteria, supporting clinical dose selections or evaluating treatment response. Each biomarker qualification effort should identify a single COU.

Figure 1: BEST Biomarker Category and Examples of Corresponding Drug Development Uses 

Source: https://www.fda.gov/drugs/biomarker-qualification-program/context-use

PROCEDURE & OUTCOMES

There are three main stages to the BQP process, as summarised below and in Figure 2. Before Stage 1, it is possible to request a pre-LOI meeting, which offers an opportunity to receive guidance on a biomarker program before a formal submission. The request includes a cover letter, specific questions to be discussed and a draft LOI. The FDA has published detailed guidance on the content elements for each of the three submission stages.

1. Letter of Intent 

Submission of a letter of Intent (LOI) by the Applicant initiates the qualification process and consists of a concise document that describes the DDT, the relevant drug development need and the proposed COU, including the supporting scientific rationale. The FDA may return the LOI submission if insufficient information is included. Within three months of receipt of a valid submission, the FDA reviews the LOI and issues a Determination Letter indicating whether the project is accepted and recommendations on next steps. 

2. Qualification Plan

The Qualification Plan (QP) submission describes all relevant data, any knowledge gaps and the analysis plan, and should address recommendations received at Stage 1. Following an assessment of completeness, within six months the FDA reviews the QP and issues a QP Determination Letter, including requests for data and recommendations regarding data needs for the Full Qualification Package. If the QP is not accepted, the request can be withdrawn or revised and resubmitted. 

3. Full Qualification Package 

The Full Qualification Package (FQP) is the final stage and ends with qualification determination. The FQP includes detailed descriptions of all studies, analyses, and results related to the DDT and its COU, as described in FDA’s response to the QP. Evidence supporting qualification should include full study protocols and reports. Following an initial assessment of completeness, the FDA will review the FQP within ten months and determine whether to qualify the proposed DDT for its proposed COU or, based upon the data submitted or to qualify a DDT for a modified COU. The FQP review concludes when FDA issues a qualification Determination Letter.

Figure 2: Summary of the BQP procedure

Source: https://www.fda.gov/drugs/biomarker-qualification-program/about-biomarkers-and-qualification

Upon qualification, the biomarker may be used under the COU for which it is qualified in any CDER drug development program to support the regulatory approval of a new drug. 

For promising biomarkers which have not yet been accepted into the CDER BQP, a Letter of Support (LOS) may be issued at request of an Applicant. The intent of the LOS is to enhance the visibility of these biomarkers, make public FDA’s support for continued development, and encourage data sharing and collaboration.

The 21st Century Cures Act includes transparency provisions requiring that summary information about the requester’s qualification submissions, FDA’s formal written determinations and a listing of qualified biomarkers will be publicly posted. As such, at each of the three above stages the FDA will publish the date of receipt and status, the requester name, the DDT Qualification Program, DDT description, proposed COU, the LOI/QP/FQP summary (whichever is applicable), information on external expert consultation, and the FDA Formal Written Decision Letter (for LOI and QP stages) or the Qualification Determination (for the FQP stage). When an LOS is issued, both the LOS and the requester’s contact information are made publicly available on the FDA website.

If an Applicant requires changes to be made to a qualified DDT, it is possible to request a post-qualification modification. This process is initiated by submitted a QP (Stage 2, as outlined above).

An individual or organisation can also request a modification to another Applicant’s qualified DDT, by submitting an LOI; the possible outcomes are that the original qualification effort may remain qualified with the modification represented as an additional qualification, or it may be determined that the original qualified DDT and COU may be subsumed into one modified DDT and COU.

OVERVIEW OF ONGOING BQP PROCEDURES

As summarised above, transparency is a key component of the DDT Qualification Programs, therefore information on all submission to the BQP is made publicly available. At present there are 30 requests at LOI (Stage 1) and 1 request at QP (Stage 2). There are a number of requests made pre-Section 507 which are in transition to being made public.

OVERVIEW OF QUALIFIED BIOMARKERS

For each qualified biomarker, the FDA publishes the requester name, a description of the biomarker, the COU, the date of the qualification decision, the FDA Letter and the FDA Reviews.  A summary of the qualified biomarkers as of April 2020 is provided in Table 1.

Table 1: Qualified Biomarkers

OVERVIEW OF LETTERS OF SUPPORT

When CDER issues a letter of support, the FDA published the requester name, description of the biomarker, the area for use in drug development, the LOS itself and requester contact information. The biomarkers issued an LOS as of June 2019 are summarised in Table 2.

Table 2: Letters of Support

BENEFITS OF BIOMARKER QUALIFICATION

As well as the potential to accelerate the overall drug development timeline for any given product and an opportunity for interaction with CDER, receiving a biomarker qualification may be valuable for securing investment and may eventually result in wider use of the novel methodology by industry. 

Recently, Chen et al sort to evaluate the use of KIM-1, a nonclinical safety biomarker for the detection of acute drug-induced nephrotoxicity in rats, following its qualification of a biomarker by CDER in 2008 (Table 1). The authors analysed the FDA DARRTS database, clinicaltrials.gov and PubMed for use of the biomarker, and found that there was increased reference to its use in drug development programs and increased use in research by the larger scientific community following qualification 1. 

CONCLUSIONS & SUMMARY

The BQP is well-established and there are numerous resources available for Applicants considering this procedure, including guidance documents published by FDA and substantial information on qualified biomarkers and ongoing BQP procedures, which are made publicly available. The BQP can be a valuable interaction for developers of biomarkers for use in drug development and it is worthwhile for developers to consider communicating with the FDA early in development.