Novel Tools for Modern Drug Development: A US Perspective.
Part II.
By Amy Cooke
Introduction
A drug development tool (DDT) is a measurement or method (and associated materials) that aids drug development. DDTs can be used in a drug development program without it going through the qualification programs. The use of non-qualified DDTs will be reviewed by the relevant FDA center(s), division(s), and office(s) as part of IND, NDA, or BLA reviews. However a DDT that has the potential to be used in multiple drug development programs should be considered for qualification. Qualification may reduce duplication of efforts, allow resource and information sharing, and facilitate regulatory acceptance of the DDT for future applications utilising the same context of use.
The US FDA has established three 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.
The FDA is also running a pilot program for DDTs that are out of scope of the three existing Qualification Programs, called The Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program, which will accept 2 to 4 submission each year. ISTAND is designed to expand DDT types by encouraging development of DDTs that would not be eligible for the BQP, AMQP or COA Qualification Program but may still be beneficial for drug development.
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 (COU), 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. The FDA has published several guidance documents to assist developers of DDTs, summarising the procedure, timelines and documentation requirements.
This article will provide an overview of the Animal Model Qualification Program (AMQP). The CDER Biomarkers Qualification Program was covered in an earlier paper, and the CDER Clinical Outcome Assessment (COA) Qualification Program will be covered in the final paper in this series.
Eligibility
The AMQP was established to address the need for publicly available, product-independent animal models intended to support the efficacy testing of multiple investigational drugs or biological products under regulations known as the ‘Animal Rule’. These regulations allow approval of drugs and biological products intended to ameliorate or prevent serious or life-threatening conditions due to toxic chemical, biological, radiological, or nuclear substances (CBRN) (e.g., organophosphorus nerve agent, smallpox virus, gamma irradiation) based on well-controlled animal studies only, where human challenge studies would be unethical. Eligible for the AMQP, which is product independent, are animal models of human diseases or conditions caused by CBRN substances for which product development would require use of the abovementioned Animal Rule.
Qualification of an animal model through the AMQP indicates that FDA has concluded that the animal model can reliably produce a disease process or pathological condition that in multiple important aspects corresponds to key elements of the human disease or condition of interest and accepts the animal model’s context of use. The context of use is a description of the appropriate use and application of the qualified animal model in drug development and regulatory review.
Process & Outcomes
There are three main stages to the AMQP process, as summarised below. Detailed information can be found in FDA guidance on this topic. Before Stage 1, it is possible to request a pre-LOI meeting, which offers an opportunity to discuss the qualification pathway before a formal submission. The request includes a draft LOI or other supporting materials to focus the discussion.
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. It should include full study protocols and analytic plans where appropriate, with an estimated time frame for completing data collection, data analysis, and reporting. 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.
Upon qualification, an animal model may be used in IND or NDA/BLA submissions without FDA needing to reevaluate the qualification conclusion, as long as certain criteria are met.
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 animal models 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).
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 submitting 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.
Benefit of Animal Model Qualification
The key benefit of the AMQP is that a qualified animal model may be used in IND or NDA/BLA submissions without FDA needing to reevaluate the qualification conclusion, thereby accelerating the drug development and review process, as long as the FDA concludes that the animal model is suitable for efficacy testing of the specific investigational drug that is the subject of the INR or NDA/BLA and the following criteria are met:
The study is conducted properly (e.g., all procedures and protocols specified in the context of use are followed).
The animal model is used for the qualified purpose (i.e., used within the context of use).
At the time of qualification, there is no new information that conflicts with the basis for qualification.
Another benefit is that the AMPQ offers Sponsors additional opportunity to interact with FDA at key stages throughout the drug development process.
Furthermore, because qualified animal models are product-independent, they have the potential to be used in multiple drug development programs targeting a particular disease thereby reducing redundancy and conserving resources.
Conclusions & Summary
The AMQP is well-established and there are numerous resources available for Applicants considering this procedure, including guidance documents published by FDA. Use of a qualified animal model is not a requirement for approval under the ‘Animal Rule’, however receiving qualification has a number of benefits, including the potential to reduce the time required for regulatory review and increased opportunity to interact with FDA.