Charlie Grudzinskas, PhD, Founder & Partner, NDA Partners LLC
Over the course of four decades of industry experience and review of hundreds of drug development programs, we have identified several key factors that we observe to be common to successful outcomes. We have distilled these factors into five key Principles of Product Development that provide high-level guidance for planning and executing product development programs.
The Principles form the basis for a decision-based approach for identifying and quantifying critical information, for projecting the probabilities of various outcomes, and for informing key stakeholders with clear and concise information. They provide a flexible blueprint for a product development plan and subsequent revisions that are required in order to keep the plan current. Application of the Principles is most effective when guided by experts with the relevant scientific knowledge and regulatory expertise, who can adapt the Principles to meet the specific needs of each product development program. These Principles are applicable to drug, biologic, medical device, and diagnostic product development programs, regardless of technology, therapeutic area, or indication. The Principles serve as guidelines only and may not apply to all product development programs in the same way. The five Principles presented below have proved to be a valuable framework for many successful product development programs.
At the outset and frequently throughout a development program, the envisaged Market Advantage should be defined in a Draft Product Label (DPL) and a Target Product Profile (TPP). The DPL and TPP should represent a consensus of all key technical, regulatory and commercial stakeholders. The DPL and TPP should justify the proposed R&D investment based on an assessment of the future market and reimbursement landscape. Both the TPP and DPL are dynamic and should be revised based upon learnings during development.
Prior to initiating each stage of a development program, a thorough assessment of the product and its potential indications, CMC and other technical characteristics, program objectives, development plan, and potential regulatory pathways is conducted – posing the question: is the candidate product still viable with respect to safety findings, formulation properties, pharmacology, toxicology, in vitro metabolic profile, and exposure-response information on key safety and efficacy biomarkers or clinical endpoints?
Carl Peck, MD, Founder, Partner & Chairman, NDA Partners LLC
The Product Development Plan (PDP) should distinguish between “targets,” “biomarkers,” “surrogate endpoints,” and “clinical outcomes.” The PDP should identify the optimal path to clinical Proof of Concept (PoC) and End-of-Phase 2 decision points. PoC studies should be conducted directly after the establishment of the range of safe doses and exposures. Intrinsic and extrinsic factors associated with significant variations in drug exposure should be identified prior to initiating Phase 3. The design and analysis plan of each study should be determined regarding data from previously completed studies.
Learning and Confirming
Learning clinical studies, conducted prior to the start of Phase 3, are used to develop quantitative, predictive models that can be adapted for new circumstances, such as new populations or safety issues. Dose/exposure/effect relationships gained from non-clinical and clinical studies inform a quantitative “drug model,” for simulations and identification of a safe, informative dosing regimen for the confirmatory trial(s).
Confirmatory clinical studies are designed to maximize an appropriate clinical value proposition and explicitly recognize all study goals and parameters. Clinical trial simulation is used to evaluate the value of the candidate designs and to assure study and statistical robustness against deviations from the protocol.
If confirming is the primary goal, then a secondary goal is to provide additional data to fully inform the final label. The overall study design should incorporate some learning features, such as a measurement of covariates, exposure, and biomarker outcomes, and a model-based data analysis plan.
Regulatory requirements, constraints, and opportunities from regulatory authorities should be addressed in the program design and reassessed at every milestone and major decision point. Program Managers should be informed of all relevant regulatory statutes, regulations, guidelines, approval pathways, historical traditions, and current trends. Early and frequent communications with regulatory authorities are encouraged and will cultivate mutually respectful relationships.
These five Principles provide guidance and structure throughout the product development process and have been successfully implemented in drug, biologic, device, and diagnostic development programs. The Principles are designed to be easily adapted to suit the needs and requirement of various types of product development programs.