Pharmaceutical and device manufacturers working to market codeveloped products are urged to bring all the needed expertise to the development process, including FDA regulatory staff and third-party payers, to make the appropriate scientific and business decisions. These experts should be convened near the beginning of the process to ensure that challenges and obstacles are identified and addressed early in the product life cycle with minimum surprises and to consider novel business and marketing arrangements to share both risks and rewards for development of these products.
The Timing of Decisions About Studying a Drug–Biomarker Combination
Consideration of the integration of biomarker development into the drug development process should occur as early as possible because of the implications for biospecimen and data collection. Early implementation of standardized procedures for biospecimen and clinical data collection and efforts devoted to characterizing biomarker targets can maximize the utility of the specimens and provide information on the targets useful in addressing future questions regarding variations in biomarker expression or modulation. Decisions on how to study a biomarker in a particular clinical trial depend on the context of the study. Key considerations include factors such as the need to collect safety data, availability of reliable assays for evaluating the biomarker and drug activity, and relationship of results to clinical benefit (see the “Preclinical and Nonclinical Development” and “Clinical Development” sections of ).
Timing of Decisions Regarding Codevelopment of Biomarker Assays
A long lead time may be needed to develop well-characterized biomarker assays. The goal is to be prepared for phase III by ensuring that appropriate biomarker-based selection strategies are in place. For example, better-developed selection strategies might have more efficiently identified the positive effects of EGFR inhibitors in early phase III trials in patients with lung (23
) and colorectal carcinomas (31
In some cases, practical business considerations may outweigh benefits of a science-based strategy because the incentives for producing biomarker assays may be substantially misaligned for the diagnostics and pharmaceutical companies during different stages of development. The long time to market is a financial risk and critical issue for both the pharmaceutical and diagnostics industries, but it is a higher risk for the diagnostics industry during early biomarker and assay development. At this stage, not much is known about the drug or the biomarker, and the chosen biomarker might not ultimately be suitable or the drug might not prove sufficiently effective to warrant full development. Well-annotated biospecimens collected using standard protocols and appropriate consents are critical to allow biomarker assay development to take place when there is sufficient knowledge available about the drug and its relationship to the biomarker. The development of a shared repository of specimens from patients receiving the treatment of interest could help to address this need.
The lack of a rigorously evaluated biomarker at the end of phase II and the large sample size required to validate a biomarker assay increase the risk to the pharmaceutical company in later development stages. Secondary approvals (cross-labeling studies)—for example, taking a drug and biomarker combination approved in a narrowly defined population into a second population or evaluating a second drug from the same chemical or mechanistic class in combination with a biomarker—are less risky for both drug and biomarker assay development.
The perceived market worth for drugs and biomarkers may also be mismatched. The drug developed with the biomarker is a value generator, whereas the diagnostic may be perceived as a commodity (sometimes offered at no cost by the pharmaceutical company). Higher reimbursement rates for diagnostic assays used in patient management would likely provide needed incentives to the diagnostics industry.
The FDA usually recommends validating biomarkers prospectively to ensure study of appropriate populations, to minimize sampling bias, and to maximize the likelihood of having adequate power to evaluate the hypothesis being tested. This ideal study approach is most appealing if it can be performed in a time- and cost-efficient manner. If timelines for studies are long, and if study size requirements are large, companies may be reluctant to involve themselves in the uncertain process of companion product development, particularly in a competitive market with rapid changes in drugs, diagnostics, and clinical decision making. If companies were able to access well-constructed biological specimen collections and clinical data in early decision making, more robust biomarker-drug candidates and more focused phase III clinical studies might result.
If companies were able to develop well-planned incremental evaluations of drug-companion diagnostic pairs across phase I, II, and III studies that provide for better product decision making or in terms of trial design and size, the cost–benefit of these incremental evaluations could potentially revolutionize the development pipeline for new drugs and diagnostics. Unfortunately, it is too early to fully understand the financial costs and risks of this approach.
Well-planned incremental evaluations of drug-companion diagnostic pairs across phase I, II, and III studies that provide for better decision making in terms of trial design would ideally increase the efficiency of the drug development process. However, limits to biological understanding and resources can make it difficult to identify or carry out an optimal sequence of evaluations in a prospective fashion. Retrospective biomarker analyses using specimens previously collected within treatment trials may also be helpful, either in the discovery process, in fine-tuning developmental plans, or in some cases in supporting submissions to the regulatory agencies. The potential biases, effects of multiplicity, missing data, and other deficiencies of such analyses must be addressed. In addition, the statistical power for detecting biomarker effects in such retrospective studies will often be low. However, the results might identify promising new or improved biomarker assays that could be introduced into phase III studies. The FDA continues to seek input from the research and development community on these issues, but there is still no clear strategy for the approval of a predictive diagnostic with therapeutic agent using the retrospective approach (59
There are situations in which biomarker assay approvals may be based on retrospective analysis alone. For example, a safety biomarker assay might be approved based on retrospective analysis of biomarker-positive and biomarker-negative specimens from patients who have been treated with approved drugs and in whom the safety outcomes are known. Early consultation with FDA scientists from both drug and device offices is encouraged when considering these strategies.