Four Key Themes from the FDA’s Companion Diagnostics Guidance That Medical Device Firms Need to Know

As of October, the U.S. Food and Drug Administration (FDA) has approved or cleared 19 companion diagnostics (CDx),1 though that number is certain to rise as DNA sequencing continues to reveal intricate correlations between genetic signature and disease and becomes more financially feasible. As the industry moves away from the “one-size-fits-all” approach to therapeutic development and toward precision medicine, it will look to the FDA for directives on the development and regulatory pathway for CDx. 

In August 2014, the FDA released its “In Vitro Companion Diagnostic Devices, Guidance for Industry and Food and Drug Administration Staff,” which defines CDx, discusses the review and approval/clearance process, and provides guidance on proper labeling for therapeutics and CDx.2 The guidance emphasizes the importance of early collaboration between the drug developer and the device manufacturer in order to accelerate access to new treatments, especially those for patients living with serious and life-threatening diseases.

An understanding of these four key themes from the CDx guidance will help manufacturers plan for regulatory-compliant development of their devices.

1. Definition of CDx
A CDx is an in-vitro diagnostic device that must provide information that is essential for the safe and effective use of a corresponding therapeutic. This includes, for example, the use of HER2 gene profiling and protein expression assays in patients for whom Herceptin (trastuzumab) treatment is under consideration. However, diagnostics that monitor organ function or other vital processes, such as serum creatinine or transaminase assays, are not classified as CDx because they do not determine whether a specific treatment can be safely and effectively used. If there is any confusion as to whether a device qualifies as a CDx, it is best to submit to the FDA to render a decision.

2. Co-Development
CDx development often occurs separately from its corresponding therapeutic, especially for smaller device companies with limited resources. However, the FDA encourages concurrent development of therapeutics and their associated CDx whenever possible in order to ensure recruitment of the intended patient populations for clinical studies.

Co-development means that device companies likely will have to partner with drug manufacturers much earlier in the development process. To create a solid development plan that outlines clinical and analytical strategies, drug and CDx regulatory contingents should participate in the regulatory team as soon as strategy discussions begin. Early and frequent check-ins with both the drug and device product review divisions of the FDA will help manufacturers submit a more comprehensive regulatory packet and reduce the likelihood of delays to approval or clearance.

3. Regulatory Pathway
The FDA will use a risk-based approach to determine the regulatory pathway for the CDx. If the CDx is used to make critical treatment decisions, such as patient selection, then it would be considered a significant-risk (SR) device according to the investigational device exemption (IDE) regulation.3 SR devices present a serious risk to the health, safety or welfare of a subject because they are used to determine treatment options that could affect survival. To understand this designation, consider the risk of administering an oncology CDx that does not accurately select the target population and thus prevents certain patients from receiving potentially lifesaving treatment.

Clinical studies for SR devices will require an IDE submission and approval from the institutional review board and FDA before the trial can begin. Sponsors are encouraged to consult with the drug and device divisions at the FDA to determine whether both an investigational new drug application and IDE are required for the study. Because of the increased regulatory scrutiny, manufacturers would be wise to request a Pre-Submission Meeting to confirm the regulatory pathway.

The FDA expects that the CDx device and its therapeutic product will ideally be co-developed and approved or cleared contemporaneously. The FDA will not approve the new therapeutic or a new indication for the therapeutic if the CDx is not already approved or cleared for that indication. An exception will be made if the new therapeutic is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists.

4. Cross-Labeling
CDx labeling must specify the intended use of the device and the name of the corresponding therapeutic (or therapeutic class, if applicable). Cleared or approved CDx will require a new 510(k) or pre-market approval (PMA) application to expand the labeling to include a new indication.

Drug labeling often includes “information about the diagnostics tests that determine how, when, or whether a therapeutic product is used.” This includes a clear definition of the patient population in which the diagnostic test is safe and effective, if applicable.

The Future of CDx Development
Device manufacturers that want to stay ahead of the game will partner early with drug manufacturers to create an efficient co-development strategy. The pharma partner should be on the same page in terms of intended use, commercialization, and reimbursement, as well as which party will bear development costs. There really should be a three-way agreement on the development plan between the device manufacturer, drug manufacturer, and the device and drug divisions of the FDA. Contract research organization partners can help device and drug manufacturers navigate the regulatory landscape and effectively prepare for Pre-Submission Meetings and 510(k) and PMA submissions.

Small medical device companies with novel CDx will face significant development hurdles, especially compared to device giants seeking to expand an indication for an already cleared or approved device. The longer development timeline and higher risk of failure associated with novel CDx require solid regulatory and clinical strategy to ensure selection of the correct patient population and continuation of the trial. Adaptive clinical trial designs can de-risk novel CDx trials by allowing analysis of accumulating data at an interim point in the trial and then a subsequent modification of intended use, if necessary.

Though several types of adaptive designs exist, population enrichment (PE) designs perhaps are the most relevant to CDx development. One scenario is an adaptive PE triple-negative breast cancer trial in which the diagnostic is used to restrict patient eligibility. An adaptive design must be agreed to before the trial begins and a discussion with the FDA will determine the final design used.

The FDA’s CDx guidance should reduce device manufacturers’ pre-market regulatory burden by providing the framework for the FDA’s expectations. However, it is important to keep in mind that the guidance does not address certain important development questions, such as required analytical validation tests or the timing for CDx introduction into a clinical trial. Reviewing related documents, for example, the FDA’s Drug-Diagnostic Co-Development Concept Paper Draft4 and its guidance on how to request a Pre-Submission Meeting5 to ask product-specific questions should help clarify some of the issues not addressed in the CDx guidance. 

References

1. List of Cleared or Approved Companion Diagnostic Devices (In-Vitro and Imaging Tools) www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm
2. In-Vitro Companion Diagnostics: Guidance for Industry and Food and Drug Administration Staff www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf
3. Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors: Significant and Non-Significant Risk Medical Device Studies www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf
4. Drug-Diagnostic Co-Development Concept Paper Draft www.fda.gov/downloads/drugs/scienceresearch/researchareas/pharmacogenetics/ucm116689.pdf
5. Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM311176.pdf

---

Sandra White is a director of regulatory affairs at ICON plc with more than 15 years of experience in medical device regulatory affairs, quality assurance, and research and development. She specializes in the regulation of in-vitro diagnostics, including the development of regulatory strategies, design of analytical and clinical study protocols, and the preparation of domestic and international regulatory submissions. White holds an M.S. in drug regulatory affairs and health policy from Massachusetts College of Pharmacy and Health Sciences and is regulatory affairs certified. 

Mehri Hezari-Adam, Ph.D., is a director of regulatory affairs at ICON plc. For more than 17 years, Hezari-Adam has advised sponsors on U.S. and Canadian regulatory strategy for drugs, biologics and combination products. She specializes in the pre-IND to approval phases of development, Canadian CTAs, FDA meetings, and orphan drug designations. She holds a B.S. and a Ph.D. in pharmacy from the University of Texas at Austin.