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Pharma Insights

How Development of Gene Therapies Impact Decisions on Their Place in Therapy

Authored by

Larry Blandford, PharmD—Column Editor1; Aaron Burke2


1Executive Vice President, Managing Partner, Precision Value & Health

2Strategic Product Marketing Director, Precision for Medicine


Precision Value & Health and Precision for Medicine are part of Precision Medicine Group, which supports the development and commercialization of gene therapies as well as companion diagnostics. Dr. Blandford is executive vice president, customer solutions with Precision Value & Health. Mr. Burke is strategic product marketing director with Precision for Medicine.


J Clin Pathways. 2019;5(9):34-35. doi:10.25270/jcp.2019.11.00104

Gene therapy has sparked significant interest among researchers, health care providers, and patients because it offers the tantalizing possibility of a cure, particularly for rare diseases with a genetic basis. While gene therapy holds great promise, this field of research is still in its nascent stages, and the optimal methods and solutions for unlocking its full clinical potential are still being defined. Commercialization of gene therapies is complex with challenges ranging from vector development and trial design to regulatory hurdles, patient selection, and reimbursement. 

In this article, we explore critical factors in the development of gene therapies, including trial management, accelerated approval pathways, and companion diagnostic development and its coordination with therapeutic development. We also discuss the implications of these factors on decisions made by clinicians, health systems, and payers regarding the place of gene therapies in the treatment pathway.  

Gene Therapy Clinical Development

Approximately 80% of rare diseases have a genetic origin,1 making them amenable to gene therapy. As with other rare disease trials, gene therapy trials may face challenges with patient recruitment. Given these potential difficulties, the Food and Drug Administration (FDA) recommends collecting pertinent data (eg, mutation type, adverse events, efficacy outcomes, biomarkers) to inform patient selection, randomization in early stages of development, stratified randomization based on disease stage/severity (if relevant), intrasubject control (if possible), and single-arm trials using historical controls.2

The FDA also recommends conducting first-in-human studies as randomized, control trials to generate efficacy and safety data to support registration but recognizes that there may be feasibility limitations. In these cases, historical controls may be considered but must be accompanied by knowledge of the natural history of the disease.2 As a result, conducting natural history studies early in the development process is necessary for obtaining robust data and endpoints in inherently small studies.3

A key factor to consider when developing a gene therapy product is the possibility for accelerated approval and market availability. Therapies for serious or life-threatening conditions with significant, unmet needs are eligible for accelerated approval through regenerative medicine advanced therapy designation, breakthrough therapy designation, fast-track designation, accelerated approval, and priority review.2,4 

As with other therapies for rare diseases or those that achieve accelerated approval, the data available to support decisions on place in treatment protocols or coverage criteria is much more limited than what health systems and payers are accustomed to having. When you add this to the likely high initial cost of these treatments, uncertainty in reimbursement and return on investment occur. The result can be delays in treatment and/or financial issues that threaten the very existence of the stakeholders involved.

Companion Diagnostic Development 

When used in conjunction with gene therapy, companion diagnostics (CDx) can help inform treatment decisions, facilitate greater certainty in benefits, and impact protocols and reimbursement decisions. Thus, the identification and development of appropriate CDx have been proposed in multiple gene therapy-related guidelines.2,5,6 Most of the currently approved CDx are in vitro diagnostic devices that provide information essential for safe and/or effective use of a corresponding drug or biologic. CDx can assist in the identification of patients who are likely to benefit from therapy or those who are likely to experience treatment-related adverse events. They may also facilitate monitoring of treatment response, enabling health care providers to adjust therapy for improved safety or efficacy.7

Ideally, CDx development should occur in parallel with drug development (Figure 1). As with development of a CDx for any other type of drug, development of a CDx for a gene therapy should begin with a clear definition of the assay’s use and what it measures, as well as the risks and benefits associated with it. In addition, it is important to define which patient population(s) would benefit from use of the assay in conjunction with therapy.8

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If the CDx is eligible, the FDA’s Breakthrough Devices Program—which replaces the Expedited Access Pathway and Priority Review Program for 510(k), de novo device, or premarket approval application submissions—could facilitate approval. To be eligible for breakthrough designation, the sponsor must demonstrate evidence that suggests the CDx would provide more effective diagnosis or treatment of a life-threatening or irreversibly debilitating disease or condition. The FDA released final guidance on the Breakthrough Devices Program in December 2018.9

Considerations for Place in Therapy and Access With Companion Diagnostics 

According to the Alliance for Regenerative Medicine, there were 372 gene therapy products in clinical trials as of Q1 2019.10 As these novel therapies advance to later stages and potential approval, the pressure to address place in therapy and financial management will increase significantly. Thus, those treatments for which a CDx has been developed and approved in parallel are likely to find their place in therapy and coverage more readily. Current reimbursement models are not designed to accommodate many of the unique factors associated with gene therapies, including high up-front costs, smaller patient populations, treatment windows, potentially curative treatment, lack of long-term safety and efficacy data, and complex administration and monitoring requirements. In our opinion, having greater clarity in identifying the patient population and monitoring response through CDx should improve clarity on place in therapy and reimbursement. That does not happen without an understanding of how the CDx itself is administered and reimbursed, reinforcing the need for the  reimbursement pathway to be managed in parallel to the treatment. 

Bringing it All Together

Development of a gene therapy is a complicated undertaking, fraught with technical challenges and regulatory complexities. The determination of place in therapy and coverage can be just as complicated and challenging. When these therapies can be guided by a CDx, their use and reimbursement—and ultimately patient outcomes—can be improved. Required are careful planning and appropriate trial design, CDx validation, and access to realize the potential tremendous benefits of gene therapies.


1. European Medicines Agency. Orphan drugs and rare diseases at a glance. Published July 3, 2007. Accessed September 27, 2019.

2. US Food and Drug Administration; Center for Biologics Evaluation and Research. Human gene therapy for rare diseases. Draft guidance for industry. Docket No. FDA-2018-D-2258. Published July 2018. Accessed September 24, 2019.

3. Cheever TR, Berkley D, Braun S, et al. Perspectives on best practices for gene therapy programs. Hum Gene Ther. 2015;26(3):127-133.

4. US Food and Drug Administration; Center for Biologics Evaluation and Research. Expedited programs for regenerative medicine therapies for serious conditions. Guidance for industry. Docket No. FDA-2017-D-6159. Published February 2019. Accessed September 24, 2019.

5. US Food and Drug Administration; Center for Biologics Evaluation and Research. Human gene therapy for hemophilia. Draft guidance for industry. Docket No. FDA-2018-D-2238. Published July 2018. Accessed September 24, 2019.

6. US Food and Drug Administration; Center for Biologics Evaluation and Research. Human gene therapy for retinal disorders. Draft guidance for industry. Docket No. FDA-2018-D-2236. Published July 2018. Accessed September 24, 2019.

7. US Food and Drug Administration. Companion diagnostics. Updated December 7, 2018. Accessed September 24, 2019.

8. US Food and Drug Administration; Centers for Devices and Radiological Health. Principles for codevelopment of an in vitro companion diagnostic device with a therapeutic product. Guidance for industry and Food and Drug Administration staff. Docket No. FDA-2016-D-1703. Published July 2016. Accessed September 27, 2019.¬

9. US Food and Drug Administration; Centers for Devices and Radiological Health. Breakthrough devices program. Guidance for industry and Food and Drug Administration staff. Docket No. FDA-2017-D-5966. Published December 2018. Accessed September 24, 2019.

10. Alliance for Regenerative Medicine. Q1 2019 Data Report. Accessed September 24, 2019.

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