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FDA Guidance for Human Gene Therapy for Hemophilia A & B

Human Gene Therapy Hemophilia Clinical Trials and FDA Guidance

Having seen an increasing number of gene therapy approvals, the FDA has issued draft guidance1 to help the developers of human gene therapy (GT) products for the treatment of hemophilia A & B.  In this article we will be focusing our attention on what guidance has been provided about the design of human gene therapy clinical trials for hemophilia A & B, including what is needed to support an accelerated approval approach. 

Importantly, it should be noted that the guidance issued does not include recommendations for products for hemophilia C or for the treatment of any bleeding disorders apart from hemophilia A and B. 

Early Phase Clinical Trials

The FDA gene therapy guidance states that development of GT for hemophilia is like those for the development of other biologics2, requiring evidence of safety and feasibility in addition to bioactivity and preliminary efficacy.  It is encouraged that prospective sponsors meet with FDA review staff early in a development program as a case-by-case assessment is warranted for the design of each clinical trial. 

From previous experiences is it known that it is not always possible to generalize the clinical benefits from recombinant factor VIII levels to those obtained by recipients of GT products, due to qualitative differences between assay results from one-stage clotting (OC) assays and from chromogenic (CS) assays.  For example, in patients with hemophilia A treated with recombinant B-domain-deleted factor VIII products, CS assays indicate higher factor activity than OC assays.  In contrast, for patients with hemophilia A who receive GT products that express a B-domain-deleted factor VIII transgene, OC assays indicate higher factor activity than CS assays.  Therefore prior to pursuing an accelerated approval process using factor activity as a surrogate endpoint, the Sponsor should investigate any discrepancies between OC and CS assay results at this stage of the development program.

Late Phase Clinical Trials

The FDA recommends the use of a within-subject Non-inferiority3 (NI) trial to demonstrate that a well-controlled study has been conducted collecting sufficient evidence to support a marketing application of the GT product. 

If a traditional approval route is to be followed, the primary endpoint for demonstrating clinical benefit should be Annualized Bleeding Rate (ABR).  If early phase trial results suggest an accelerated approval approach, then factor activity could be considered as a surrogate endpoint4. Remember though that for an accelerated route, it is necessary to resolve any discrepancies in factor assay results from the various assay methods and to determine a target factor activity level within the range of factor activity of the normal population.

Late Phase Study Design

In the guidance the study period is divided into two design phases, firstly pre‑administration of the GT product and then post administration.

During the pre-administration phase the recommendations are:

  • Only enroll patients who have not required dose adjustments to their prophylactic replacement therapy for at least 12 months
  • Avoid using historic or retrospective data to estimate pre-GT administration rate of ABR but rather observe patients for a 6 months lead-in period to collect data for estimating the pre-administration rate within the study
  • Enroll patients who use on-demand therapy prior to study entry in a separate cohort. Analysis of efficacy in this cohort may provide evidence to support the primary endpoint results.

During the post-GT product administration phase

  • Use the same exogenous replacement therapy as in the lead-in phase to prevent or treat bleeding during the interval from post-GT product administration to steady state factor level
  • Include a washout period following exogenous factor replacement therapy to measure factor activity
  • Include a pre-specified target factor activity level or duration from treatment that specifies the timing to discontinue exogenous factor prophylaxis
  • Specify when assessment of ABR rates and durability of response is to begin (e.g., 3 weeks after steady state levels of factor activity is reached, and exogenous factor prophylaxis is discontinued)
  • Collect data for analyses of supportive endpoints as related to the pre-treatment phase
  • Include a plan for initiation, dosing and tapering of corticosteroids for management (treatment or prophylaxis) of immune-mediated liver dysfunction
  • Include an assessment plan to correlate factor activity and bleeding rates.

Non-Inferiority Trial

The aim of a non-inferiority design in hemophilia is to demonstrate that the ABR of the investigational GT product is not more than a clinically insignificant amount M above the ABR of the comparator, i.e. in lay terms the GT product performs no worse than the standard product.  With this type of trial objective, it is very important to carefully consider a relevant clinical difference in ABR rates and what fraction of this will be defined as the non-inferiority limit M.  FDA guidance is provided on how to design a non-inferiority trial3, but if you are unfamiliar with this type of study it may be worth consulting with a statistician as the choice of M affects both the likelihood of the trial successfully demonstrating non-inferiority and has a huge impact on the required sample size of the study.

As the recommended study design requires a within-patient comparison of the GT product compared with the standard comparator, the guidance provides a short explanation of the type of statistical analysis that could be used, ‘One possible approach is to take the difference of each pair of ABRs, and then test that the median of the differences is less than M using the Wilcoxon Signed Rank test.  We recommend that you also report a 95% confidence interval (CI) on the median of the ABR difference.’  Again, a statistician can advise on whether this approach is most appropriate or whether there may be a more powerful method of statistical analysis available.


Recommendations are provided for frequency of monitoring both in the short and longer term for the following endpoints

  • Factor activity levels
  • Liver function
  • Vector related antibodies
  • Interferon-γ secretion from peripheral blood mononuclear cells
  • Inhibitor antibodies to factor VIII or factor IX
  • Viral shedding5, if appropriate
  • Adverse events
  • Emergence of new clinical conditions including malignancies, neurologic, rheumatologic or autoimmune disorders

More guidance about gene product follow-up in general is provided in Long Term Follow-Up After Administration of Human Gene Therapy Products6.

Interestingly, the FDA are encouraging sponsors to collect patient experience data during product development, and to submit such data in the marketing application as they may provide important additional information about the clinical benefit of a GT product. But a caveat is included that ‘The treatment landscape for hemophilia is evolving.  Therefore, the benefit-risk profile of the investigational product will be evaluated in the context of the treatment landscape at the time of our review of a marketing application.’  

RWD Data in Gene Therapy Trials Whitepaper

Quanticate has an extensive experience in the therapeutic area of hemophilia. Our statistical consultancy team would be happy to provide support and guidance for your development programme if you have a need for these types of services please Submit a RFI and member of our Business Development team will be in touch with you shortly.


1. Draft Guidance for Industry: Human Gene Therapy for Hemophilia, dated July 2018 https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610801.pdf

2. Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products, dated June 2015 https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM564952.pdf

3. Non-Inferiority Clinical Trials to Establish Effectiveness; Guidance for Industry, dated November 2016,  https://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf

4. Guidance for Industry; Expedited Programs for Serious Conditions – Drugs and Biologics, dated May 2014, https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf

5. Guidance for Industry; Design and Analysis of Shedding Studies for Virus or Bacteria-Based GT and Oncolytic Products, dated August 2015, https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinfor mation/guidances/cellularandgenetherapy/ucm404087.pdf

6. Draft Guidance for Industry; Long Term Follow-Up After Administration of Human Gene Therapy Products, dated July 2018,  https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610797.pdf


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