Human Gene Therapy Products Incorporating Human Genome Editing Guidance

June 14, 2022

Dockets Management Staff (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852

Re: Comments for Docket No. FDA-2021-D-0398: Human Gene Therapy Products Incorporating Human Genome Editing; Draft Guidance for Industry

Dear Sir/Madam:

The American Society of Gene & Cell Therapy (ASGCT) appreciates the opportunity to comment on the draft guidance document, Human Gene Therapy Products Incorporating Human Genome Editing. ASGCT is a nonprofit professional membership organization comprised of more than 5,500 scientists, physicians, clinicians, and other professionals working in gene and cell therapy in settings such as universities, hospitals, and biotechnology companies.

The mission of ASGCT is to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease. Many of our members have spent their careers in this field performing the underlying research that has led to today’s robust pipeline of transformative therapies. By bringing together members from diverse backgrounds, ASGCT strives to be a catalyst for transformative medicine using genetic and cellular therapies to control and cure human disease. We appreciate FDA’s ongoing willingness to hear from stakeholders about ways to improve and adapt policies to consider the unique attributes of these therapies.

I. General Comments

ASGCT appreciates that FDA is working to provide additional guidance to gene therapy sponsors to further promote development of new therapies for patients. We believe that this guidance broadly strikes an appropriate balance between setting baseline expectations for sponsors and providing needed flexibility to evaluate data for individual development programs based upon the benefit-risk of the unmet medical need and the condition being treated. That said, ASGCT does have a number of specific suggestions for adjustments or edits that we believe would represent improvements in the final guidance.

II. Specific Comments

1. Selection of GE Components (lines 66-159)

Section III.A of this guidance, “General Considerations,” implies that best available or optimal gene editing components be selected when developing a GE technology. For example, the guidance includes the following on lines 119-120 about the delivery method: “When determining the optimal delivery method of the GE components, it is important to consider the advantages and limitations of each potential method…” This implied expectation also includes the method by which the DNA sequence will be achieved, and the type of genomic modification needed for the desired therapeutic effect.

While we agree that developers should consider the advantages and limitations of components, we respectfully request that the final guidance address two important clarifications:

• These advantages and limitations should not be compared or evaluated in relation to other products under development. We believe each development program and the resulting BLA should be in the context of potential of unmet need, available therapies, severity of the condition, the intended patient population, and the safety, efficacy and quality data provided in the BLA.

• These advantages and limitations should take into account that over the full course of a product development program, technologies may evolve. This should not be a regulatory barrier to development of a particular product or have a negative impact on how FDA reviews a BLA if the safety, efficacy and quality data of such BLA meet licensure standards.

2. General Chemistry, Manufacturing, and Controls (CMC) Considerations (lines 161-351)

a. General Thoughts

ASGCT appreciates the inclusion of GE-specific CMC considerations in this draft guidance, and we offer in the table below a few specific suggestions for potential line-item changes. More generally, as ASGCT shared at our 2021 FDA Liaison Meeting,1 advances in manufacturing and analytical techniques have improved control and characterization of products in the gene therapy field writ large, including in GE applications, but the link between product characteristics and clinical performance is still evolving. Small clinical trial populations that are characteristic of gene therapy product development make statistical analysis of CMC data from gene therapy batches challenging. Rapid innovation in the GE field warrants a CMC framework that remains flexible, risk-based, and correlated with the extent of clinical experience. ASGCT would like to reiterate several recommendations from our 2021 FDA Liaison Meeting that are applicable to GE product development:

• We encourage FDA to take a pragmatic approach to the application of statistical analyses of specifications early in development. With limited data, these may not be as meaningful as robust qualitative analysis. Additionally, we recommend that FDA and sponsors use available data and science-based risk assessment to guide the evolution of specifications at the appropriate point of development (including post-marketing if so justified).

• When considering potency assays, ASGCT recommends FDA allow a risk-based approach in the context of the unmet medical need of the patient population in its requirements for potency assays of CGT products. The development of one strong potency assay addressing the main mechanism of action(s) of the final drug product should be sufficient for product release, obviating the need for other potency assays as product release tests. Additional measures of potency should be continued throughout development, but as general characterization assays with no acceptance criteria. Expectations for potency assay qualification and specification setting need to take into account the complexity of the assay, known correlation with clinical outcomes, and data availability. Finally, ASGCT urges FDA to allow continuous validation of potency assays during review and post-licensure to refine acceptance criteria for products where high replicate batch data is challenging (e.g., autologous products or those that have especially complex modes of action).

b. Level of Material Control Required

As we noted above, ASGCT appreciates the inclusion of GE-specific CMC considerations in this draft guidance, in addition to the previous guidance Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry (January 2020) ² Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs): Guidance for Industry. https://www.fda.gov/media/113760/download . However, ASGCT is concerned that the current recommendations could be overly burdensome and unnecessary for certain GE products. ASGCT requests that FDA further consider the level of material control needed relative to nature of the materials, frequency of use, and proximity to patients. Specifically, the Society would like to request that FDA consider adding additional language in the final guidance that reflects the nature of the materials (synthetic vs bioactive; nuclease vs. nucleic acid) and how frequently it is anticipated to be used during the product life cycle.

For example, consider a sponsor using a plasmid in combination with a nuclease to edit a stem cell that would be further manufactured into a Master Cell Bank (MCB), then a Working Cell Bank (WCB), then differentiated into a therapeutic product. Once the GE cell is created, there is no need to use the plasmid again because the GE stem cell is replenishable and can serve as the seed stock to support all future clinical phases. This is a one-time use of the plasmid, and the proximity of the initial cell to the patient is considerably downstream.

• If the sponsor has already manufactured the one-time use plasmid under non-GMP conditions with approved Phase I/II trials in progress and/or successfully completed, the guidance seems to suggest that the sponsor would need to re-make all components under GMP and re-establish the GE cell clone in order to support late phase/commercial development (lines 218-224): “For most Phase 1 clinical investigations, sponsors should follow the recommendations in FDA’s Guidance for Industry: CGMP for Phase 1 Investigational Drugs for the manufacture of these components (see 21 CFR 210.2(c); Ref.5). However, for later Phase studies and for licensure, GE components must be manufactured according to CGMP standards (21 CFR Parts 210 and 211), with particular consideration for control of reagent quality, manufacturing process, and analytical methods.” This seems unnecessary.
• In addition, in this instance, how should the sponsor approach stability testing for both the bacterial and plasmid cell bank? Lines 235-240 offer guidance that does not seem applicable to a one-time use situation, but which casts a broad net in terms of when such stability tests would be required: “We also recommend GE components be assessed for stability. Outlines of stability protocols and any available stability data should be provided in the IND. Stability studies should be conducted on all GE components (e.g., lyophilized and reconstituted materials), if applicable. Stability studies should include stabilityindicating tests assessing critical product attributes, such as purity and functionality, that may be affected during storage.”

In some cases, commercial entities intend to make hundreds of one-time use plasmids. As a result of this guidance, effectively all one-time use plasmids should be made under GMP for all clinical phases through commercialization, from the very beginning, or the manufacturer risks having to recreate the initial cell, MCB and WCB at each phase of clinical study as GMP requirements increase (and then establishing comparability back to the original product). The challenge with such a recommendation would be multi-faceted. First, all nonclinical and early phase data to support safety and efficacy is based on cells derived using non-GMP material. Second, the cost to manufacture under GMP would represent an unexpected cost and time burden to the sponsor, further delaying the production of a therapeutic product. And finally, proximity to the patient is significantly downstream of the critical raw material which entails manufacture of multiple banks (MCB and WCB) that undergo significant testing and are further differentiated into drug product that is, again, thoroughly tested.

Therefore, ASGCT respectfully requests that FDA clarify in the final guidance whether FDA’s intention is that a sponsor in this situation must always ensure both bacterial MCB and plasmids are manufactured under GMP at the start. ASGCT recommends flexibility for certain components, consistent with phased GMP requirements.

3. Distinguishing In Vivo and Ex Vivo GE Applications (lines 272-351)

ASGCT appreciates the sections of the guidance in which FDA specifies recommendations for in vivo and ex vivo human GE drug product types (lines 272-351). As the science for these different human GE drug products continues to evolve, FDA may want to consider clarifying whether recommendations for in vivo and ex vivo approaches are meant to be the same or different in other areas of the guidance, such as III.B subsection 2 on “Genome Editing Component Manufacture and Testing” (lines 226-233). ASGCT’s goal is to ensure that, where it occurs in the guidance, conflation of in vivo and ex vivo approaches is intentional.

4. Study Endpoints (lines 592-599)

As an organization representing a diverse group of stakeholders in the gene therapy and gene editing fields, who have varying levels of regulatory experience on their development teams, ASGCT believes FDA should be clear and direct in this guidance regarding regulatory expectations for study endpoints. The guidance states:

“For efficacy studies, the primary endpoint should also reflect a clinically meaningful effect of the GE product” (lines 594-596).

This is inconsistent with previous FDA guidances. FDA’s recent Human Gene Therapy for Neurodegenerative Diseases: Draft Guidance for Industry, ³ 3 Human Gene Therapy for Neurodegenerative Diseases: Draft Guidance for Industry. https://www.fda.gov/media/144886/download  which applies to GE products as well as other gene therapies, states:

“[i]n trials intended to provide evidence of effectiveness to support a marketing application, primary efficacy endpoints should be either clinically meaningful endpoints that directly measure a clinical benefit, or [emphasis added] surrogate endpoints that are reasonably likely to predict a clinical benefit…[u]se of a surrogate endpoint may be appropriate when a GT product directly targets an underlying, well-understood and welldocumented monogenic change that causes a serious neurodegenerative disorder. In these cases, the GT product could alter the underlying genetic defect and thereby treat or cure the disease” (pg. 11, para. 5).

Furthermore FDA’s Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics, ⁴ Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics. https://www.fda.gov/media/86377/download  which applies broadly to all products, notes:

“The two types of endpoints that can be used as a basis for accelerated approval are: (1) a surrogate endpoint that is considered reasonably likely to predict clinical benefit and (2) a clinical endpoint that can be measured earlier than IMM that is reasonably likely to predict an effect on IMM or other clinical benefit (also see section VII.D.2.)… A clinical benefit is a positive therapeutic effect that is clinically meaningful in the context of a given disease…” (pg. 17, para. 3).

The current language in this draft suggests that for GE products, the agency has a different policy view on the use of surrogate endpoints and accelerated approval for these products. If this is the case, ASGCT strongly objects to this assertion and asks for greater clarity from the agency regarding the legal and scientific basis for this determination. If this is not the case, we believe that the same policies FDA has established in previous guidance should be clarified in this guidance for GE products to prevent inconsistent interpretation about expectations for efficacy endpoints between related guidances. Lacking clarification of FDA’s intent, ASGCT recommends that this section should be removed from the GE guidance to prevent confusion.

As with all products, we believe that FDA’s expectations for safety and durability at the time of approval should be established in the context of the disease and patient population, including severity of the condition, unmet need, and the perspectives of patients.

III. Line-by-line Recommendations

Below, the Society has provided specific line-item recommendations for FDA’s consideration.