Regulatory Roundup 3Q '23

October 3, 2023
Regulatory Roundup visual in DHC orange


September 27, 2023 meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee

The Cellular, Tissue, and Gene Therapies Advisory Committee convened on September 27, 2023 to discuss and make recommendations to FDA on the biologics license application (BLA) from BrainStorm Therapeutics, Inc. for debamestrocel for the requested indication “treatment of mild to moderate amyotrophic lateral sclerosis (ALS).”  

There were several unusual aspects of this BLA and AdComm. First, at the time of BLA submission, FDA determined that the application was “scientifically incomplete to demonstrate substantial evidence of effectiveness, and that the manufacturing information was grossly deficient to ensure adequate product quality” (source: FDA Briefing Document ) and took the uncommon action of Refuse to File (RTF). After a meeting to discuss the reason for RTF, BrainStorm had the option to submit a new, complete application which addressed the deficiencies, or request that the application be Filed over Protest (FOP). BrainStorm chose FOP. The second unusual aspect is that FDA convened an AdComm for a BLA that was FOP. Publicly available information, such as the company’s press releases, indicate that BrainStorm lobbied FDA to hold an AdComm. The third unusual aspect was that BrainStorm notified FDA of a request to change the originally requested indication “for the treatment of amyotrophic lateral sclerosis (ALS)” to “for the treatment of mild to moderate amyotrophic lateral sclerosis (ALS)” on September 22, 2023—five days before the AdComm. FDA noted in their presentation that the analyses in their briefing document, and conclusion that the data to not provide substantial evidence of effectiveness, remained relevant to the narrower subset of less advanced disease. A final unusual aspect that we will note here is that in 2021, the FDA acting commissioner issued a rare public statement on an investigational product, stating that the data did not support the proposed clinical benefit of the product.  

The conduct of the AdComm itself followed the norm of BLA discussion meetings, with presentations by the applicant, FDA, and an open public hearing with numerous impassioned testimonials by patients and patient advocates in support of approval of the product. The Applicant’s presentations argued that evidence of a positive benefit:risk supporting approval was provided by positive results in a prespecified subgroup with early disease, that a “floor effect” resulted in data bias in the Phase 3 trial, and supportive evidence was provided by biomarker data showing a biological effect, and urged that FDA exercise regulatory flexibility. The FDA’s presentations countered that the both the Phase 2 and Phase 3 studies failed all primary and key secondary endpoints, survival was worse in the treated group compared to placebo in the Phase 3, subgroup analyses were exploratory and did not provide substantial evidence of effectiveness, and that a floor effect had not been observed.  FDA also stated that there was no clear association of changes in biomarkers and clinical benefits.  

The FDA posed the following questions to the committee:

1) Please discuss the data presented in support of effectiveness for treatment of mild to moderate amyotrophic lateral sclerosis (ALS), including consideration of the mechanisms of action proposed by the sponsor, biomarker data including neurofilament data, and the clinical data.

2) Voting question: do the data presented demonstrate substantial evidence of effectiveness for treatment of mild to moderate ALS?
a) yes
b) no
c) abstain

3) If the answer to Question 2 is no, please discuss potential designs for a trial to demonstrate substantial evidence of effectiveness for MSC-NTF for the treatment of mild to moderate ALS.


The voting question result was 1 (yes), 17 (no), and 1 (abstain). The committee discussed concerns about control of product manufacturing, that the mechanism of action of the product had not been established, the biomarker data were not supportive, and the clinical data did not provide substantial evidence of effectiveness, and that safety concerns had been raised by the worse survival rate in treated patients at the end of the study. The committee members acknowledged the unmet medical need for safe and effective therapies in the devastating disease of ALS.  

FDA’s decision on the application is due on December 8, 2023. FDA is not required to follow the recommendation of advisory committees, but frequently does.  

Materials from the meeting are available here.

II. Support for Clinical Trials Advancing Rare Disease Therapeutics Pilot Program (START)

Applications accepted: January 2, 2024, to March 1, 2024

The announcement for a new clinically- focused pilot program dubbed “START”, for Support for Clinical Trials Advancing Rare Disease Therapeutics, was released on September 29. 2023 in the Federal Register.

The goal of START is to “provide a mechanism for addressing clinical development issues that otherwise would delay or prevent a promising novel drug or biological product from progressing to the pivotal clinical trial stage or pre-BLA/pre-NDA meeting stage.” FDA gives examples of issues including clinical study design, choice of control group, fine-tuning the choice of patient population, selecting appropriate endpoints for efficacy trials to support marketing approval, selecting statistical methodology, leveraging nonclinical information, or product characterization.

FDA states that the pilot will be milestone-driven. The milestone examples given are progression of a development program to pivotal clinical study stage or the pre-BLA or pre-NDA meeting stage. Upon reaching the milestone, participation in the pilot will be considered concluded.

Applications will be accepted from January 2, 2024, to March 1, 2024, via amendment to the applicant’s IND. FDA will select up to three participants each in CBER and CDER.

The eligibility criteria for CBER regulated products are:  

1. IND has been submitted in or converted to Electronic Common Technical Document (eCTD) format, unless the IND is of a type granted a waiver from eCTD format [see FDA’s guidance for industry entitled “Providing Regulatory Submissions in Electronic Format--Certain Human Pharmaceutical Product Applications and Related Submissions using the eCTD Specifications” (February 2020)] and remains in active status.

2. Sponsor has demonstrated substantial effort to ensure that that Chemistry, Manufacturing, and Controls (CMC) development aligns with clinical development, for example, through documented control of manufacturing and testing procedures to ensure clinical and CMC development timeline are in alignment.

3. The product is OTP-regulated IND for a cellular or gene therapy under which the product is being developed toward a marketing application.

4. The product is intended to address an unmet medical need as a treatment for a rare disease or serious condition, which is likely to lead to significant disability or death within the first decade of life. A rare disease or condition “means any disease or condition which affects less than 200,000 persons in the United States…” (Section 526(a)(2) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bb(a)(2))).  The START Pilot Program in CBER is not intended to encompass all rare diseases, but only a subset of rare diseases that are likely to lead to significant disability or death within the first decade of life.

Criteria for selection of participants will include:

1. potential clinical benefits of the product,

2. whether resolution of the specific issues noted by the sponsor in their request to participate in the pilot could be facilitated through enhanced communication to improve efficiency of program development,

3. whether there is an BT or RMAT designation for the product,

4. whether CMC development timeline aligns with clinical development plans, and

5. while INDs for combination products (21 CFR 3.2(e)(1)) may be eligible, products that require significant cross-Center interactions (e.g., complex combination products) may be less likely to be selected for the pilot.  

FDA emphasizes that a key factor is application readiness, e.g., sponsors who demonstrate having the ability to move the program forward towards a marketing application.

The benefit to selected participants will be enhanced communications with FDA review staff.  FDA intends to hold an initial meeting with participants to discuss the program and the pathway to milestone identified as the goal for a specific product. Additional communications may include traditional meetings plus emails and telecons on an as-needed basis. The number of total communications is not defined, but will be a point of negotiation as implied by “as agreed upon by the sponsor and FDA.”

For information, including the contents of the application, please refer to the FR notice. FDA’s press release on START includes links to other related information. It is possible that FDA will update this page prior to the January 4, 2024 start of acceptance of applications.  

In summary, we would describe the START pilot as an excellent opportunity for sponsors to obtain the additional FDA interactions they have been seeking. We strongly encourage everyone who fits the eligibility criteria to consider applying. We at DHC are available to help clients evaluate whether their products meet the eligibility criteria and craft their development plans to apply for the START pilot.

III. BLA review updates (from Q3, 2023)

No new BLA approvals of CGT products occurred in Q3 after the exciting pace of approvals in the first half of the 2023. The Action Due Date (ADD) for remestemcel-L was in early August, but Mesoblast announced on August 3rd that FDA issued a Complete Response Letter to the remestemcel-L BLA resubmission.  

Other recent news is that the FDA extended the ADD for Iovance’s lifileucel from November to February 24, 2024.

Three BLA ADDs fall in the month of December 2023. These are Brainstorm’s debamestrocel which was discussed at the Cell, Tissue, and Gene Therapies Advisory Committee (CTGTAC) meeting on September 27, 2023. Vertex’s exa-cel for sickle cell disease will be discussed by the CTGTAC on October 31, 2023 and the ADD is December 8, 2023. The last ADD for 2023 is for bluebird bio’s lovo-cel, also for sickle cell disease, on December 20, 2023.

IV. CGT BLAs under US FDA Review

The following information on BLAs under US FDA review was obtained from company press releases.

V. Upcoming Advisory Committee Meeting

 October 31, 2023: FDA’s Cell,Tissue, and Gene Therapies Advisory Committee (CTGTAC) will meet on October 31, 2023 to discuss Vertex Pharmaceuticals, Inc. biologics license application for exagamglogene autotemcel (exa-cel). Vertex has requested an indication for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises.

Meeting materials, including the draft agenda, roster, FDA and applicant briefing documents will be posted approximately 2 days in advance.  

Slides are usually posted on the day of the meeting.  


VI. Recent FDA Guidance Documents of interest to CGT: Q3 2023

1. Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products; Draft Guidance for Industry
(Draft open for comment until 11/13/2023)
FDA also posted a webinar providing a high-level overview of this guidance document, here.  

2. Human Prescription Drug and Biological Products: Labeling for Dosing Based on Weight or Body Surface Area for Ready-to-Use Containers: “Dose Banding”

3. Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products

4. Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications

5. Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence

6. Institutional Review Board (IRB) Review of Individual Patient Expanded Access Submissions for Investigational Drugs and Biological Products

7. Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products


VII. Rules & Legislation

On September 29, FDA announced a Proposed Rule About Laboratory Developed Tests. FDA stated “The proposed rule seeks to amend the FDA’s regulations to make explicit that IVDs are devices under the Federal Food, Drug, and Cosmetic Act, including when the manufacturer of the IVD is a laboratory. Along with this amendment, the FDA is proposing a policy under which the FDA intends to provide greater oversight of LDTs, through a phaseout of its general enforcement discretion approach to LDTs.”


VIII. Upcoming FDA Workshops

Warrior Families: Advancing Regenerative Medicine Through Science: Thursday, October 5th from 11:00 a.m. – 12:15 p.m. ET.

NIST-FDA Workshops on Measurements and Standards for Advanced Therapy: November 1-3, 2023

Identification & Standardization of Methods for Assessing Gene Therapy Product Activity & Comparability & the Evaluation of T-Cell Therapies: November 16-17, 2023

IX. Pilots

CMC Development Readiness Pilot (CDRP) year two applications will be accepted staring Oct 2, 2023  

See Kimberly Benton's prior write-up on the CDRP, here.  

FDA’s Rare Disease Endpoint Advancement (RDEA) PilotProgram

RDEA proposals may be submitted on a rolling basis and must be received by the last calendar day of each quarter.

RDEA Pilot Program webpage and the RDEA Pilot Program Frequently Asked Questions webpage.

X. Other

OTP Learn: Welcome to OTP Learn (Office of Therapeutic Products; previously OTAT Learn), the Center for Biologics, Evaluation and Research's (CBER) web page for industry education.

XI. Past FDA Workshops and Town Halls

The following links to the Meeting Materials include access to the recorded video link, transcript, or slides. 

Related Posts

Join the Quarter Horse Newsletter

We’ll send you a quarterly newsletter all things DHC!
Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.