Last updated: 6 November 2024
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FDA is establishing the Split Real Time Application Review (STAR) pilot program under the Prescription Drug User Fee Act (PDUFA) VII Commitment Letter. This post is an attempt to provide the FDA information on the program, in a Q & A format.
What is the aim of STAR?
The aim of STAR is to shorten the time from the date of complete submission to the action date, in order to allow earlier patient access to therapies that address an unmet medical need.
To which products, application types and therapeutic areas does STAR apply?
- The program applies to both drugs and biologics, collectively referred to as drug(s)
- STAR is available for certain supplemental new drug applications (sNDAs) and supplemental biologics license applications (sBLAs) that propose new uses of approved therapies to address an unmet medical need.
- The program is available across all therapeutic areas.
What are the eligibility criteria for an application to be considered for STAR?
FDA will consider an application eligible for the STAR pilot program if all of the following criteria are met:
1. Clinical evidence from adequate and well-controlled investigation(s) indicates that the drug may demonstrate substantial improvement on a clinically relevant endpoint(s) over available therapies. Breakthrough Therapy Designation (BTD) or Regenerative Medicine Advanced Therapy Designation (RMAT) is not required, but above criteria must be met.
Applicants should consider the following when providing clinical data that “may demonstrate substantial improvement”:
- The qualifying standard of “substantial improvement” for STAR is the same standard used to qualify for either BTD or RMAT.
- While FDA generally anticipates that most non-inferiority trials will not demonstrate substantial improvement, if a non-inferiority trial has built in superiority analysis and the results show substantial improvement over available therapies, then the trial may meet the STAR criteria for substantial improvement.
- Efficacy supplements relying on real-world evidence (RWE) to demonstrate substantial improvements on a clinically relevant endpoint(s) over available therapies are not currently included in STAR.
2. The application is for a drug intended to treat a serious condition with an unmet medical need.
3. No aspect of the submission is likely to require a longer review time (e.g., requirement for new Risk Evaluation and Mitigation Strategies (REMS), etc.)
4. There is no chemistry, manufacturing, or control information that would require a foreign manufacturing site inspection (i.e., domestic site inspections may be allowed if it does not affect the expedited timeframe).
The request to enter the STAR pilot must include an attestation statement that clarifies there will be no foreign manufacturing sites associated with the supplement. FDA will verify the attestation statement once the agency receives the Part 1 Submission. If there are any foreign manufacturing sites, the supplement will no longer be eligible for review under STAR.
5. A supplement must qualify for priority review in order to be in the STAR program.
Submitting a STAR eligibility request
If an applicant believes a proposed efficacy supplement fulfils the conditions outlined in the Eligibility Criteria, the applicant may submit a STAR Entry Request as either:
1) a stand-alone teleconference request
For a stand-alone teleconference, the sole focus and discussion will be whether the proposed supplement qualifies for STAR. There will be no meeting minutes, but a letter documenting the decision will be sent after the teleconference. If the applicant wishes to discuss additional questions (e.g., content and format of the proposed supplement), they must submit the STAR Entry Request combined with a Type B pre-sNDA/sBLA meeting request.
2) as part of a Type B pre-sNDA/sBLA meeting request.
The STAR Entry Request must provide:
- Topline results from the adequate and well-controlled trials
- Proposed labeling
- An explanation of how the proposed application meets each STAR criterion
- The subject line of the cover letter should clearly state “STAR Entry Request”
How will accepted STAR applications be submitted?
Accepted STAR applications will be submitted in a “split” fashion, specifically in two parts with the components submitted approximately two months apart.
What documentation must a STAR submission include?
A STAR Part 1 Submission must include all of the following:
- All components of the sNDA/sBLA efficacy supplement (e.g., complete datasets, proposed labeling, clinical protocols and amendments, topline efficacy and safety results), except for final clinical study reports for the adequate and well-controlled investigation(s) supporting the proposed claim and the electronic common technical document (eCTD) module 2 clinical summaries.
- A document providing topline results for each of the adequate and well-controlled investigations, along with the applicant’s overall interpretation of the effectiveness and safety.
- Clinical protocol and amendments for pivotal trials
- Statistical analysis plan and statistical programs
- Tables, figures, and listings
- Death summaries
- As applicable, the items described in CDER’s bioresearch monitoring (BIMO) inspections draft guidance (also refer to this guide) should be provided to facilitate development of clinical investigator and sponsor/contract research organization inspection assignments. This information is requested for all major (i.e., pivotal) trials used to support safety and efficacy in the application. Please note that if the items described in CDER’s BIMO draft guidance are provided elsewhere in the submission in the format described, applicants can provide the location or a link to these items.
A STAR Part 2 Submission* must include all of the following:
- Clinical study report(s)
- Integrated summary of safety
- Integrated summary of effectiveness
The FDA review process for STAR applications
- FDA will begin to review the data once the agency receives the complete Part 1 Submission.
- The PDUFA review clock will start once the agency receives the Part 2 Submission, which will include the following and represents the complete application:
- the final clinical study report(s)
- the Integrated Summary of Safety, and
- Integrated Summary of Effectiveness.
FDA will communicate the intent for an expedited action in the filing letter.
What does acceptance into STAR not guarantee?
Acceptance into STAR does not guarantee:
- an expedited review; however, the agency will make every effort to do so for applications in the program. Under limited circumstances, the review process may be extended, for example, when an applicant submits a Major Amendment during the pending application.
- an application approval. The application must still meet the applicable standard for approval.
If an applicant is disqualified from the STAR Pilot program can they resubmit an application
If an applicant is disqualified from the STAR pilot program due to incomplete submissions, they may still submit a complete application at a later time; however, they would not receive the benefits of the STAR program review.
Opportunity for a limited number of original marketing applications to be submitted and reviewed following the STAR pilot program paradigm
On 4 November 2024, The FDAs CBER and CDER announced an opportunity for a limited number of original marketing applications to be submitted and reviewed following the STAR pilot program paradigm.
FDA is interested in gaining experience with the STAR pilot program paradigm, which is intended to benefit public health by providing earlier access to therapies that address an unmet medical need.
Starting on 2 December 2024, CDER and CBER will each be accepting, on a voluntary basis, a limited number (1-2) of original marketing applications. Qualified applications will be accepted for this pilot in the following manner:
- The first two proposed applications (for each Center) that qualify based on the acceptance criteria outlined below, and
- The proposed applications having the earliest planned submission date.
- Applicants will identify the date by which they plan to submit Part 1.
- If for any reason they are unable to submit by that date, the next qualified applicant in the queue will be accepted instead.
Acceptance criteria:
- Clinical evidence from adequate and well-controlled investigation(s) indicates that the drug may demonstrate substantial improvement on a clinically relevant endpoint(s) over available therapies
- Intended to treat serious condition with an unmet medical need
- No aspect of the submission is likely to require a longer review time (e.g., requirement for new REMS, etc.)
- No chemistry, manufacturing, or control information that would require a foreign manufacturing site inspection
Source: FDA 02 2023, FDA 11 2024