FDA Wants a Second Set of Eyes on Your First-in-Human CMC Package
A good part of my consulting work over the past year has been reviewing CMC modules for first-in-human INDs, usually a few weeks before submission, when the options for fixing anything are limited. So I read FDA's Expedited IND Pilot announcement with a lot of interest. The agency is essentially formalizing the review I often get asked to do, and moving it earlier.
The Expedited IND Pilot
On September 15, FDA opened applications for the Expedited IND Pilot, part of HHS Operation TrialBlazer. Sponsors apply as a pair with a "qualified research institution" (QRI), which can be an academic medical center, a health network, a CRO, or a regulatory advisory firm. The QRI provides nonclinical, clinical, and CMC input, and FDA then reviews discrete components of the IND on a rolling basis during the pre-IND phase rather than waiting for the full package. The 30-day clock only starts when the final IND goes in.
A few details are worth noting. The cohort is small, 8 to 10 sponsor-QRI pairs. Applications close October 30, and selections are announced December 18. FDA also describes the QRI as "an accountable scientific partner whose endorsement of the submissions is a meaningful checkpoint," and says the pilot may inform a future accreditation model for QRIs.
For the CMC piece specifically, FDA expects the QRI to be able to "assess whether a sponsor's manufacturing and controls approach is appropriate for the stage of development and flag issues that complicate FDA review." That sentence is a pretty good job description for a phase 1 CMC reviewer.
What a second set of eyes usually finds
Whether or not you apply, it is useful to ask what a QRI would flag in your package. From the phase 1 CMC sections I have reviewed, the same few issues come up again and again.
Specifications that were copied, not justified. A platform mAb specification gets dropped onto a bispecific or a fusion protein without asking which attributes actually matter for this molecule. The limits look reasonable, but there is no link between them and the characterization data or the tox lot.
A tox lot that is not clearly representative. The comparison between the GLP tox material and the clinical material is often thin, a side-by-side table of release results with no discussion of process differences or the attributes most likely to shift. This is the question reviewers tend to ask first, and it is the hardest to answer late.
A potency assay that is not ready. For complex modalities, the cell-based assay is frequently still being developed when the IND is being written. A phase-appropriate binding assay plus a clear plan and timeline for the functional assay is usually fine. Saying nothing is not.
Characterization that stops at release testing. Phase 1 does not require a full characterization package, but intact mass, peptide mapping, and a basic look at charge and size variants on the clinical lot go a long way. For ADCs and bispecifics, this is where you show that you understand the product-related impurities specific to your format.
Stability that does not support the clinical plan. Limited real-time data with no supportive stress or accelerated data, and no clear statement of how shelf life will be extended during the trial.
Is the pilot worth applying to?
For a small sponsor with a novel molecule and a first-in-human trial planned in the US, I think it is worth a serious look. The rolling review is the real value. Getting FDA feedback on the CMC module before the 30-day clock starts lowers the risk of a hold on something fixable, and the pilot application itself forces you to describe where your CMC program stands, which is a useful exercise on its own.
That said, it is a pilot with 8 to 10 slots, and FDA states that participation does not change the standards for a safe-to-proceed decision. The sponsor also remains fully responsible for the content. A QRI does not make a weak package strong. It makes the weaknesses visible earlier, which is only useful if there is time to act on them.
Practical takeaways
1. Do the QRI review yourself, now. Whether or not you apply to the program, have someone outside the program read the CMC module against the issues above before you submit. That is the direction the FDA is moving.
2. If you apply, choose a QRI with real CMC depth for your modality. FDA explicitly allows QRIs to bring in external SMEs for gaps. A strong clinical partner with a generalist CMC reviewer will not help much on an ADC or a cell therapy.
If you are preparing a first-in-human IND and want a CMC read before FDA sees it, I am happy to talk.