The FDA released today a database of complete response letters (CRLs) sent to manufacturers of small molecule and biologic drug candidates that were eventually approved for marketing in the US between 2020 and 2024. This transparency opens a window to information that is not always publicized by the sponsoring manufacturer.
Sometimes, CRLs are announced by drug makers in press releases, quarterly earnings calls, or reported in other venues, but inconsistent reporting is generally the case. There is no regulatory requirement for drug candidate sponsors to make this information public, despite the value that it would provide investors and other groups. Of course, corporations would rather not highlight negative news, and the same goes for the pharmaceutical industry.
Perusing the FDA’s new database reveals more information about the types of deficiencies resulting in the CRLs rather than specific failings of any individual manufacturers. Forty-six CRLs for biologic drugs are included in the database, about 40% of which apply to 351(k) applications for biosimilar drugs. Based on original filing dates from 2016 and 2017, it is clear that manufacturers were initially finding their way through the FDA approval of their biologic licensing application. Some applications were rejected due to basic issues, such as inconsistencies in pharmacokinetic data reporting, immunogenicity analysis questions, or missing information. Production facility inspections led to many CRLs (and that is the case even today). Furthermore, in several CRLs, FDA cited its own inability to conduct inspections of production facilities during the COVID-19 pandemic. In one case, the CRL was issued because of missing copy on the product label. In all cases, FDA redacted information to protect proprietary details.
Interestingly, two letters included in the database involved granting provisional approval for Celltrion’s and Samsung Bioepis’ requests for ustekinumab interchangeability (final approvals were not granted pending exclusivity expiration for the first interchangeable product). I’m not sure why these were included in the database—perhaps more interchangeability confusion?
The More CRL Information, the Better
As the FDA’s database only includes CRL information for products that were subsequently approved by the FDA between 2020 and 2024, we lack the clearest view of individual or multiple CRLs of products that did not advance through the registration system, or the opportunity to review the earliest CRLs issued for biosimilar candidates. I’m hopeful that FDA will fully embrace this transparency and publish all CRLs as they are released to the sponsors.
Selfishly, this would enhance the accuracy of BR&R biosimilar database of approved drugs and submitted applications, which we publish and update as much as possible. For example, several companies submitted 351(k) applications on insulin biosimilars two years ago, but no further information on their progress or FDA rejection have been released. Not to pick on Lupin, but the company submitted its BLA application for a pegfilgrastim biosimilar in June 2021, followed by the sound of crickets. Virtually every biosimilar manufacturer, from Alvotech to Sandoz, has received some form of CRL for their efforts over the past 10 years, but in general these have been hiccups along the way to approval not insurmountable barriers to biosimilar access.
From a manufacturer standpoint, an expansion of the FDA’s CRL database would enforce a bit more transparency in real time for investors, industry competitors, consultants, and the public. It will also be interesting to track trends and CRL-specified issues for biosimilars in the present and in the future. One may hope that with years of experience in production and development certain types of citations by FDA inspectors or scientific reviewers will become less common or vanish altogether. That might not be reasonable for manufacturers that more recently entered (or newly entered) the US biosimilar market. Much of this will be answered in the next generation of biosimilar submissions (e.g., Xolair, Perjeta, Keytruda, Opdivo).
The FDA faces many challenges today. I don’t buy into the “Make America Healthy Again” political leanings of the administration. I question leaders’ grasp of its frequent use of the phrase “gold standard science.” But I can appreciate the benefits of this particular effort to improve transparency.
