Today, the FDA released another batch of Product‑Specific Guidances (PSGs), outlining its current thinking on the bioequivalence (BE) testing requirements for generic products – twenty‑five new BE guidances and twenty‑one revised guidances.  The listing can be found here.

The FDA has various goals regarding publication of these PSGs that are tied to getting information to prospective generic developers of the products.  As the program has progressed over the years, the FDA has endeavored to issue PSGs for products that, in many cases, are protected by periods of patent or market exclusivity well before the first legal marketing dates of prospective generic products to facilitate bringing the generic products to market as soon as possible.  The FDA webpage linked above notes that “as part of FDA’s commitments under the Generic Drug User Fee Amendments Reauthorization of 2022 (GDUFA III), FDA will issue PSGs consistent with the following goals:

  • For complex products approved in new drug applications (NDAs) on or after October 1, 2022, a PSG will be issued for 50 percent of such NDA products within 2 years after the date of approval, and for 75 percent of such NDA products within 3 years after the date of approval.
  • FDA will continue to develop PSGs for complex products approved prior to October 1, 2022, for which no PSG has been published.
  • For non-complex drug products approved in NDAs on or after October 1, 2022 that contain a new chemical entity (NCE) (as described in section 505(j)(5)(F)(ii) of the FD&C Act), a PSG will be issued within 2 years after the date of approval for 90 percent of such products.”

Some of the products on the new PSG list comply with those goals and others represent a prioritization of products (e.g., a sponsor has requested such information via a controlled correspondence or based on a current public health need) for which FDA has not yet issued its recommendations.

The twenty‑one revised PSGs may represent a potential problem for generic applicants in that they may be for already approved applications, applications in development where their firms have already completed BE studies under recommendations in original PSGs, or have already submitted ANDAs containing studies that relied on previous PSGs.  In addition, when the FDA issues new PSGs, for which no advice has previously been issued, it could also impact the work that generic companies have already undertaken for applications in the same various stages outlined for the revised PSGs.  Under GDUFA III, the FDA opened lines of communication for discussing such situations with firms by permitting either telcons or meetings when firms finds themselves in need of advice after PSGs are issued.

While you probably know all of that already, it never hurts to point out both problems and options for resolution of these special circumstances.

One thing that caught my eye in the revised list of PSGs was the inclusion of lithium carbonate in multiple forms, i.e., tablet, capsule, and extended-release tablets.  Looking back at the first ANDA lithium carbonate capsule approval, the summary of approval indicates that the BE requirements included a single‑dose crossover design under fasting conditions as well as comparative dissolution testing between the brand and the proposed generic.  Now, the Agency is recommending a single-dose, two-treatment, two-sequence, four-period, fully replicate crossover in vivo study under both fasting and fed conditions.  In addition, the FDA has concluded that lithium is a narrow therapeutic index drug, which leads to other analytical considerations to establish BE.  When a big change like this occurs, the wonder is whether the FDA will ask holders of approved or pending applications to repeat BE studies to comply with the new recommendations.  My guess is that the OGD’s phone may be ringing right now from sponsors of lithium carbonate applications.