Yesterday, the FDA issued a guidance document titled Development of Abbreviated New Drug Applications During the COVID-19 Pandemic – Questions and Answers (here). The guidance covers three broad areas:
- Generic drug product development
- ANDA submission and assessment and
- Marketing and exclusivity.
The guidance offers many hints on how the Agency may deal with issues that can impact ANDAs that are specifically associated with Covid-19 issues or complications that can occur. It must be recognized that the Q&A format outlines areas where OGD will accommodate certain digressions from normal practices, but it also provides straight responses to frequently asked questions where there will not be an opportunity for relief. The document makes clear that the provisions of the guidance will remain in effect only during the declared public health emergency.
Some of the issues addressed include how to handle exhibit batches or RLD batches that may have expired when such studies were interrupted during the Covid-19 pandemic; discusses that the use of expired RLD batches are generally not acceptable; addresses whether a firm can use two or more batches to complete an interrupted bioequivalence study and under what conditions some of these issues may be acceptable.
One answer helps to answer a recurring question and demonstrates the Agency’s thinking on the issue of the use of a foreign-approved product for bioequivalence testing if the approved RLD is not available. The Agency refers to a November 17, 2014 citizen petition response to Docket No. FDA-2013-P-0846 and concludes: “Because of the potential for bioequivalence inconsistencies that may result from even slight differences between a non-U.S.-approved product and the U.S. RLD (for example: small differences in critical specifications could potentially affect key performance characteristics), it is Agency policy not to accept BE studies based on a non-U.S.-approved product to show that a drug is bioequivalent to the U.S. RLD.” This answer cites the fact that a foreign-approved product is not approved under section 505(j) or 505(c) and thus is not suitable for use as a reference product.
There are several other responses dealing with the impact of testing regarding sample collection, analysis, statistical treatment, etc., on which the Agency opines.
FDA appears to stand firm on the requirements for the number and type of submission batches required for ANDA acceptance, and it appears that the requirement stands for the usual 6 months of room temperature and accelerated stability results on the exhibit batches should be provided at the time of submission; however, the door is open for exceptions, but they must be agreed to by OGD prior to submission and the request for deviation should be submitted and approved in a controlled correspondence. Unless there is a drug shortage or other overarching need for the drug product that can be used to treat symptoms or be of use in the pandemic, it is not likely that there will be much leeway on the Agency’s stability expectations at the time of ANDA submission. Oh yes – don’t waste the Agency’s time in asking whether an ANDA can be submitted without a required bioequivalence study! Applications submitted without the required bioequivalence testing will be issued a refused-to-receive letter.
The Agency expresses its long-held position that an ANDA that has tentative approval cannot be considered approved and in no instance can be marketed without final approval. In addition, the FDA addresses the issue of delayed inspections and the impact on ANDA approval.
For the most part, while there are some minor points of regulatory relief identified in the guidance, don’t expect too much. Review the entire guidance and see where there are opportunities but remember that deviations from FDA expectations could result in unexpected consequences unless the Agency blesses them first.