As drug shortages are once again front-page crises news, demanding drastic action by FDA—currently with a particular focus on sterile, injectable platinum-based chemotherapy drugs—a refresher on the scope of FDA’s tools to address a drug shortage is useful.
While the total number of annual drug shortages may not be reaching its previous peak in 2011, the number of products in or in danger of shortage today continues to have significant impacts on healthcare in the United States.
In other words, FDA may be getting better at mitigating some shortages, but others nonetheless continue and the underlying root causes that trigger or sustain ongoing shortages have not abated. This suggests that systematic issues remain in the pharma industry and, without novel solutions such as providing greater incentives for investment in quality drug manufacturing, drug shortages will continue to crop up with frequency.
Drug shortages, and FDA’s ability to respond to them, have received congressional and White House attention over the years, including most recently through the CARES Act in 2020. It remains to be seen whether the recent media attention on cancer patients not being able to access treatment will trigger additional congressional scrutiny and/or new authority for FDA.
FDA’s Toolkit
Ultimately, FDA, once aware of a shortage or potential shortage, has a number of tools to address any given shortage and to mitigate its particular impact. (Manufacturers should, among other things, bear in mind that reporting requirements related to shortages may be applicable to their products, on which the CDER recently posted draft guidance.)
Depending on the circumstances creating the shortage, FDA may elect from among its available tools to
- expedite certain FDA actions (i.e., reviews or inspections of pending applications seeking to alleviate a drug shortage or required lot release activities applicable to biologics);
- consider shortage-driven requests from manufacturers (i.e., extending expiration dating of products that could serve to alleviate a shortage or working to develop risk mitigation measures to allow individual batches of a product to be released even when quality assurance requirements may not otherwise be met);
- exercise temporary regulatory flexibility including, at times, in the form of enforcement discretion to permit temporary importation of foreign-sourced, unapproved, alternative-source products that can be utilized to help alleviate a shortage; and/or
- for controlled substances, coordinate with the Drug Enforcement Administration on individual product quota allocations that can be modified to mitigate a shortage.
In considering the degree to which regulatory flexibility may be appropriate in a given circumstance, FDA takes a risk-based and risk-minimizing approach when considering available alternative mitigation strategies. Regulatory flexibility measures that FDA uses include permitting the marketing of drug products with known quality issues, but with controls in place to mitigate the shortcomings (e.g., the addition of filters to address particulates, requiring additional testing or third-party oversight or certification, employing specific instructions or information to providers and/or patients). FDA may also permit continued distribution of a product while an NDA or ANDA supplement to address an identified issue is under review by FDA.
The option of permitting the temporary importation of an unapproved drug, as was recently approved for importation of cisplatin from China, will normally be used only when other solutions have been exhausted. In determining whether importation of an unapproved drug may be appropriate, FDA requests and considers information from the manufacturer of the foreign-sourced product, including
- the amount of the product that could be supplied and related distribution plans;
- information about the identity of the proposed product;
- information about the manufacturing and testing facility(ies) used in the production of the proposed product and their inspectional history(ies);
- batch records, Certificates of Analysis, and related tests and release specifications;
- labeling information; and
- a draft “Dear Healthcare Provider” letter describing any differences between the proposed product and the US-approved shortage product.
Conclusion
FDA’s authorities and attention to the drug supply chain shortages tends to be focused on the mitigation and resolution rather than prevention of shortages. Its authority to prevent shortages is more limited, though it continues to encourage the adoption of Quality Management Maturity practices to bolster continued and stable manufacturing meeting quality requirements, to prevent facility shutdowns and related actions that are frequent underlying causes of drug shortages.
Fostering quality manufacturing of products subject to shortage is a sound policy, but FDA is limited in its ability to address these and other systemic issues facing the industry. Without further addressing the root causes of shortages, whether by FDA or other stakeholders, we’re likely to continue experiencing them.