In May (May 2022), the FDA issued draft guidance to spell out the types of drugs that are vulnerable to shortages and should be subject to risk-management plan reporting. What does the industry think?

FDA’s plan for risk-management plan reporting
In May, the US Food and Drug Administration (FDA) issued a draft guidance, Risk Management Plans to Mitigate the Potential for Drug Shortages, which builds on the agency’s efforts to mitigate drug shortages and supply-chain disruptions by assisting drug manufacturers and related manufacturers with the development, maintenance, and implementation of risk-management plans. The agency asked for feedback on its plan, and in comments to the draft guidance, several industry trade groups, including the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents innovator bio/pharmaceutical companies, the Biotechnology Innovation Organization (BIO), which represents the biotechnology industry in the US, and the Association of Accessible Medicines (AAM), which represents generic-drug companies and manufacturers.

What is in the draft guidance?
The draft guidance describes a framework for stakeholders to consider when developing risk-management plans that aligns with principles in the International Council for Harmonization (ICH) guidance, Q9, Quality Risk Management, and identifies risk factors to consider when developing the content of risk-management plans. The FDA notes in its draft guidance that the steps needed to reduce risks of a disruption in drug supply may vary among the different manufacturers in the supply chain for a given drug.

The guidance applies to applicants with an approved new drug application, abbreviated new drug application, or an approved biologics license application as well as to manufacturers of components, including active pharmaceutical ingredients (APIs), and to manufacturers of drug-led, drug-device or biologic-led, biologic-device combination products.

The draft guidance contains an outline of products in which risk-management plans are required, when manufacturers of drug products, APIs, and associated medical devices must develop, maintain, and implement risk-management plans that identify and evaluate risks to the supply of a drug product. The draft guidance contains an outline of products in which risk-management plans are recommended. While certain types of drug products and APIs would be of particular concern to the FDA because of the potential effect on patient care, the FDA has found that certain drug products, such as those with less redundancy in their supply chains, are at higher risk of shortage. The FDA proposed that three types of drug products be required to have an risk-management plan: (1) prescription drug products that are life-supporting, life-sustaining, or intended to prevent or treat a debilitating diseases or condition; (2) any API included in the above-listed drug products; and (3) any medical device used to prepare or administer the prescription drug products listed above.

The issuance of the draft guidance follows a 2019 report by the FDA’s Drug Shortages Task Force, which called for the adoption of risk-management plans to assess risk and to predict and prevent supply disruptions that could potentially lead to a drug shortage. In 2020, Congress passed the Coronavirus Aid, Relief, and Economic Security (CARES) Act to require certain manufacturers to develop, maintain, and implement, as appropriate, risk- management plans that identify and evaluate risks to a drug’s supply.

Industry feedback
Feedback from AAM. One of the major criticisms of the draft guidance came from the AAM, which represents generic-drug companies and manufacturers, which expressed concern that the draft guidance was too broad and that it identifies a more extensive range of products subject to risk-management plans than as identified in prior law.

“AAM is concerned, however, that the draft guidance advances an unnecessarily broad interpretation of the statute that requires individual, product-specific RMPs [risk-management plans] for prescription drug products,” said AAM in its August 31, 2022, comments submitted to the FDA. “Further, the draft guidance recommends the development of RMPs for products not included in the statute as requiring an RMP—a recommendation that many manufacturers will interpret as a requirement. As a result, the guidance as written is unnecessarily burdensome and may cause unintended product discontinuations and contribute to, rather than mitigate, drug shortages.”

AAM is recommending that the FDA clearly state in the guidance document that risk-management plans are to be developed at the establishment level (i.e., site level) and individual, product-specific risk-management plans are not required. In addition, AAM requests that the FDA provide a list of products that require risk-management plans or further elaborate on which products are covered by the requirement. AAM also requests clarification of the responsibilities of other stakeholders, including inactive ingredient suppliers, packagers, and distributors, who it says should not be required to develop risk-management plans. Furthermore, AAM requests additional guidance on what documentation the FDA will be looking for regarding risk-management plans during inspections. Finally, AAM also is concerned that the FDA has unrealistic expectations about manufacturers’ ability to share risk-management plans with other stakeholders, and FDA should modify the guidance to describe more generally the types of information that it feels would be helpful to share that would not be considered confidential information or trade secrets.

Feedback from BIO. BIO, which represents the biotechnology industry, said that while it understands the potential benefits for risk-management plans in enhancing drug availability, it believed that the section of the guidance that identified products for risk-management plans is more prescriptive than necessary and that risk factors should be considered holistically using a risk-based approach. “Additionally, RMPs [risk-management plans] are a new requirement for manufacturers and implementation for the required products will require a considerable time investment and have a substantial learning curve,” said BIO in its comments to the FDA. BIO also notes that while in general, FDA guidelines are non-binding on the agency or the public, the recommendations provided by guidances carry substantial weight and suggested the wording a “risk-based approach” rather than “recommendations” be used.

BIO also noted that that the definition of the covered products (i.e., life-supporting, life-sustaining, etc.) in the draft guidance are subject to interpretation from individual manufacturers. “API manufacturers may be unaware if their products are used for these purposes, especially if their products are used in multiple products or for multiple indications,” said BIO in its comments, and recommends that the FDA publish a list of the APIs that are covered and for which risk-management plans are required.

BIO also raised concerns over the terms and definitions of “primary stakeholder”, “secondary stakeholder” and “other stakeholder” to describe “manufacturer.” “These stakeholder definitions are very broad and could be interpreted that manufacturers of any step in the active pharmaceutical ingredient (API) or drug product manufacturing process need to prepare RMPs [risk-management plans] for the designated products,” said BIO in its comments. “Such a requirement would be highly burdensome to manufacturers of API intermediates or drug product intermediates (e.g., milling operations, granulation operations) and could be non-value added since manufacturers of intermediates might not have knowledge of the information needed to provide a meaningful RMP [risk-management plan]. ” BIO is recommending that the requirement for API risk-management plans be limited to the manufacturer of the final API.

Feedback from the Bulk Pharmaceutical Task Force. The Bulk Pharmaceuticals Task Force (BPTF), a U.S.-based association for manufacturers of APIs, excipients, and pharmaceutical intermediates, agreed that API manufacturers are not aware of whether the API they are making are used in a drug that is “life-supporting” or “life-sustaining,” as identified by the draft guidance. It is recommending additional clarification from the FDA on those APIs considered to be marketed for life-supporting or life-sustaining purposes. The BPTF says a list of essential medicines, for example the list of essential medicines from the World Health Organization, may be used as a starting point, but the BPTF notes that not all of the APIs listed are always marketed for this purpose. It is recommending that the FDA provide a specific list of APIs subject to the guidance.

BPTF is also recommending that drug-product manufacturers should be the entity primarily responsible for preparation of risk-management plans and for indicating to their API suppliers whether a given API would need to be the subject of a risk-management plan. BPTF recommends that if API manufacturers are to be required to identify APIs in risk-management plans that are life-supporting or life-sustaining, drug-product manufacturers must be required to provide information to the API manufacturers on the end use of all products intended to be marketed for that purpose. Alternatively, BPTF recommends that API manufacturers should only be required to prepare a risk-management plan for an API when specifically advised by the drug-product manufacturer that the substance is used in a covered application, and that risk-management plan should be used as a component of the drug product manufacturer’s risk-management plan

Additional input from BIO. BIO also notes that the current draft guidance uses the term API (active pharmaceutical ingredient), which usually applies only to small-molecule drugs rather than the more inclusive term “drug substance.” BIO recommends: (1) clarity on the scope of the guideline in the introduction to include biologics and vaccines and (2) replacement of the term “active pharmaceutical ingredient (or API)” with “drug substance,” wherever appropriate throughout the guidance.

BIO also provided input on the timing of the implementation of the guidance, once finalized. BIO is requesting a period of at least two years from publication of a final guideline before FDA reviews risk-management plans during inspections or as part of a records request to ensure that manufacturers have adequate time to understand and properly implement practices to assist with the preparation of risk-management plans.

Feedback from PhRMA. In its comments, PhRMA, which represents innovator bio/pharmaceutical companies, said that the draft guidance would benefit from a number of changes to enhance clarity for stakeholders developing and implementing risk-management plans to mitigate drug shortages.

First, PhRMA supported FDA’s recommendations that stakeholders use the quality risk-management process and principles described in the ICH Q9 guideline, Quality Risk Management, but in finalizing the guidance, PhRMA says that the FDA should update the guidance to reflect recent changes made in the revision to the ICH Q9(R1) draft guidance. “The draft guidance uses terminology and presents concepts that differ from those in the revised Q9(R1) draft guidance,” said PhRMA in its comments. “For example, the ICH Q9(R1) guideline refers to ‘hazard identification’ whereas the FDA draft guidance refers to ‘risk identification.’ Rather than using different terms and concepts that could create confusion or introduce inconsistency, PhRMA recommends that, in finalizing this guidance, the FDA align with the terminology and concepts as presented in the Q9(R1) guideline, once finalized, and that to the extent practicable, the FDA ensure harmonization with existing ICH guidelines.”

Second, PhRMA is encouraging the FDA to modify its recommendation that risk-management plans undergo at least an annual internal review and revision throughout the lifecycle of a drug and instead is recommending that a risk-based approach to the frequency of risk-management plan review and revision. For instance, PhRMA notes that early in the product lifecycle, frequent review and revision of a risk-management plans may be appropriate or when a manufacturer has switched to a new supplier. On the other hand, PhRMA says that risk-management plans for products with long-established supply chains may not need annual review and revision and that products where there are already multiple suppliers of an API may need less frequent assessments of risk-management plans as risks of supplier disruption are already mitigated through the use of multiple suppliers.

Third, PhRMA is also recommending that the FDA update the guidance to explicitly acknowledge that existing Pharmaceutical Quality System processes (consistent with ICH Q10) used to maintain a state of control and drive continuous improvement could be used to support risk-management plans and the review process where appropriate. This may include process performance/product quality monitoring, management reviews, and annual product quality reviews.

PhRMA also recommends that the FDA specifically acknowledge that risk-management plans for similarly situated products (e.g., those using the same supplier) may cross-reference or otherwise incorporate overlapping concepts. For example, risk-management plans for products that source the same raw material from the same facility can use the same risk-mitigation approach to geographic risk factors.

PhRMA is further encouraging the FDA to address, as appropriate, how risk-management plans fit into other ongoing FDA initiatives, including both the Quality Metrics and Quality Management Maturity initiatives.