By Alexander J. Varond –
FDA recently issued its final rule on permanent discontinuance or interruption in manufacturing of certain drug or biological products. To those familiar with the proposed rule issued in 2013, a review of the final rule will not bring many surprises. We discussed the proposed rule and FDA’s “Strategic Plan for Preventing and Mitigating Drug Shortages” here.
The final rule requires “all applicants of covered approved drugs or biological products—including certain applicants of blood or blood components for transfusion and all manufacturers of covered drugs marketed without an approved application—to notify FDA electronically of permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (or a significant disruption in supply for blood or blood components) of the products in the United States.”
Ongoing Effort to Address Drug Shortages
The rule represents the latest step in an ongoing effort to address drug shortages in the United States. Recall that President Obama, in 2011, issued an Executive Order to address the issue. We blogged on that here. That same year, the Government Accountability Office released a report finding that FDA needed increased authority to address the growing problem of drug shortages. We blogged on that here. Congress then amended the Federal Food, Drug, and Cosmetic Act (FDCA) (via FDASIA), in 2012, and further addressed the drug shortage issue. Our summary of FDASIA can be found here.
FDASIA amended the FDCA to give FDA the authority to require all manufacturers of certain drugs to notify FDA six months in advance of a permanent discontinuance or interruption in manufacturing. It also required FDA to maintain a list of drugs in shortage. This is FDA’s shortage list in its current incarnation. Finally, FDASIA gave FDA the authority to apply its drug shortage provisions to biological products. FDA’s final rule implements FDASIA’s changes and substantively modifies 21 C.F.R. §§ 310.306, 314.81(b)(3)(iii), and 600.82.
Recent Statistics on Drug Shortages
FDA notes in its preamble to the final rule that although the number of drug and biological product shortages quadrupled from approximately 61 in 2005 to more than 250 shortages in 2011, the number of shortages has decreased in the last several years. The preamble reports the following figures:
Table 1: Drug Shortages
Thus, it appears that the increase in early notifications to FDA that began as a result of the 2011 Executive Order (Executive Order 13588) has enabled FDA to work with stakeholders to prevent shortages. FDA reports the following statistics:
Table 2: Drug Shortages Prevented
According to FDA, these shortages were prevented by using such tools as, working with manufacturers to resolve manufacturing and quality issues, expediting FDA inspections and review of submissions to prevent shortages, identifying and working with manufacturers willing to initiate or increase production to cover expected gaps in supply, and exercising regulatory flexibility and discretion under certain circumstances.
The final rule requires that a covered entity notify FDA in writing of a permanent discontinuance of manufacture or interruption in manufacturing that is likely to lead to a meaningful disruption in the supply of a product that is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition. Radiopharmaceuticals are excluded from these requirements. Notably, a meaningful disruption does not include interruptions such as routine maintenance “so long as the manufacturer expects to resume operations in a short period of time.”
The final rule defines “life support or life sustaining” as “essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life.” “Intended for use in the prevention or treatment of a debilitating disease or condition” is defined as “intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-to-day functioning.” In the preamble to the final rule, FDA notes that this definition is different than the Agency’s definition of “medically necessary,” which it uses in its Manual of Policies and Procedures on shortages.
The rule defines “product” in a way that significantly increases the frequency with which covered entities must notify FDA. That is, a covered entity must notify FDA of a discontinuance or interruption for specific strengths, dosage forms, and routes of administration. FDA provides an example:
[I]f Applicant X experiences an interruption in manufacturing of the 50-milligram (mg) strength of a drug product that would be subject to § 314.81(b)(3)(iii), but the 100-mg strength continues to be manufactured without delay, under the rule, Applicant X must notify FDA of the interruption in manufacturing of the 50-mg strength if the interruption is likely to lead to a meaningful disruption in the applicant’s supply of the 50-mg strength.
Thus, when determining whether an interruption in manufacturing is likely to lead to a meaningful disruption in supply, triggering the notification requirement, a manufacturer or applicant may only consider whether the manufacturing disruption will affect the manufacturer’s own ability to meet demand for its product – even if the manufacturer has such a small market share that its disruption is unlikely to affect the market as a whole.
The final rule applies to the following covered entities:
- All applicants with an approved NDA or ANDA for a covered drug product;
- All applicants with an approved BLA for a covered biological product, other than blood or blood components;
- Applicants with an approved BLA for blood or blood components, if the applicant is a manufacturer of a significant percentage of the U.S. blood supply; and
- All manufacturers of a covered drug product marketed without an approved NDA or ANDA in its entirety to covered drug products marketed without an approved NDA or ANDA).
With regard to timing, notifications must be submitted electronically to FDA:
- At least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing; or
- If 6 months’ advance notice is not possible because the permanent discontinuance or interruption in manufacturing was not reasonably anticipated 6 months in advance, as soon as practicable thereafter, but in no case later than 5 business days after the permanent discontinuance or interruption.
Such notifications must include the name of the product and applicant, whether the notification relates to a permanent discontinuance or interruption, a description of the reason for the permanent discontinuance or interruption, and an estimated duration of the interruption.
Covered entities that fail to submit adequate notification will be issued a noncompliance letter from FDA informing the entity of its failure to adequately notify FDA. The covered entity will then have an opportunity to respond. If FDA does not find that the covered entity had a reasonable basis for failing to adequately notify FDA, the Agency will make the letter and the applicant’s response to the letter public. As we noted when the proposed rule was issued, while the Agency’s ability to publicize violations is generally one of its most powerful and well-utilized enforcement tools, it may be comparatively weak in this context, where the unfavorable publicity seems unlikely to expose a violative company to private litigation in the absence of extenuating circumstances.