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Final Rule – Drug Shortage Regulation: Incentive for Development of “Unapproved” Drugs?

Drug shortages can have serious and immediate effects on providing needed therapies to patients, and preventing shortages is a current priority for FDA. FDA has taken a variety of actions to eliminate, mitigate, and prevent shortages (Executive Order 13588; Interim Final Rule; and Draft Guidance for Industry on Drug Shortages), while working within the confines of the statutory and regulatory framework, partnership with manufacturers and other stakeholders.

With the passage of FDASIA, FDA was given important new authorities related to drug shortages. For example, section 1001 of FDASIA broadened the scope of the early notification provisions of the statute by requiring manufacturers of all covered prescription drugs (approved or “unapproved”) to notify FDA of a permanent discontinuance or temporary interruption in manufacturing. FDASIA also allowed FDA to require, by regulation, early notification of discontinuances or interruptions in manufacturing of biologics. FDASIA requires FDA to send a non-compliance letter to firms that fail to notify FDA in accordance with section 506C of the FD&C Act, as amended by FDASIA. Section 506C also authorizes FDA to expedite reviews of drug applications and supplemental applications and to expedite inspections that could help mitigate a shortage. On October 31, 2013, FDA issued its Strategic Plan for Preventing and Mitigating Drug Shortages. The plan contains details on the origin of drug shortages, FDA’s processes and procedures for helping to prevent or mitigate shortages, and FDA’s strategy for strengthening those processes and procedures. On November 4, 2013, FDA published a proposed rule proposed rule for public comment to help implement FDASIA’s expanded notification requirements. As a result of these actions, FDA helped prevent 282 drug shortages in 2012, 170 shortages in 2013, and 78 shortages in the first three quarters of 2014 (see Second Annual Report of Drug Shortages for Calendar Year 2014).

On July 8th, 2015, the Food and Drug Administration (FDA or the Agency) published the final rule for Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products to further strengthen FDA’s ability to identify potential drug shortages and to prevent or mitigate the impact of these shortages. The final rule, consistent with FDASIA, formalizes FDA’s current practice of maintaining public lists of drugs and biological products in shortage, available on FDA’s Web site for products regulated by CDER (FDA Drug Shortage Database) and for products regulated by CBER (CBER-Regulated Products: Current Shortages). The rule will take effect on September 8, 2015.

The rule requires all applicants of certain approved drugs or biological products, including applicants of blood or blood components for transfusion (‘‘blood or blood components’’) that manufacture a significant percentage of the U.S. blood supply, and all manufacturers of certain drugs marketed without an approved application (‘‘unapproved drug manufacturers’’), to notify FDA electronically of a permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (for drugs and biological products other than blood or blood components) or a significant disruption in supply (for blood or blood components) of the product in the United States (parenthetical added). The rule requires notification to FDA at least 6 months prior to date of the permanent discontinuance or interruption in manufacturing, or, if 6 months’ advance notice is not possible, as soon as practicable, but in no case later than 5 business days after the permanent discontinuance or interruption in manufacturing occurs.

Importantly, as a result of this rule, the authority citation for 21 CFR 310 21 CFR 310 will be revised to add §310.306 (applicability of the rule for notification of a permanent discontinuance or an interruption in manufacturing of marketed prescription drugs for human use without approved new drug applications).

Drug shortages continue to pose a real challenge to public health and often entail shortages of critical drugs to treat cancer, to provide parenteral nutrition, or to address another serious medical conditions. These shortages can delay or deny needed care for patients, creating a potential lapse in medical care. Shortages can also lead prescribers to use second-line alternatives, which may be less effective or pose additional risks. Many of the drug shortages are for older drug products.

FDA continues to encourage pharmaceutical companies interested in making drugs in short supply to submit applications so that there are multiple manufacturers making these drugs. An increase in companies submitting applications for older drugs which have been in the subject of ongoing shortages has taken place.

Collaborations between FDA’s shortages staff, the unapproved drugs team, and the Office of New Drugs has provided a partnership to reduce the number of unapproved drugs while working to prevent drug shortages.

A growing number of manufacturers have successfully obtained approval for formerly unapproved products. Two formerly unapproved drugs that have received FDA approval are neostigmine methylsulfate injection (Bloxiverz—NDA 204078; Eclat Pharms, LLC; approved May 31, 2013) and vasopressin (Vasostrict—NDA 204485; Par Sterile Products; approved April 17, 2014).

Approval of formerly unapproved products helps alleviate FDA’s concerns about a potential market disruption or shortage of these drugs, because the manufacturers of approved drugs have been required to meet current application and manufacturing standards, a process that helps to ensure the drug is produced the same way every time, meeting quality standards and thus lowering the risk for shortage.

As a result of the emphasis on mitigating drug shortages, incentives exist for companies to evaluate the potential development of currently unapproved drugs.


Stacey Ayres, PhD
Director of Scientific Research Services