FDA could approve major manufacturing changes that may prevent or alleviate drug shortages even if those changes are not immediately compliant with current good manufacturing practices, under legislation being drafted by the House Energy and Commerce Committee to reauthorize the prescription drug and other user fee programs.

The draft bill, which is intended for discussion purposes, has a number of add-ons to the fees, including incentives for antibiotic development and a clarification of the accelerated drug approval process, as well as revisions to the agency’s mission statement. A section on protecting the pharmaceutical supply chain is still being written.

The drug shortages section directs FDA to expedite review of supplemental applications for major manufacturing changes that may prevent or alleviate verified or anticipated drug shortage and gives the agency 60 days to complete the process.

As part of the review, FDA could “deem” the change to be in compliance with cGMPs if the manufacturing facility has a plan to achieve full compliance, has sufficient resources to do so, demonstrates adequate progress toward full compliance, and implements interim controls to ensure drug quality, such as additional in-process or release testing of the drug or its active ingredients, excipients or components.

Expedited review of both major and minor manufacturing changes is one option FDA already uses to address drug shortages. Even though the reviews are expedited, FDA could be hard-pressed to meet a 60-day deadline given all the activities that could be involved.

“The time it takes to approve an application under expedited review depends on multiple factors including the completeness of the application, the complexity of the change and any potential risks involved with that change that may require additional review time, and whether an inspection is needed,” the agency told “The Pink Sheet.”

Limited Expansion Of Shortage Pre-Notification

The notification section of the drug shortages portion of the discussion draft would be an incremental expansion of existing law. Currently, a manufacturer must notify FDA six months before it discontinues production of a life-supporting or life-sustaining drug, or one intended for prevention of a debilitating disease or condition, if the company is the sole manufacturer of the product.

The draft bill would expand the pre-notification requirement by including interruption in production as a reason for notification and by applying it to all manufacturers, not just sole sources of the therapies. However, the draft also specifies that notification is required only if a discontinuance or interruption in production is likely to produce a drug shortage and that if a six-month notification is not possible, FDA could be notified “as soon as practicable.”

The proposed changes might have little practical impact. FDA in December broadened the pre-notification requirement, issuing an interim final rule that says discontinuance includes both permanent and temporary interruptions in manufacturing and redefines sole manufacturer Also see "FDA’s Drug Shortage Reg Adds More Manufacturers, Products To Notification List" - Pink Sheet, 19 December, 2011..

The draft also falls short of the all-drug approach sought by physicians and pharmacists, who must juggle therapies when shortages occur and provided the impetus for drug shortages legislation Also see "Drug Shortages Bill In Senate Would Increase Manufacturing Disclosures To FDA" - Pink Sheet, 14 February, 2011.. Their approach is contained in bills by Reps. Diana DeGette, D-Colo., and Tom Rooney, R-Fla., in the House and Sens. Amy Klobuchar, D-Minn., and Robert Casey, D-Pa., in the Senate that would apply the notification requirement to prescription drugs as a whole; the DeGette/Rooney measure specifies that it covers biologics as well as drugs Also see "Drug Shortage Legislation Gains Momentum With Bipartisan House Bill" - Pink Sheet, 27 June, 2011..

Several House Republicans signaled their dissatisfaction with the notification-centric approach during hearings on the issue earlier in the year Also see "GOP Drug Shortage Strategy Pushes FDA Reform, Reimbursement Over Notification" - Pink Sheet, 13 February, 2012.. Their regulation-loosening approach seems to have been favored by the drafters of the bill over the existing legislation.

Members of the Senate Health, Education, Labor and Pensions Committee indicated during December hearings they favor that all manufacturers notify FDA of issues that could cause a shortage, but they have yet to release a draft proposal delineating their remedy for drug shortages.

List of Drugs Subject To Notification

In a directive that would clarify for sponsors who could be subject to the notification provision, the committee draft calls on FDA to write final regulations that contain a list of drugs whose discontinued or interrupted production is likely to cause a drug shortage, and definitions of “life-supporting,” “life-sustaining,” and “intended for use in the prevention of a debilitating disease or condition.” The rules would be due within 18 months.

The draft also would mandate a publicly available list of drugs in short supply, including the drug and manufacturer names, the reason for the shortage and the anticipated duration of the shortage. Possible reasons for a shortage include cGMP requirements, regulatory delay, shortage of an active ingredient or non-active component, discontinuation of drug production, delays in shipping or an increase in demand.

Other shortage provisions would require 30-day review by the Attorney General of requests for increased production of Schedule II controlled substances associated with a shortage; a study by the Government Accountability Office of the cause of drug shortages and recommendations for alleviating or preventing them, including incentives; and an FDA annual report on shortages and agency mitigation actions, such as expedited review of new manufacturing sites and suppliers.

Drug Shortage Provisions In Draft PDUFA Bill Would Expedite Major Manufacturing Changes

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