Earlier this month, the Food and Drug Administration (FDA) released a notice for public comment in the Federal Register regarding ideas stakeholders and the public may have for combating drug shortages. As noted on FDA’s own blog, the agency believes that despite the progress made over the last year, even more can be done and is therefore turning to the American public for advice.
Comments due by Thursday, March 14, 2013. The Docket Number is FDA-2013-N-0124.
Background
As we previously wrote this summer, the President signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144) on July 9, 2012. Section 1003 of FDASIA adds section 506D to the Federal Food, Drug, and Cosmetic Act (the FDCA) to require the formation of a task force to develop and implement a strategic plan for enhancing the Agency’s response to preventing and mitigating drug shortages. Section 506D of the FDCA (21 U.S.C. 356) requires that the drug shortages strategic plan include the following:
- Plans for enhanced interagency and intra-agency coordination, communication, and decisionmaking;
- Plans for ensuring that drug shortages are considered when the Secretary initiates a regulatory action that could precipitate a drug shortage or exacerbate an existing drug shortage;
- Plans for effective communication with outside stakeholders, including who the Secretary should alert about potential or actual drug shortages, how the communication should occur, and what types of information should be shared;
- Plans for considering the impact of drug shortages on research and clinical trials; and
- An examination of whether to establish a “qualified manufacturing partner program” as described in section 506D(a)(1)(C) of the FD&C Act.
Per the directive in section 506D, FDA has formed an internal Drug Shortages Task Force (Task Force) to develop and implement the drug shortages strategic plan. The Task Force is seeking comments from the public on issues related to the development of this strategic plan. Importantly, although FDASIA refers only to a drug shortages strategic plan, FDA anticipates that the strategic plan will consider prevention and mitigation of both drug and biological product shortages. Accordingly, FDA expressed its interest in receiving comments on the following questions from all parties, including those with an interest in biological products:
- In an effort to address the major underlying causes of drug and biological product shortages, FDA is seeking new ideas to encourage high-quality manufacturing and to facilitate expansion of manufacturing capacity.
- To assist in the evaluation of product manufacturing quality, FDA is exploring the broader use of manufacturing quality metrics. With that in mind, FDA would like input on the following issues: What metrics do manufacturers currently use to monitor production quality? To what extent do purchasers and prescribers use information about manufacturing quality when deciding how to purchase or utilize products? What kinds of manufacturing quality metrics might be valuable for purchasers and prescribers when determining which manufacturers to purchase from or which manufacturers’ products to prescribe? What kinds of manufacturing quality metrics might be valuable for manufacturers when choosing a contract manufacturer? How frequently would such metrics need to be updated to be meaningful.
- The use of a qualified manufacturing partner program similar to one used under the Biomedical Advanced Research and Development Authority (BARDA) has been suggested as a potentially useful approach to expanding manufacturing capacity and preventing shortages. FDA recognizes that there are important potential differences between the BARDA program and the use of a parallel program to address shortages. For example, the BARDA program covers a relatively stable and limited number of products, but drugs at risk of shortage are many, may change rapidly over time, and are difficult to predict in advance. In addition, FDA does not have funding to pay manufacturers to participate in a drug shortages qualified manufacturing partner program or to guarantee purchase of the end product. With these differences in mind, is it possible to design a qualified manufacturing partner program that would have a positive impact on shortages?
- Are there incentives that FDA can provide to encourage manufacturers to establish and maintain high-quality manufacturing practices, to develop redundancy in manufacturing operations, to expand capacity, and/or to create other conditions to prevent or mitigate shortages?
- In FDA’s work to prevent shortages of drugs and biological products, FDA regularly engages with other U.S. Government Agencies. Are there incentives these Agencies can provide, separately or in partnership with FDA, to prevent shortages?
- When notified of a potential or actual drug or biological product shortage, FDA may take certain actions to mitigate the impact of the shortage, including expediting review of regulatory submissions, expediting inspections, exercising enforcement discretion, identifying alternative manufacturing sources, extending expiration dates based on stability data, and working with the manufacturer to resolve the underlying cause of the shortage. Are there changes to these existing tools that FDA can make to improve their utility in managing shortages? Are there other actions that FDA can take under its existing authority to address impending shortages?
- To manage communications to help alleviate potential or actual shortages, FDA uses a variety of tools, including posting information on our public shortages Web sites and sending targeted notifications to specialty groups. Are there other communication tools that FDA should use or additional information the Agency should share to help health care professionals, manufacturers, distributors, patients, and others manage shortages more effectively? Are there changes to FDA’s public shortage Web sites that would help enhance their utility for patients, prescribers, and others in managing shortages?
- What impact do drug and biological product shortages have on research and clinical trials? What actions can FDA take to mitigate any negative impact of shortages on research and clinical trials?
- What other actions or activities should FDA consider including in the strategic plan to help prevent or mitigate shortages?
Other Drug Shortage News
In addition, FDA recently announced the approval of the first generic version of the cancer drug Doxil (doxorubicin hydrochloride liposome injection). Doxil is currently on FDA’s drug shortage list. The generic is made by Sun Pharma Global FZE (Sun). Doxorubicin hydrochloride liposome injection is administered intravenously by a health care professional. Sun’s generic will be available in 20 milligram and 50 milligram vials.
In February 2012, to address the shortage of doxorubicin hydrochloride liposome injection, FDA announced it would exercise enforcement discretion for temporary controlled importation of Lipodox (doxorubicin hydrochloride liposome injection), an alternative to Doxil produced by Sun and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. that is not approved in the United States. Enforcement discretion was also used to release one lot of Janssen’s Doxil made under an unapproved manufacturing process.
In addition, a federal judge also recently approved a consent decree with Ben Venue Laboratories, FDA announced. The company, a subsidiary of Boehringer Ingelheim, suspended its manufacturing capabilities in 2011 after receiving a string of warning letters from FDA over the maintenance of its current good manufacturing practices (CGMPs).
According to RAPS, “the quality control problems had led to widespread shortages of various critical medications, including Doxil (doxorubicin), a cancer drug.” As of October 2012, that enforcement discretion continues even as Ben Venue’s manufacturing capabilities have started to come back online. That same month, Ben Venue announced that both “FDA and the European Medicines Agency (EMA) were reviewing a new shared manufacturing method that would see initial supplies of Doxil manufactured at Ben Venue, while a second facility would ensure the quality and sterility of the drug.”
“Under the terms of the consent decree, Ben Venue is permitted to continue to manufacture and distribute more than one hundred important drugs that are essential for patient care,” the company said in a statement. “Ben Venue is also permitted to continue drug-development activities, and may file abbreviated new drug applications (ANDAs), and, as remediation progresses to the FDA’s satisfaction, receive ANDA approvals and manufacture other products.”
However, the consent decree restrains Ben Venue from manufacturing and distributing drugs from its Bedford, Ohio, facility until FDA determines that its operations are compliant with the FDCA.
In a statement, FDA’s Acting Associate Commissioner for Regulatory Affairs Melinda Plaiser explained that the consent decree was enacted in response to serious, systemic concerns. “The company’s failure to promptly address these problems put patients at risk of receiving poor-quality drugs and compromises the availability of medically necessary products,” said Plaisier. “This company continued to violate the law, and FDA took action to help ensure that medicines that consumers rely on are safe, effective, and of high quality.”
Ben Venue acknowledged those concerns in its own statement, noting that it has already spent more than $300 million to upgrade its facilities to address some of the systemic quality deficiencies that had plagued it in recent years. The company also noted that since its October 2012 announcement of the return of limited manufacturing capabilities, it has resumed production on additional manufacturing lines. That consent decree was subject to the approval of a federal court, which FDA announced it received on 31 January 2013.
FDA’s statement on the matter also indicates that Ben Venue’s CEO, vice president of operations and vice president of quality operations were all named defendants under the decree, providing it with significant leverage if the company violates its terms.
The agency will also likely be glad to have the facility’s capacity back up and running. Ben Venue is a manufacturer of numerous sterile injectable drugs, and in the wake of its shut down and subsequent drug shortages, FDA came under fire from Congress for two reasons: the shortages and pharmaceutical compounding.
In the first instance, FDA was slammed by legislators for not working harder to keep the manufacturing facility open, with a congressional report alleging that FDA did not have a “sufficient focus in ensuring access to and a continued supply of needed medicines over the last several years.”
“Although manufacturers are reluctant to speak publicly about problems with their governing agency, the Committee found that the new political regime at FDA is largely to blame for the sudden spike of shortages that began in 2010,” quoted RAPS. FDA, meanwhile, hit back at that report, saying that responsibilities for the shortages “live largely outside of FDA’s purview.”
“It is the manufacturer’s responsibility to ensure that its products are safe, effective and of high quality,” wrote Jeanne Ireland, then-assistant commissioner for legislation at FDA. “When products manufacture under problematic manufacturing conditions pose a safety threat to patients—such as glass shards or metal shavings in vials of injectable drug products or fungal contamination of the product—manufacturers generally must stop production to resolve the problem before resuming manufacturing and distribution.”