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Actions and Recommendations

Table of Contents: A Review of FDA’s Approach to Medical Product Shortages

This analysis has made clear that drug shortages are the result of a large number of overlapping causes.  Accordingly, there is no single or simple solution that is likely to solve this problem; addressing it will require a multifaceted approach addressing many aspects of the problem simultaneously and involving multiple stakeholders including health-care professionals, industry, regulators, payers, Congress, and others.  The Agency’s primary role in this context is to work with manufacturers to aid in the mitigation and, whenever possible, the prevention of shortages. 

These recommendations primarily focus on FDA.  As in earlier sections of the report, most observations are directed toward drug shortages, but certain recommendations with relevance to other medical products are also included.

Immediate Actions

1. Write a letter to drug manufacturers reminding them of their current legal obligations to notify FDA in advance of the discontinuation of certain drugs and urging them to voluntarily notify FDA of other potential disruptions to the supply of drugs that are not currently required, as soon as they become aware of them

Currently, with certain exceptions, drug manufacturers are required to notify the Agency six months before discontinuing manufacturing only if they are the sole producer of a drug that is approved under section 505(b) or 505(j) of the FD&C Act and that is life-supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition.  It is apparent from the accounts of Agency staff that there are many instances in which manufacturers fail to notify FDA.  This letter, combined with the recent national attention devoted to drug shortages, should lead to an improvement in notification with minimal cost and effort to the Agency and, as a consequence, an enhanced ability to prevent shortages. 

2. Develop guidance and regulations that clarify and enhance the information on potential drug shortages that is submitted by industry

Together with the letter to industry in Immediate Action 1, these will expand notifications beyond what is currently required and help FDA work with industry to prevent and mitigate shortages.

3. Provide additional staffing resources for FDA’s efforts to prevent and mitigate shortages

Despite the growing number of drug shortages, CDER’s DSP has operated with essentially the same number of filled positions since 2004.  Additional resources will be used to accommodate expected increases in notification and for such tasks as maintaining the newly developed database.

4. Support legislation that requires early notification by manufacturers for drug shortages and provides new authority to FDA to enforce these requirements

Additional explicit authorities for FDA to require and enforce early notification would be helpful.  Therefore the Administration supports legislation before Congress, authored by Representatives DeGette and Rooney, and Senators Klobuchar and Casey, to provide these authorities.  HHS and FDA will work with the sponsors to consider improvements to their bills and any other relevant legislation to maximize the impact for preventing and mitigating shortages and address this public health challenge.  For example, some of these improvements would be designed to address the so-called “gray market,” including requiring better tracking for medications.

5.Implement and maintain a database that can analyze the characteristics of drug shortages

Although DSP has retained information on past drug shortages in the form of weekly reports describing the current status of that week’s most significant shortages and a library of emails, these data are not suitable for systematic analysis.  In consultation with DSP staff, a new database containing information on drug shortages from January 1, 2010 onward has been developed.  This new database captures various characteristics of each drug shortage, including drug class, reason for shortage, Agency action taken, and duration of shortage.  The information captured in this database will allow the Agency to improve its tracking of drug shortages, to more consistently characterize each shortage, and to rapidly identify and analyze new trends in shortages.  The Agency will also use it to assess the effectiveness of any enhanced notification requirement enacted by Congress.

Longer-term Actions

6. Identify factors that contribute to success or failure in preventing drug shortages and continue exploring new approaches to preventing drug shortages under existing authorities

Despite the challenges described above, DSP reports that FDA prevented 38 drug shortages in 2010 and 99 in 2011 to date, an increase that DSP staff attribute, at least in part, to improved notification by manufacturers.  Preventable shortages tend to be those where options include expedited reviews of changes in manufacturing practices, sites or suppliers, or discretion with regard to particular lots at ports of entry into the United States.  A thorough examination of how FDA prevented specific shortages was beyond the scope of this report.  However, FDA should conduct a comprehensive identification of the factors that have led to these successes so that lessons learned can be replicated, amplified, and disseminated.  A similar examination of shortages that took place, including those that occurred despite FDA’s efforts to prevent them, would also be worthwhile.  In so doing, FDA should continue exploring and using new approaches to help prevent and mitigate shortages under existing statutory authorities.

7. Identify the quality issues in manufacturing practices that have contributed to severe drug shortages and develop approaches to addressing them

FDA should identify and examine the lapses in manufacturing protocols and non-compliance with current quality standards that have lead to drug shortages and to recalls.  This work should better focus industry’s and FDA’s attention on those manufacturing factors that will most help maintain the safety and quality of medical products and ensure their continued availability.  It may also inform reviews of the agency’s current regulatory requirements.

8. Encourage product manufacturers to develop and maintain a plan for back up manufacturing and sources of Active Pharmaceutical Ingredients and other essential product components

According to stakeholders with whom the authors met, APIs are increasingly being obtained from foreign sources that may be susceptible to supply disruptions.  Although shortages of drug APIs have not been the predominant reason for the rising number of drug shortages (more commonly the problem occurs during manufacture of finished product at domestic plants), data on shortages handled by DSP that are generally among the more serious place this figure at 8% for injectable drugs and 20% for non-injectables.  Drug API disruptions have even resulted in device shortages in the recent past (e.g., the heparin shortage resulted in shortages of devices using heparin to prevent clotting, such as oxygenators used in bypass machines).  The Agency should explore having manufacturers submit to the Agency a plan, at approval and annually, to address potential disruption of their primary API supplies and other essential components to ensure that manufacturers are better prepared for supply interruptions.  Similar requirements should be considered for manufacturing procedures as well.  The burden of such requirements upon industry will need to be carefully considered before moving forward.

9. Explore development of a sentinel reporting network (e.g., major healthcare systems, wholesalers, physician specialty societies) to facilitate early warning of drug shortages

As noted elsewhere in this report, FDA does not always learn promptly about product shortages. Any system that increases reporting must ensure that, in the pursuit of more “signal,” DSP is not overwhelmed with “noise.”  FDA should therefore explore the feasibility of creating sentinel reporting sites (e.g., major healthcare systems, wholesalers, and physician specialty societies) to facilitate the expeditious reporting of high quality information on drug shortages.

10. Encourage wholesalers to develop and publicize their procedures for distributing medical products in shortage

The wholesaler interviewed for this report described a system whereby drugs in shortage were distributed to its regional offices in proportion to previous orders.  Other wholesalers may operate on a first-come, first-serve basis.  Regardless, the lack of transparency contributes to a climate in which distrust between the various links in the supply chain can be rife.  This is compounded by “leakage” of products to gray market suppliers. 

The adoption and publication by wholesalers of a uniform, industry-wide policy on the distribution of shortage drugs could reduce confusion among recipients, allow for more consistent distribution, and reduce leakage to gray market distributors.

11. Continue to maximize public disclosure of information regarding medical product shortages in FDA’s possession, within the bounds of what must remain confidential

Many pharmacists and clinicians would like to know the reasons behind a particular shortage because it allows them to gauge the likely duration of a shortage based on their prior experience and to adjust their clinical decisions accordingly.  It would also facilitate communications with patients if a drug were scarce.  The Agency is often aware of the reasons behind a shortage, but if the information is protected from public disclosure because it is confidential commercial information, generally the Agency cannot disclose this information without the permission of the manufacturer.  The Agency should continue to carefully consider what information can be publicly disclosed and when disclosure is not permitted without sponsor consent.  The Agency should also attempt to persuade manufacturers to voluntarily allow broader dissemination of the reasons behind their shortages.  The Agency should consider working with all stakeholders to maximize disclosure of information provided to the public about shortages, including the reason for a particular shortage and alternative therapies, if they have the same FDA-approved indications.

12. Continue improving communication between FDA’s field investigators and the Center for Drug Evaluation and Research’s Office of Compliance and Drug Shortage Program staff

Communication is essential for the Agency to efficiently and effectively prevent and mitigate shortages.  Information that might be relevant should be shared on a timely basis with all FDA stakeholders.  There currently appears to be an informal process for communication between ORA field investigators and CDER’s Office of Compliance and DSP staff.  Interviews with Agency staff indicate that, while this consultation process appears to be occurring, it could be streamlined and formalized so that the roles and responsibilities of Agency offices in addressing shortages are clarified and strengthened. 

CDER’s Office of Compliance has multiple SOPs that require the Office to communicate with DSP staff when a potential recall or action is to be taken.  FDA should undertake a thorough review of CDER-ORA interactions and determine whether similar SOPs can be developed in other areas, among other potential improvements.

13. Improve the Drug Shortage Program’s web site as a communications tool for health-care providers and other members of the public

Many stakeholders, particularly pharmacists and clinicians, seem unclear on the differences between the lists of drug shortages maintained by DSP and ASHP.  The differing inclusion criteria between the two lists (primarily that FDA lists, for the most part, shortages of medically necessary drugs and does not include regional shortages) should be better highlighted to raise public awareness and address criticism that DSP’s list is shorter than ASHP’s.  Although the Frequently Asked Questions document 1 on FDA’s drug shortage web page does mention the differences in the two lists, it might be preferable to highlight this distinction at the very top of the list of FDA’s current shortages. 

DSP should also consider maintaining a “dashboard” of metrics that would allow the public and the media to better monitor the overall status of drug shortages and enhance public accountability (see Appendix 3).  These potential metrics would have to be assessed for feasibility of collection, usefulness of the data for month-to-month comparisons, among other factors.

14. Explore the feasibility of developing a model based on available data on drug shortages, manufacturer characteristics, and market factors with the goal of assessing the probability of future shortages

The ability to assess the risk of a particular medical product going into shortage could allow for more focused and potentially more effective prevention efforts.  However, little research has been done on this question, at least in the drug area.  Such research would face significant challenges, but has the theoretical potential to alter how shortages are managed or even prevented.

While it seems clear that a large proportion of recent drug shortages involve injectable generics, this does not establish how much more frequent shortages among injectable generics are compared to other products.  Even that is quite different from predicting whether a particular drug is likely to go into shortage in a given period of time, or the kind of information that would be necessary to identify particular drugs as prevention targets.  There are a number of inherent challenges to such an approach, one of which is the large number of unique injectable products available in the United States.  Data from IMS National Sales PerspectiveTM, an audit that tracks national sales estimates of product packages into retail drugstores, hospitals, clinics, and other non-retail type outlets, provided to the authors of this report by the Office of Planning and Informatics in CDER, suggest that there were an estimated 1468 injectable products sold in 2010, where products are defined by unique combined molecule, dosage form, and strength combinations.  One thousand and twelve products (69%) have at least one generic product

However, DSP only has data on actual drug shortages and, to a more limited extent, prevented shortages.  To develop a model that might predict drug shortages would require extensive model development and validation and the identification of a control group of drugs not in shortage.  Presumably FDA could assemble such a control group from other FDA and external databases.  The Agency would have to incorporate market information on products and manufacturers into the model.  While the feasibility of developing a model that could accurately assess the likelihood of a shortage is unclear at this point, the Agency should give such efforts full consideration because of the inherent public health value of preventing shortages before they occur.

 


 

1. Center for Drug Evaluation and Research, Food and Drug Administration. Frequently Asked Questions about Drug Shortages. Available at: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050796.htm (accessed September 28, 2011).

 

Next Section: Conclusion