FDA Guidance Notification of Prescription Drug or Biologic Product Drug Shortages

There have been significant media coverage and government oversight surrounding drug shortages over the past few months.  On October 31, 2011, FDA sent a letter to manufacturers of prescription products reminding them of their mandatory reporting requirements under section 506C and encouraging them to voluntarily report to the Agency any disruptions in supply that could lead to a product shortage, even beyond those situations covered by mandatory reporting.  On the same day, the President issued Executive Order 13588 directing FDA to use all available administrative tools to expand the Agency’s efforts to combat the problem of drug shortages. 

In addition to these steps, FDA recently released draft Guidance to Industry on “Notification to FDA of Issues that May Result in a Prescription Drug or Biological Product Shortage.”  The Guidance to industry explains requirements for notification to FDA of a discontinuance of certain drug products under section 506C of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as implemented by 21 C.F.R. §§ 314.81(b)(3)(iii) and 314.91. The guidance reflects amendments to the implementing regulations published as an interim final rule on December 19, 2011 (effective January 18, 2012).  The guidance is only for drugs, regulated by CDER, and biologics, the Center for Biologics Evaluation and Research (CBER). 

Under section 506C of the FD&C Act, “sole manufacturers” are required to report to FDA discontinuances of drug products that are “life-supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition.”  

Why Notification to the FDA of Issues that May Lead to a Drug Shortage is Critical 

FDA is concerned about the rising incidence of drug shortages in the United States, particularly those involving drugs that are manufactured by a small number of firms and for which there are no good therapeutic substitutes available.  The number of drug shortages has been rising steadily over the last five years, nearly tripling from 61 in 2005 to 178 in 2010.  In 2011, FDA tracked over 250 drug shortages.  Drug shortages can create significant public health concerns.  Causes of drug shortages may include: 

• product quality concerns,
• manufacturing problems,
• difficulty in acquiring component parts or active pharmaceutical ingredients (API),
• increases in demand, and
• shipping delays, among other things. 

Notifying FDA in advance of incidents that may result in a drug shortage helps FDA work with manufacturers to take early action to prevent or alleviate shortages.  For example, in 2011, early notification by manufacturers allowed the FDA to help prevent shortages of 195 drugs, including 86 drugs produced by one company.   

Overview of Current Drug Shortage Reporting  

Since 1997, section 506C has required manufacturers to notify the Agency of a discontinuance of certain drug products.  Following enactment of section 506C, FDA promulgated regulations at 21 C.F.R. §§ 314.81(b)(3)(iii) and 314.91 to implement the statute.  Under section 506C, a manufacturer that is the sole manufacturer of a drug that is approved under section 505(b) or 505(j) of the FD&C Act (and that is not a product that was originally derived from human tissue and was replaced by a recombinant product) is required to notify FDA at least six months prior to discontinuing manufacture of the drug, if the drug is “life­supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition.” 

The FDA originally interpreted this requirement to apply only to permanent manufacturing discontinuances.  Mandatory notification under section 506C has been critical in enabling FDA to assist manufacturers in preventing or mitigating some drug shortages. For example, when notified of a discontinuance under section 506C, FDA has been able to expedite review of potential new products and suppliers and exercise regulatory flexibility for the product in shortage or an alternative product, where such action would not compromise patient safety. 

However, while mandatory notification of permanent discontinuances is helpful in preventing or mitigating some drug shortages, this limited requirement is not sufficient to address the magnitude of the current drug shortage problem. In 2010, only 8% of drug shortages were due to permanent discontinuances of drug products; the majority of shortages were the result of problems at the manufacturing facility, delays in manufacturing or shipping, and API shortages.  Moreover, biological products licensed through a biologics license application (BLA) under section 351 the Public Health Service Act are also vulnerable to shortages, but are not subject to mandatory reporting under section 506C. Under current law, manufacturers are therefore not required to report to FDA the majority of situations that could lead to a drug shortage. 

Consequently, in response to the Executive Order, FDA published the IFR, which expands the application of our authority under section 506C to require mandatory notifications in additional circumstances, and clarifies who is responsible for notifying the Agency of a discontinuance. Moreover, in addition to mandatory notification under section 506C, to effectively work with manufacturers to more fully combat the drug shortage crisis, FDA strongly encourages companies to voluntarily notify the Agency of any other issues that could lead to a shortage of any prescription drug or biological product supplied in the U.S. 

SCOPE AND LOGISTICS OF MANDATORY NOTIFICATION  

Under section 506C of the FD&C Act: 

• if you are a sole manufacturer of a prescription drug product approved under section 505(b) or 505(j) of the FD&C Act (and that was not originally derived from human tissue and replaced by a recombinant product); and
• that product is “life-supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition”;
• then you are required by statute to notify the Agency of a discontinuance of that drug product at least six months prior to discontinuing manufacture of the product.  

Sole Manufacturer 

FDA defines Sole Manufacturer as “an applicant that is the only entity currently manufacturing a drug product of a specific strength, dosage form, or route of administration for sale in the United States, whether the product is manufactured by the applicant or for the applicant under contract with one or more different entities.” The definition is intended to do three things. 

First, it clarifies that “sole manufacturer” means the only applicant currently supplying the U.S. market with the drug product.  It does not mean the sole holder of an approved new drug application (NDA) or abbreviated new drug application (ANDA).  Accordingly, a manufacturer may not rely on the Orange Book (FDA’s publication on “Approved Drug Products with Therapeutic Equivalence Evaluations”) as the source for determining whether it is a sole manufacturer.  Instead, the manufacturer should use commercial data or other methods to determine whether or not it is the only entity currently manufacturing for sale in the U.S. the product in question.   

It is the manufacturer’s responsibility to determine whether it is a sole manufacturer. Manufacturers who have questions about this determination may contact the drug shortages staff.  Contact information for the CDER and CBER drug shortages programs. 

Second, the definition of sole manufacturer clarifies that the specific strength, dosage form, and route of administration of the product are critical in determining if a manufacturer is a sole manufacturer.  The definition of sole manufacturer is linked to the specific strength, dosage form, and route of administration, because these characteristics may be critical for the targeted needs of particular patients.  For example, a patient may be prescribed an injectable form of a particular drug product because the patient is not capable of swallowing an oral pill.  If the injectable form is discontinued, the patient may be unable to continue life-saving treatment, even if the oral form is still available. 

Moreover, recent experience has shown that discontinuances of a specific strength, dosage form, or route of administration of a drug product may lead to a shortage of another strength, dosage form, or route of administration of the product, compounding patient difficulties in obtaining the drug product.  For instance, in the previous example, if the oral form of the drug product is discontinued, providers may prescribe the injectable form to all patients.  This increase in demand for the injectable form of the product may cause a shortage of the injectable form. 

If the FDA is notified in a timely manner of the discontinuance of the oral form, we may be able to work with manufacturers and other stakeholders to avoid, or mitigate the impact of, a shortage of both formulations of the product.  Accordingly, to enable the Agency to work most effectively with manufacturers and other stakeholders to prevent or mitigate potential shortages, discontinuances of a specific strength, dosage form, or route of administration of drug products subject to section 506C must be reported to FDA.  

Third, the IFR makes clear that it is the application holder of the drug product subject to section 506C who bears the responsibility for reporting a discontinuance to the Agency. For purposes of section 506C, an application holder will be considered a “manufacturer” even if the application holder contracts that function out to another entity. The application holder is responsible for establishing processes with contract manufacturers that ensure the application holder’s compliance with section 506C and the IFR. 

The intention of section 506C is to alert FDA to possible disruptions in supply of certain drug products important to patient care to allow us to work with the manufacturer or others to minimize, to the extent possible, disruptions in patient access to those products.  Considering this intention, FDA encouraged manufacturers to be over-inclusive when determining whether they are a sole manufacturer. 

 “Life-supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition.”  

In 2007, the Agency interpreted “life-supporting or life-sustaining” to mean “a drug product that is 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.”  FDA has interpreted “debilitating disease or condition” to mean a “serious disease or condition.”  FDA should therefore be notified under section 506C if a drug product that is used to treat or prevent a serious disease or medical condition is discontinued. 

What Information to Report to the Agency  

Under section 506C, sole manufacturers are required to notify FDA of a discontinuance of a drug product subject to section 506C.  FDA now defines “discontinuance” to mean “any interruption of manufacturing of a drug product described in paragraph (b)(3)(iii)(a) for sale in the United States that could lead to a potential disruption in supply of the drug product, whether the interruption is intended to be temporary or permanent.”   Thus, the term “discontinuance” now includes both temporary and permanent interruptions in manufacturing, if the interruption could lead to a disruption in supply of the product. 

Any permanent discontinuance of manufacturing by a sole manufacturer will lead, per se, to a disruption in supply of the product; thus, all permanent discontinuances must continue to be reported to FDA.  

Temporary discontinuances must be reported to the Agency only if the discontinuance reasonably could be expected to lead to a disruption in supply of the product. For example, the following circumstances would trigger notification to the FDA of a discontinuance of a drug product subject to section 506C: 

• A business decision to permanently discontinue manufacture of a drug product;
• A delay in acquiring API or inactive ingredients that leads to, or could lead to, a temporary interruption in manufacturing of a drug product;
• Equipment failure or contamination affecting the quality of a drug product that necessitates an interruption in manufacturing while the equipment is repaired or the contamination issue is addressed;
• Manufacturing shut-downs for maintenance or other routine matters, if the shut­down extends for longer than anticipated or otherwise could disrupt supply. 

Conversely, a manufacturer would not be required to notify FDA if a discontinuance is part of the normal manufacturing schedule and is not expected to lead to a disruption in supply of a drug product subject to section 506C. FDA provides examples of these situations in the guidance as well.  For example, FDA need not be notified in the following circumstances: 

When and How to Notify the Agency  

Section 506C requires manufacturers to notify the Agency at least six months prior to discontinuing manufacture of a drug product subject to section 506C.  The six month period may be shortened if the FDA finds “good cause” exists for the reduction based on information submitted to the Agency by the manufacturer in a certified written request.  Manufacturers must notify the Agency at least six months prior to the discontinuance unless: 1) the manufacturer has submitted a written certification of “good cause”; and 2) the Agency has affirmatively made a determination to allow a reduction in the notification period for one of the good cause reasons listed in 21 C.F.R. § 314.91(d), including if: 

(1)  a public health problem may result from continuation of manufacturing for the 6-month period;

(2)  a biomaterials shortage prevents the continuation of the manufacturing for the 6-month period;

(3)  a liability problem may exist for the manufacturer if the manufacturing is continued for the 6 month period;

(4)  continuation of the manufacturing for the 6-month period may cause substantial economic hardship for the manufacturer;

(5)  the manufacturer has filed for bankruptcy under chapter 7 or 11 of title 11;

(6)  the manufacturer can continue distribution of the drug product to satisfy existing market need for 6 months; or

(7)  other good cause exists for the reduction. 

The only exception to this requirement is if a manufacturer is unable to notify FDA of a temporary discontinuance six months prior to the discontinuance because it was an unforeseen occurrence (e.g., unexpected contamination).  Under those circumstances, a manufacturer need not submit a written certification of good cause requesting a reduction in the notification period. Instead, the manufacturer must notify FDA as soon as possible after it knows that a discontinuance will occur.  In any other instance, a manufacturer seeking a reduction in the six-month notification period must submit a written certification of good cause and obtain affirmative Agency approval of the reduction in the notification period. 

The IFR requires manufacturers to report a notice of a discontinuance to FDA either electronically or by telephone according to instructions on the FDA’s drug shortages website.  As indicated on the website, products regulated by CDER should be reported to the CDER Drug Shortages Coordinator, and products regulated by CBER should be reported to the CBER Products Shortage Coordinator. 

SCOPE AND LOGISTICS OF VOLUNTARY NOTIFICATION  

Unlike mandatory notification, voluntary notification includes prescription biological products licensed under a BLA.  The Agency encourages manufacturers of all prescription drug or biological products to voluntarily notify the Agency of issues that may result in a shortage or potential disruption in supply of that product in the U.S. market.  FDA encouraged manufacturers to notify the Agency even if they are not a sole manufacturer of a drug or biological product, as described in relation to mandatory reporting under section 506C. 

What Information to Report to the Agency  

FDA encourages manufacturers to notify the Agency’s drug shortages staff of the following issues (not exhaustive) if they reasonably could be expected to lead to a potential shortage or disruption in supply of a prescription drug or biological product: 

• product quality problems, such as the presence of particulates or impurities, microbial contamination, and stability concerns;
• interruptions or other adjustments in manufacturing that temporarily halt production and that may adversely affect market supply, such as renovation of manufacturing facilities;
• delays in acquiring critical raw materials or components, or loss of raw material or components (e.g., vials, stoppers, bottles) suppliers;
• transfer of manufacturing to an alternate facility  
• loss of a production line or production capacity
• any production problems that occur during or after manufacturing that could result in supply disruptions  
• import delays  
• unexpected increases in demand; and
• product discontinuances, even if you are not a sole manufacturer or the product in question is not subject to section 506C.  

WHAT FDA DOES WITH INFORMATION REPORTED  

Once FDA is notified of any incident that could result in a product shortage, whether a required notification of a discontinuance under section 506C or a voluntary notification, the Agency will work closely with the manufacturer to help prevent a shortage. FDA may undertake a variety of actions to help prevent or mitigate a product shortage, including the following: 

• Expedite review of submissions from manufacturers.
• Identify additional sources of supply or alternate manufacturers that can initiate or ramp-up production.  
• Find new/additional sources of raw material.
• Consult with/advise sponsors on resolution of manufacturing or quality issues.
• Exercise regulatory discretion for the temporary importation of a non-U.S. product, in rare instances.   

FDA posts information about all actual shortages on the FDA drug shortages website.  However, FDA does not post on its website information regarding potential shortages, because FDA is sensitive to the possibility that this could lead to increased stockpiling of a product facing a potential shortage, possibly worsening the situation. 

ADDITIONAL CONSIDERATIONS FOR MANUFACTURERS  

FDA also recognized that adequate attention to good manufacturing practices, including by implementation of well-defined risk management systems at all layers of the supply chain, and through continuous evaluation and investment in manufacturing operations will help avoid many manufacturing problems that lead to product shortages. 

Contingency planning by manufacturers may also help prevent some shortages. Analysis of 127 drug shortages between January 1, 2010 and August 26, 2011 showed that approximately 60% of the shortages were caused by circumstances that may have been avoided or mitigated if the manufacturer had undertaken enhanced redundancy or contingency planning.    

FDA encouraged manufacturers to make contingency plans for responding to situations that could lead to a shortage.  This could include building redundancy into manufacturing capabilities, establishing relationships with and adequate controls over contract manufacturers, and/or identifying and seeking approval for alternative API and component suppliers.