FDA Issues Proposed Rule and Strategic Plan to Address Drug Shortages

By Jennifer M. Thomas –

I have monitored the drug shortage issue over the last few years with professional interest and general concern (see here).  However, the situation was recently brought home to me when I took my four-month old in for her second round of vaccinations a few weeks ago, and was told that she would have to wait for one of her vaccinations because it was not available.  Of course, waiting won’t hurt her.  But I realized how much my anxiety and frustration would be compounded if the shortage could potentially impact my daughter’s health, or worse, if it actually did.  That unacceptable situation is faced by too many mothers and fathers every day in this country.

So it was with heightened personal interest that I read FDA’s recently released Strategic Plan for Preventing and Mitigating Drug Shortages (“Strategic Plan”), and Proposed Rule on Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products (“Proposed Rule”).  For those who lack the time to wade into these relatively lengthy documents, this post provides bullet-point highlights and a brief evaluation of each document.

Proposed Rule

• The Proposed Rule was authorized by the 2012 FDA Safety and Innovation Act (“FDASIA”).  (FDASIA: (1) expanded the FDCA’s drug shortage notification provision to all manufacturers of medically important approved or unapproved drugs – not just sole manufacturers of approved drugs – in cases of either a permanent discontinuation or a temporary interruption (FDASIA § 1001(a)); and (2) specifically authorized the Secretary to “by regulation apply [the notification requirement] to biological products . . . if the Secretary determines such inclusion would benefit the public health.”  FDASIA § 1001(a).  See our summary here);
• It requires manufacturers to notify FDA of a discontinuance or temporary interruption in manufacturing 6 months in advance, or as soon as practicable;
• It applies to all manufacturers of medically important drugs (life sustaining, life supporting, or intended to treat or prevent a debilitating disease or condition), whether approved or unapproved; and
• It expands the notification requirement to biologics.

FDA’s Proposed Rule contains few surprises, but certain elements are noteworthy.  For instance, an applicant-holder is solely responsible for notifying FDA even if it contracts out the manufacture of the product in question.  The applicant-holder is directed to work with its contract manufacturers and ingredient suppliers to develop a system of notifying FDA that avoids duplicative notifications.  This is one of the only narrowing elements of a proposed rule seemingly intended to maximize the total number of notifications submitted to the Agency. An example of that trend is FDA’s determination that for purposes of notification, a “product” refers to a specific strength, dosage form, or route of administration.  Thus, if a manufacturing disruption relates to only one strength of a particular drug or biologic, FDA must be notified even if other strengths remain available.  Further, when determining whether an interruption in manufacturing is likely to lead to a meaningful disruption in supply triggering the notification requirement, a manufacturer or applicant may only consider whether the manufacturing disruption will affect the manufacturer’s own ability to meet demand for its product – even if the manufacturer has such a small market share that its disruption is unlikely to affect the market as a whole. 

While efforts to broaden the scope of notification are consistent with FDASIA’s intent, it seems questionable whether FDA truly has the capacity to analyze and act on each of the notifications submitted pursuant to its proposed rule.  This is particularly true because, as the Agency itself acknowledges, 6 month advance notification is in most cases entirely aspirational – often only a few days advance notice is practicable, or notice may even post-date the manufacturing disruption itself.

Perhaps most importantly, FDA’s authority to enforce timely notification is limited to issuance of a public noncompliance letter.  While the Agency’s ability to publicize violations is generally one of its most powerful and well-utilized enforcement tools, it may be comparatively weak in this context, where the unfavorable publicity seems unlikely to expose a violative company to private litigation in the absence of extenuating circumstances.

Strategic Plan

FDA was required to create and submit the Strategic Plan to Congress pursuant to FDASIA § 1003.

• The Strategic Plan was mandated by FDASIA, created by FDA’s Drug Shortage Task Force, and will be submitted to Congress.
• It reflects a two-pronged FDA strategy to address drug shortages by:
  • Improving FDA’s response to shortage notifications from manufacturers:
    • Streamlining the agency’s internal process, clarifying the roles and responsibilities of various groups within FDA that are working to prevent shortages; and
    • Improving communications with the public and healthcare providers, including enhancing the drug shortages webpage and rolling out a new smartphone application to provide real-time shortages information.
  • Addressing the root causes of shortages (primarily quality and other manufacturing issues):
    • Creating an Office of Pharmaceutical Quality within FDA – a clearinghouse for manufacturer questions about how best to improve and ensure quality;
    • Providing incentives to manufacturers for making manufacturing quality improvements or for taking action to prevent or end a drug shortage; and
    • Engaging in a risk-based approach to detect early warning signals of potential shortages, so that FDA can intervene before a shortage occurs.
• It also includes suggested actions that manufacturers should consider to help prevent shortages, and mitigate the effects of shortages when they occur, including:
  • Building a robust inventory before making manufacturing changes;
  • Communicating regularly with contract manufacturers to update information about their processes, facilities, and capacities;
  • When notifying FDA of a potential shortage, including:
    • Information about proposed actions to address the current  shortage and similar shortages in the future;
    • A realistic estimate of how long the manufacturing disruption can be expected to continue;
  • Pursuing a dialogue with FDA about long-term solutions, including remediation efforts to upgrade aging manufacturing facilities; and
  • Having a plan in place to mitigate the impact of shortages

The Strategic Plan is a well-intentioned document, but seems to represent only the beginning of FDA’s analysis rather than the finished product.  For example, FDASIA directed FDA to include in the Strategic Plan “an examination of whether to establish a ‘qualified manufacturing partner program’.”  FDASIA § 1003.  However, the current Plan refers only to FDA’s continued examination of the possibility of a partner program, and the development of further information surrounding such a program.  This, despite public comments analyzing the viability of a partner program, and the existence of a potential model in the Biomedical Advanced Research and Development Authority ("BARDA") partner program. 

FDA also requested public comment about manufacturing quality metrics that would be most useful for purchasers and prescribers, and for manufacturers in choosing a contract manufacturer.  However, its Strategic Plan places the onus on purchasers by calling on them to make use of already published data (such as the manufacturer’s history of inspection outcomes and classifications, recalls, etc.)  FDA claims to be limited because “buyers ultimately decide how or whether they will use this data when they make purchasing decisions.”  However, this statement evades the question of whether FDA is making information public in a way that is readily understandable and usable by purchasers, prescribers, and other manufacturers.  For example, at least one public comment suggested a type of scoring system based on inspection history, remediation efforts, etc.  FDA’s Strategic Plan does not appear to contemplate that idea, or any other system for consolidating and reporting information about manufacturing quality.

Finally, FDA minimizes its own ability to “offer financial or other economic means to promote innovation in quality manufacturing.”  While no one would expect FDA to dole out cash rewards for quality improvements, the agency cannot fail to understand the financial impact of even its smallest indication of favor towards a company – particularly a publicly traded one.  For example, simply expediting review of new facilities for companies that have exhibited exemplary manufacturing quality standards would be a significant boon to those companies.  Expedited product review would be an even greater benefit.  Even a public scoring system, as discussed above, that incorporated the proactive measures taken by a company to improve quality, or prevent or mitigate shortages, would be a way for FDA to reward desirable behaviors.  The Strategic Plan does not analyze these possibilities.

In conclusion, while the Agency seems to be expending significant resources to address the issue of drug shortages, it remains unclear whether those efforts will produce better outcomes than have already resulted from the heightened awareness and voluntary response produced by President Obama’s 2011 Executive Order (see our previous post here).  Even FDA cannot confirm that its Proposed Rule and Strategic Plan will have a real impact on drug shortages.  When asked for concrete examples of shortages that would have been prevented or improved had FDA’s Proposed Rule or its Strategic Plan been in place a year ago, the Agency had no response.