The US' generic pharmaceutical manufacturing industry is taking issue with one of the core components of a new drug shortage strategy laid out by the US Food and Drug Administration (FDA), calling it well-intentioned but infeasible and even harmful in some cases.

Background

Drug shortages emerged as a major issue in 2011 and 2012, with many generic sterile injectable drugs experiencing supply shortages. Investigations into the matter brought to light a number of reasons for the shortages, including:

• gray market pharmacies purchasing drugs experiencing low stock, and then re-selling them at massive markups
• government reimbursement policies not allowing for prices to match market demand
• low profit margins causing companies to cease manufacturing older drugs in favor of newer, higher-profit-margin ones
• quality manufacturing problems experienced by many manufacturers of sterile products
• overly aggressive inspections by FDA

In response to these challenges, FDA has taken a number of actions intended to mitigate the effects of drug shortages over the course of the last year. Among them:

• allowing the import of certain unapproved drugs to ease especially dire shortage situations
• asking manufacturers to notify FDA of any impending supply problems or disruptions
• working one-on-one with manufacturers experiencing problems
• approving novel manufacturing agreements for some facilities to allow them to release some products for further processing or quality checks-a significant deviation from the usual quality-by-design parameters of current good manufacturing practices (CGMP)
• expediting the reviews of substitute medications
• formulating a strategic plan on drug shortages, as required by Title X, Section 506D of the Food and Drug Administration Safety and Innovation Act (FDASIA)

In October 2013, FDA released a long-awaited rule intended to require companies to report any drugs that were actively experiencing shortages or that would conceivably encounter shortages in the near future. In other words, any event that could lead to a "meaningful disruption in supply" would need to be reported to FDA.

Reporting Deadlines

Key to the rule was a provision that a manufacturer must-even if they cannot offer warning six months or more in advance of the disruption-give FDA notice within five days of being made aware of the potential disruption. Failure to do so would result in FDA issuing a "public noncompliance letter" to the company.

"In our experience, even if it is not possible for an applicant to notify the Agency before a permanent discontinuance or an interruption in manufacturing occurs, it should generally be possible for the applicant to provide notice within a day or two," FDA wrote.

"[It] should always be possible for the applicant to notify the Agency no later than five days after the permanent discontinuance or interruption occurs, even in the event of a natural disaster or some other catastrophic incident," FDA added. The agency may grant "good cause" exemption to this requirement in certain cases, it said.

GPhA: Not 'Practicable'

But in comments submitted on 3 January 2013 to FDA, the Generic Pharmaceutical Association (GPhA) said that despite FDA's contention, it's not always feasible to report a discontinuance or interruption in manufacturing to FDA within five business days.

"A fixed time period to report should only apply in instances where the discontinuance can be confirmed and should not apply just simply upon recognition of a potential problem," GPhA wrote. The group explained that a five-day time period for reporting might encourage "significant over-reporting" of problems since many manufacturing operations encounter disruptions-most small-on a daily basis.

Conversely, even some seemingly minor problems can later turn into far larger problems upon a full and thorough investigation, GPhA contended.

"[At] the outset of an investigation a manufacturer of a drug may reasonably believe that manufacturing will commence promptly with no meaningful disruption in the supply of its drug in the US," the group wrote. "If the investigation uncovers new facts or takes longer than expected, however, this belief may change. It is possible that the manufacturer, based upon the investigation, will determine that it will not be able to make the product for a much longer time than anticipated (or will cease to manufacture the product)."

The opposite of this is also true, GPhA added, noting that a problem that appears prima facie serious may later turn out to be easily solved.

Reporting all of these problems on a precautionary basis might actually contribute to shortages, the group wrote. This might happen by causing providers to stockpile drugs, for example.

The letter goes on to recommend the statutory language used by legislators in FDASIA: Reporting should be done "as soon as practicable."

This "practicable" standard should be used instead of FDA's 5-day reporting period, GPhA argued, noting its situational flexibility. Failing this, FDA should instead implement a tiered system where companies need to report based on a confirmed, rather than suspected, issue.

The comment period on the rule ended on 4 December 2013.