FDA Comes Out With Draft Guidance for Drug Shortages

FDA Comes Out With Draft Guidance for Drug Shortages

February 22nd, 2012 // 1:26 pm @

Source: Pharmalot

Last October, the FDA wrote drugmakers to remind them they are required to report any life-savings meds that are discontinued and encourage them to voluntarily report any supply disruptions that could lead to a shortage (read the letter). Now, the agency has issued a draft guidance that instructs drugmakers on the specific procedures for notifying the FDA and what will happen to that information.

At the same time, the agency disclosed plans to relieve shortages of two badly needed cancer meds – Doxil and methotrexate – both of which were made by a Boehringer Ingelheim subsidiary known as Ben Venue Laboratories that recently halted supplies and suspended operations after regulators found serious manufacturing violations (back story here, here and here).

To address the Doxil shortage, the FDA will allow temporary imports of a replacement drug called Lipodox that is made by Sun Pharma, a step the agency says should end the shortage “in the coming weeks.” For methotrexate, the agency approved an application by Hospira to maker of a preservative-free formulation that is expected “to further bolster supply and help avert a shortage.” The FDA says it expedited a review of an application for APP Pharmaceuticals.

The moves are an outgrowth of an executive order that was issued by the White House in response to the growing crisis over prescription drug shortages, and assigned the FDA to broaden reporting of potential shortages; speed reviews of applications to begin or alter production of these drugs; and provide more info to the US Department of Justice about possible collusion or price gouging (back story).

In fact, since the October letter was sent, the FDA maintains that a six-fold increase in voluntary notifications has been received from drugmakers concerning potential shortages. Put another way, since the executive order was issued, the FDA says 114 shortages have been prevented, out of a total of 195 shortages prevented overall last year, according to an agency statement.

Despite such statistics, the problem has grown more concerning. A recent survey of oncologists found that ongoing shortages – most of which are injectables used for treating cancer – are not only preventing patients from receiving timely or the most appropriate treatments, but patients are dying sooner than they would otherwise and tumors are recurring more often (see this).

Meanwhile, the FDA acknowledges that mandatory notification of permanent discontinuances is helpful in preventing or mitigating some drug shortages, but is a limited tactic. In 2010, for instance, only 8 percent of shortages were due to permanent discontinuation. Most shortages were due to problems at manufacturing facilities, delays in manufacturing or shipping, and shortages of active ingredients.

The guidance seeks to improve the odds by refining the definition of a sole manufacturer, which is required to report a discontinuation. The defintion is linked to 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,” the FDA writes.

The guidance also specifies that the application holder is responsible for reporting a discontinuation, even if the actual production is contracted to a third party. This language was added, no doubt, in response to the troubles at Ben Venue, which was conducting extensive contract manufacturing work for other drugmakers – Doxil, for instance, was made for Johnson & Johnson.

What should be reported to the FDA, though? The agency lists the following: a business decision to permanently discontinue manufacture of a drug; a delay in acquiring API or inactive ingredients that leads to, or could lead to, a temporary interruption in manufacturing of a drug while alternative suppliers are located; equipment failure or contamination affecting the quality of a drug that necessitates an interruption in manufacturing while the equipment is repaired or a contamination issue is addressed, and manufacturing shut-downs for maintenance or other routine matters, if the shutdown extends for longer than anticipated or otherwise could disrupt supply of a drug.

What are the exceptions? These would include shutdowns for routine maintenance that would result in re-openings on a planned schedule and power outages in which a drugmaker expects to be able to resume production within a relatively short timeframe. Another example: regularly scheduled production stoppages of a particular drug in a plant used to make more than one med.

As to voluntary reporting, the agency encourages drugmakers to pick up the phone when they find: 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 may adversely affect supply, such as renovations; delays in acquiring critical raw materials or components, or loss of raw material or components; transferring production to an alternate facility; import delays, and loss of a production line or production capacity, among other things.

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