Drug makers would have to inform FDA about business decisions that could result in drug shortages, under legislation introduced Feb. 7 by Sens. Amy Klobuchar, D-Minn., and Robert Casey, D-Pa.

Such decisions, which are those "that may affect the manufacture of the drug," would include actions such as mergers and a change in production output.

The goal of the bill (S. 296) is to warn FDA about possible drug unavailability so it can take mitigating actions and give health care providers advance notice.

For pharmaceutical companies, it would expand the situations they must report to FDA, open them up to civil penalties for failing to do so, and create the possibility of FDA collaboration on continuity of operations plans for medically necessary drugs vulnerable to shortages.

Currently, only the discontinuation of a sole-source product that is life-supporting or life-sustaining, or used to prevent a debilitating condition, is subject to a six-month pre-notification requirement.

S. 296 would require drug makers to give FDA notice not only about discontinuations, but also about interruptions and adjustments in the manufacturing process, and the requirement would apply to prescription drugs in general.

What Is A Drug Shortage?

S. 296 would define drug shortage as "a period of time when the total supply of all versions of a drug available at the user level will not meet the current demand for the drug at the user level."

The six-month pre-notification requirement would be retained for a discontinuation or planned interruption or adjustment of a drug's manufacture. But for other interruptions or adjustments, reporting would be necessary "as soon as practicable," a term that is not defined by the bill.

Affected adjustments are those related to the supply of raw materials, including active pharmaceutical ingredients, production capabilities, business decisions, and other adjustments determined to be appropriate by FDA.

Defining the schedule of civil monetary penalties for violating the notification requirements is left up to the agency, which is given 180 days to do so.

Business Confidentiality An Issue

Expanded notification is worth considering, Gordon Johnston, Vice President of Regulatory Science for the Generic Pharmaceutical Association, said in an interview.

But for industry, he noted, key issues are how FDA handles the information it receives and what is the trigger for FDA to contact other suppliers as the agency seeks to address drug shortages.

A system to mitigate the effects of shortages must "accomplish the goals but still maintain business confidentiality," he stressed. GPhA has not completed its evaluation of S. 296 and its impact on industry operations.

FDA To Identify Vulnerable Drugs

In addition to expanding the information sent to FDA so it can respond to potential shortages, S. 296 would require the agency to be proactive in flagging drugs that could be vulnerable to shortages.

FDA would have to establish "evidence-based" criteria to identify drugs that could become unavailable.

Criteria To Identify Vulnerability

To determine whether a drug is vulnerable to shortages, FDA would have to establish criteria based on:

Number of manufacturers
Sources of raw material or API
Supply chain characteristics, such as production complexities
Availability of therapeutic alternatives

Once a drug has been identified as vulnerable, FDA would be directed to collaborate with the manufacturer "to establish and improve continuity of operations plans with respect to medically necessary drugs," so they have a process to address drug shortages. FDA would define "medically necessary."

Health Care Providers Seek Advance Notice

The bill stems from concerns raised by pharmacist and physician groups that must deal with the fallout when their supplies run low.

The American Society of Health-System Pharmacists, the American Society of Anesthesiologists, the American Society of Clinical Oncology and the Institute for Safe Medication Practices convened a drug shortage summit last fall to garner input from FDA, industry and the health care community on how to deal with the issue.

They provided Klobuchar with several options that made their way into the bill, including expansion of the notification requirement to all drugs.

There may be cases in which a shortage of a non-medically necessary drug could present a problem, Joseph Hill, ASHP director of federal legislative affairs, explained to "The Pink Sheet."

If the drug is an alternative therapy for a drug in short supply, the increased demand could create a cascading shortage effect, he suggested.

The need to move beyond informing FDA only about discontinuations was stressed by Hill.

"We would like to see manufacturers notify FDA as quickly as possible about any issue relating to supply of raw materials, manufacturing problems, business decisions, etc. that impact the ability of the manufacturer to produce the product. The idea here is that FDA could then make contingency plans to deal with the shortage," he said.

The importance of providing notifications beyond discontinuations also was noted by FDA during a December stakeholder meeting on reauthorization of the Prescription Drug User Fee Act.

As an example of how this can help, the agency reported that for the year 2010 through mid-December, 28 product shortages were averted because advance notification allowed the agency to take mitigating actions. As of Dec. 15, the agency said, there had been 178 shortages for the year, compared to 157 in all of 2009.

Drug shortages are taking on a political dimension outside the legislation as well; the agency has been pressed to intervene on supply issues related to drugs for lethal injection (see Also see "Imports Of Lethal Injection Drug A Law Enforcement Issue, FDA Says" - Pink Sheet, 14 February, 2011.).

Causes Of Drug Shortages

The reasons for drug shortages are many and occur in different parts of the health care system, according to an FDA presentation at a recent PDUFA V stakeholder meeting:

Manufacturing difficulties/compliance issues
Corporate decisions/discontinuations
Market concentration/limited capacity
Raw material/API shortage
Changes in clinical practice
Emergency situations
Hospital/pharmacy-based issues

Incentives To Promote Production

Participants in the drug shortage summit, whose recommendations were released Jan. 10, identified several steps to help make the drugs' continued production economically viable.

Incentives, such as tax credits, could be used to encourage manufacturers to produce critical drugs, they suggested. This approach could also be taken to allow the upgrade of manufacturing plants to meet or exceed good manufacturing practices, in exchange for guaranteed production of the therapies.

FDA's Unapproved Drugs Initiative was cited as the culprit for several shortages – including concentrated morphine sulfate solution and levothyroxine injection.

The cost and complexity of filling out a New Drug Application for unapproved drugs can deter firms from keeping their products on the market, according to the drug shortage summit summary report.

For unapproved drugs deemed to be critical therapies, participants recommended an expedited approval pathway, reduction or elimination of the NDA user fee, and possibly incentives to encourage companies to pursue approval.

The backlog of Abbreviated New Drug Applications also is cited as a contributing factor in shortages. The group suggested that for drugs in short supply, FDA expedite its review process for ANDAs and for supplemental applications covering a new source for active pharmaceutical ingredients or a new manufacturer.

Other recommendations include:

Establish improved processes to extend product stability for products in short supply
Require manufacturing redundancies, such as multiple manufacturing sites for sole source products
Evaluate processes for new product specifications
Define criteria for identifying critical drug therapies that are vulnerable to drug shortages

The recommendations are viewed by summit participants as potential solutions worth exploring and four working groups are being formed to do just. The groups will assess which ones can be implemented based on each option's feasibility, impact and the resources needed to put it into effect, as well as legal requirements and the potential for unintended consequences.

The working groups will prioritize and develop detailed action plans for the recommendations selected for implementation.

By Cathy Dombrowski

Drug Shortages Bill In Senate Would Increase Manufacturing Disclosures To FDA

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