ADDRESSING PRODUCTION PROBLEMS
Manufacturers now support stronger early notification requirements, largely to reduce complaints about industry responsibility
for most shortages. FDA reports that most supply problems arise from GMP and product quality failings, along with difficulties
obtaining active ingredients or problems at a manufacturing site. Industry consolidation has reduced the number of generic-drug
firms making sterile injectables, Cox observed at the FDA workshop, and it takes time for another manufacture to establish
a facility to produce these more complex and costly medicines.
Reliance on contract manufacturers also has led to shortages for both brand and generic drugs. Johnson & Johnson faces serious
supply problems for cancer and AIDS treatment Doxil (liposomal doxorubicin) because its contract producer, Boehringer Ingelheim's
Ben Venue Laboratories, decided to exit the CMO business.
The strong link between manufacturing issues and shortages raises questions about pharma's commitment to quality production.
FDA wants manufacturers to prevent shortages by developing continuity of supply plans, with backup suppliers and alternative
production strategies for critical products. Industry has a responsibility, FDA officials assert, to proactively identify
and promptly resolve manufacturing problems and to implement quality-by-design strategies to prevent failures.
An alternative view is that FDA creates shortages through overly aggressive enforcement of manufacturing rules. Agency officials
maintain that they don't halt production for minor violations, but only for significant problems with drug sterility and contamination.
Before requesting a drug recall or seizure, they check to make sure such action won't precipitate a shortage. But strong action
is needed when inspectors find glass and metal particles in vials and new impurities and degradants. In some cases, companies
have been cited multiple times for violations and still fail to correct manufacturing deficiencies until threatened with total
FDA officials also emphasize that they can act fast to help bring online a new producer or new supplier when needed. "We
can turn things around in a matter of weeks," Kweder insisted at the House hearing, in response to manufacturer claims that
FDA requires two-to-three years to approve a new manufacturing site. "This is not business as usual," she stated.
But stakeholders feel there is more that FDA and other government agencies can do to prevent critical shortages. FDA should
revise how it calculates risks and benefits from regulatory action to give greater weight to patient safety issues that arise
with shortages. The federal government should establish stockpiles for medically necessary drugs, as done for treatments against
bioterrorist attacks and pandemics. And antitrust officials should scrutinize proposed pharma company mergers to assess how
the combination would affect limited drug supplies.
At the same time, there's interest in providing more incentives for manufacturers to enter depleted markets. Tax credits or
rebates could spur manufacturers to update facilities or launch production of low-profit drugs. Some kind of exclusivity could
be offered for new production of a drug in short supply. Or, generic-drug makers might be eligible for reduced user fees on
applications to produce hard-to-obtain medicines.
Shortages in controlled substances, such as long-acting painkillers and drugs to treat children with attention deficit hyperactivity
disorder, are generating calls for the Drug Enforcement Agency (DEA) to work more closely with FDA and industry to modify
limits on active ingredients. Manufacturers receive DEA annual quotas on controlled drug substances, but would like a way
to transfer allotments when one company ceases production.
There's also support for more resources for FDA to deal effectively with shortages. FDA formed the drug-shortage program in
1999 to manage anticipated supply disruptions from the Y2K shift to the new millennium. But with only five staffers and limited
legal authority, FDA is hamstrung in preventing supply disruptions.
Parallel to the shortage crisis, FDA has been campaigning for more authority to control counterfeiters and manage an increasingly
global pharma supply chain. A number of bills before Congress would empower FDA to deal more forcefully with illegal imports
and to address drug manufacturing problems. The challenge is to ensure that efforts to strengthen FDA clout does not aggravate
At a hearing Sept. 14, before the Senate Health, Education, Labor, and Pensions (HELP) Committee, Deborah Autor, recently
named FDA deputy commissioner for global regulatory operations and policy, presented a long list of desired policy changes
to promote drug safety and level the playing field between domestic and foreign manufacturers. Autor wants mandatory recall
authority for drugs, power to detain and destroy violative imports at the border, and much stiffer penalties for noncompliance.
Drug manufacturers and importers would have to register and list manufacturing facilities using identifier numbers, and importers
would have to demonstrate that they meet quality standards, instead of FDA proving that they do not. Autor also seeks more
authority to enforce track-and-trace standards, which would help hospitals and physicians know whether drugs from unknown
or unusual sources are legitimate.
Industry supports many of these changes, but is wary that continued shortages will spur calls for even greater government
intervention in the market. The danger is that added rules could make low-profit drug markets less attractive to manufacturers.
Yet, patients are waiting: Short supplies of drugs to treat children with leukemia in the US is "shameful," lamented oncologist
Len Lichtenfield at the FDA workshop. "Maybe we need more government intervention."
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, firstname.lastname@example.org