Drug Shortages Create Crisis for Manufacturers, Regulators

The outcry from physicians, pharmacists, and patients over disruptions in the supply of vital medicines to treat cancer, pain, and other serious conditions is drawing attention on Capitol Hill and throughout the healthcare system. Oncologists cannot obtain widely-used chemotherapies to treat seriously ill patients. Surgeons are postponing operations because they lack key anesthetics and pain medications. Doctors are struggling to obtain vital parenterals for premature babies and for patients requiring infusion. And dozens of clinical trials have been halted because investigators don't have adequate supplies of cancer drugs used as components of treatment arms or as controls.

Jill Wechsler

While there always have been periodic drug shortages, the problem has become much more acute in the past two years. The main culprit appears to be drug-manufacturing and supply-chain failings, particularly related to the production of generic sterile injectables. Decisions by firms to exit certain low-profit markets often leave only one or two producers for a widely-used parenteral or other product. Some manufacturers have had to halt production due to problems meeting GMPs. Such developments raise charges that too-strict FDA oversight aggravates the problem—or that industry negligence and business practices put the public health at risk. Another possibility is that policies and practices that drive down reimbursement for old-line generics discourages industry investment in certain therapeutic categories.

These issues made headlines in September as Congressional committees held hearings on the drug shortage crisis and broader pharmaceutical supply-chain problems. An FDA public workshop on Sept. 26, 2011, provided a forum for health professionals, patient advocates, drug distributors and manufacturers to air concerns and propose remedies for short drug supplies. The resulting publicity has boosted Congressional interest in legislation to address pharmaceutical supply-chain issues in general, and the drug shortage situation in particular. FDA has prepared a report analyzing steps it can take to tackle shortages with its current limited authority, and the Government Accountability Office (GAO) is examining the causes and responses to the drug-shortage crisis.

GETTING WORSE

Policymakers may take action because, despite extensive FDA efforts, "drug shortages are getting worse," said Douglas Throckmorton, deputy director of FDA's Center for Drug Evaluation and Research (CDER), at the FDA workshop. The agency recorded 178 drug shortages in the US in 2010, up from 157 in 2009—and much more than the 50–60 per-year range of previous years, reported Edward Cox, coordinator of CDER's drug-shortage program. The problem is even more serious when looking at all drugs and biologics: the University of Utah Drug Information Service recorded 210 shortages this year as of mid-September, slated to surpass last year's total 211 short-supply problems. And because supply problems often last more than a year, some 260 active shortages are in the Utah tracking system.

Moreover, 74% of the shortages reported to FDA last year involved sterile injectables—and almost all of them for "medically necessary" drugs, noted Howard Koh, assistant secretary for health in the US Department of Health and Human Services (HHS), at a September hearing before the House Energy and Commerce Health subcommittee.

Shortages in parenterals have taken a toll on hospitals and clinics: a survey by the American Hospital Association in June 2011, found that virtually all hospitals have experienced at least one drug shortage this year, and half report 21 or more supply problems. This builds on a March survey by the Premiere Healthcare Alliance that documented soaring shortages along with exorbitant prices for these products (see the June 2011 Washington Report column, "Safety Concerns and Shortages Challenge Manufacturers").

Koh cited a long list of underlying factors driving the short-supply trend: industry consolidation, limited raw materials, changes to inventory and distribution practices, production delays, increases in demand, and business decisions to close down a manufacturing site. When there are only one or two sources for a crucial drug, explained pharmacist Richard Paoletti of Lancaster (Pennsylvania) General Health, a small shift in production lines, plus just-in-time inventory controls at hospitals, make it hard to buffer the impact.

INFORMATION PLEASE

One response is for manufacturers to inform FDA in advance of supply problems. The agency reports that early warnings helped it head off 38 potential shortages in 2010 and 99 so far this year. When FDA knows of a looming supply interruption, its staff can expedite the review and approval of supplements for new suppliers, alternative production sites and changes in specifications—actions responsible for most (84) shortage preventions this year. Sometimes, FDA can bend the rules to permit continued marketing of a violative product with some corrective action. And the agency has had some success in encouraging other firms to ramp up production or to enter a market through speedy regulatory actions.

FDA also has approved temporary importation of unapproved sources to fill supply gaps, a strategy that helped alleviate shortages this year in several cancer drugs. APP Pharmaceuticals worked with FDA to reduce a shortage of the widely used anesthetic propofol by importing the product from Germany.

Unfortunately, FDA often lacks information on looming shortages because, under current law, only sole-source manufacturers of critical medicines have to notify FDA of plans to discontinue production. Some companies voluntarily inform FDA of problems likely to lead to short supplies, but most do not, and often the information comes in too late for timely resolution.

To remedy this limitation, Congress is looking to enact legislation that would require six-months advance notification of production changes for a broad range of prescription drugs. Rep. Diana DeGette (D-CO) has bipartisan support for legislation in the House, and Sens. Amy Klobuchar (D-MN), and Robert Casey (D-PA) lead the early-notification campaign in the Senate. They propose leeway for manufacturers who show that a manufacturing problem could not be anticipated, as well as penalties for failure to comply. A related proposal requires manufacturers to inform FDA of situations that make a product vulnerable to shortages, such as a single API source, to highlight the need for back-up emergency sources.

Although advance notification may help FDA head off some shortages, the danger is that wider release of such information could lead to hoarding and price gouging. Gray-market profiteers are inundating health professionals with faxes and phone calls offering scarce drugs at huge markups. Rep. Elijah Cummings of Maryland, top Democrat on the House Oversight and Government Reform Committee, launched an investigation of secondary distributors last month, seeking information on sources and profits for certain drugs. His targets include high-priced offers of leukemia treatment cytarabine by Allied Medical Supply (Florida); Superior Medical Supply (Colorado) offers for paclitaxel; Premium Health Services (Maryland) sales of leucovorin; fluorouracil offers from PRN Pharmaceuticals (Maryland); and Reliance Wholesale (Florida) marketing of magnesium sulfate.

To avoid profiteering, FDA wants to be informed by manufacturers of possible shortage situations, but doesn't necessarily want to make that information public right away, noted Sandra Kweder, deputy director of CDER's Office of New Drugs at the House hearing. The agency first wants to assess if the problem is real, its likely impact, and what actions can be taken to mitigate difficulties. "Early notification to FDA is a very useful tool," said Kweder, "but it's different from early publication."

Advance notification is not always possible. FDA officials concede that many manufacturing problems cannot be anticipated (e.g., equipment breakdowns and plant fires, and earthquakes, volcanoes, and other natural disasters)can suddenly disrupt supplies and material transport.

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 shutdown.

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.

BALANCE NEEDED

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 drug shortages.

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, jwechsler@advanstar.com.