Patients, Investigators Seek Flexibility at FDA

Drug shortages have been front-page news in recent months as physicians, pharmacists, and patients voice outrage over disruptions in the supply of medicines to treat cancer, pain, and other serious conditions. Oncologists can't obtain widely-used generic injectables to treat critical 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.

Jill Wechsler

The Food and Drug Administration (FDA) is responding by exercising flexibility in enforcing manufacturing standards and speeding the approval of alternative products and production lines. Such efforts can help sponsors of cancer and AIDS trials avoid shutdowns due to short supplies of key products used as comparators or in treatment cocktails.

Similarly, FDA officials emphasize flexible approaches for developing and approving innovative therapies to treat rare disorders. Agency critics often cite excessive FDA regulation for driving up the cost of drug development, but FDA officials maintain that they frequently bend the rules to speed new products to market, both to facilitate access to short-supply medicines or to spur research and development of orphan drugs.

Shortages hit research

FDA recorded 178 drug shortages in the United States in 2010, up from 157 in 2009—and much more than the 50 to 60 range of previous years, reported Edward Cox, coordinator of the drug shortage program in the Center for Drug Evaluation and Research (CDER). The main culprit appears to be drug manufacturing and supply chain issues, particularly related to production of generic sterile injectables, Cox explained at an FDA public workshop held in September for health professionals, patient advocates, biomedical researchers, and manufacturers to air concerns and propose remedies for the supply crisis. Industry consolidation, lack of raw materials, changes in distribution practices, and business decisions to discontinue certain products all contribute to the current drug supply crisis. Some observers also blame FDA for being overly strict in enforcing manufacturing standards and for ignoring the potential harm of shortages in calculating risks and benefits of regulatory actions.

One less-noticed aspect of the drug shortage crisis is its impact on clinical trials. Shortages in generic cancer therapies are shutting down oncology studies because investigators cannot obtain adequate supplies of drugs used as controls or in combination for treatment arms. More than 150 trials sponsored by the National Cancer Institute (NCI) are plagued by shortages. Many sponsors have halted patient accrual for fear they might have to switch to a new comparator or treatment components, which could compromise data later on.

Many of the cancer drugs in short supply—including doxorubicin, daunorubicin, 5-FU, paclitaxel, bleomycin, and cytarabine—are essential to treatment and research, explained Howard Koh, Assistant Secretary for Health in the Department of Health and Human Services, at a hearing in September before the House Energy and Commerce Health subcommittee. NCI currently is sponsoring 96 clinical trials that include combination or control arm drug regimens that require a supply of doxorubicin, and even more involve the use of paclitaxel. A shortage of only a few weeks can have "a ripple effect on the availability of new drugs and treatment combinations tomorrow," warned Robert DiPaola, Director of The Cancer Institute of New Jersey.

Shortages also are a major issue for AIDS clinical trials supported by the National Institute of Allergy and Infectious Disease, Koh pointed out. Supply problems involving liposomal doxorubicin (Doxil) made by the Janssen unit of Johnson & Johnson, as well as short supplies of first-line antibiotics to treat life-threatening infections associated with AIDS, are blocking studies that seek to compare different AIDS regimens.

Seeking solutions

Policy makers are reviewing the full range of relevant factors, including whether too-low reimbursement for old-line generics discourages industry investment in this market. Congress also is looking to enact legislation that will prevent shortages by requiring manufacturers to notify FDA six months in advance of anticipated changes in prescription drug production.

Additional remedies may arise from analyses of the shortage crisis from both FDA and the Government Accountability Office.

In some shortage situations, clinical trial sponsors can utilize alternative regimens, even if these are not part of the original protocol. However, such changes often expose patients to more toxic or less effective treatments. New consent forms may be required, and sudden changes in site and therapy discourage patients from participating in research.

The broader solution lies in efforts by manufacturers and FDA to prevent drug shortages through compliance and regulatory actions. Agency officials maintain that they don't halt production for minor violations, but for significant problems with drug sterility and contamination, such as metal particles in vials and new impurities and degradants. In addition, the agency says it can bend the rules to permit continued marketing of a violative product.

By exercising regulatory flexibility, FDA has been able to expedite the review and approval of supplements authorizing new suppliers and manufacturing changes. Advance warning of likely supply interruptions helped FDA head off 38 potential shortages in 2010, and 99 so far this year. And the agency has had success in encouraging other firms to ramp up production or to enter a market.

Encouraging orphans

Regulatory flexibility also is key to FDA approval of new treatments for rare diseases, according to research sponsored by the National Organization for Rare Disorders (NORD). FDA legally requires "substantial evidence" of effectiveness to approve a new drug for market, which traditionally has meant two or more well-controlled clinical trials. But the agency frequently modifies the scope of study data needed to develop an innovative therapy for a serious condition. Many treatments for rare disorders have been approved based on relatively few patients in only one clinical study.

An analysis of 135 non-cancer orphan drugs approved by FDA from 1983 to mid-2010 by Frank Sasinowski, attorney with Hyman, Phelps, & McNamara and NORD Chairman, shows that 90 therapies benefited from more flexible regulatory approaches. At last month's conference on orphan drugs sponsored by NORD and the Drug Information Association, Sasinowski presented his report as evidence that FDA has not become more conservative, but has a strong history of using a variety of strategies to facilitate the approval of critical new drugs.

FDA applauded the analysis, hoping it will help fend off criticism from industry and the investment community that agency regulatory policies are dampening investment in new drug development. CDER Director Janet Woodcock acknowledged that orphan drug development requires flexible regulatory standards, citing previous agency adoption of more moderate rules for producing clinical supplies in small quantities and for reduced toxicity testing for very small early clinical studies. Woodcock noted that FDA has approved many orphans with only one clinical trial and that it plans to update its 1998 guidance on substantial evidence to further clarify this approach. The NORD analysis of the agency's history in dealing with orphan drugs over nearly 30 years, she added, will be "extremely helpful."

FDA also plans to beef up staff to support an expanded rare disease program. The FDA-industry agreement for renewing the Prescription Drug User Fee Act, which is slated for enactment next year, supports an additional five staffers in CDER's Rare Disease Program in the Office of New Drugs, plus a Rare Disease Liaison in the Center for Biologics Evaluation and Research (CBER). These staffers will encourage FDA reviewers to exercise "flexibility and scientific judgment" when evaluating investigational studies and marketing applications for orphan drugs and engage in outreach to industry and patient groups regarding orphan drug development.

The program also will develop and disseminate guidance and policies designed to facilitate development of drugs and biologics for rare diseases. This includes new approaches to studying these therapies, including non-traditional study designs, endpoints, dose selection, patient-reported outcomes, and statistical analysis. There will be future public meetings to discuss the complex clinical trial issues for studying rare diseases and additional training for CDER and CBER reviewers on these challenges. By 2016, FDA will evaluate whether these activities spur submission of more rare disease applications that lead to more approvals.

NORD wants FDA to go further and forcefully articulate its regulatory flexibility posture so that it will be very clear to agency reviewers and other staffers. While some agency offices have utilized unconventional strategies to approve new therapies for rare diseases, this willingness to rely on less extensive clinical data is not uniform across the agency. And many of the drugs that have benefited from regulatory flexibility did so based on a case-specific assessment, and not on broader rules or policies. In pressing FDA to clarify its policy to treat orphans differently, NORD hopes to reduce uncertainty for sponsors, clinical investigators, and financial investors that FDA will support special approaches for orphan drug development. This, hopefully, will spark interest among pharma companies and venture capitalists in tackling more of the thousands of rare diseases that lack any treatment.

Jill Wechsler is the Washington Editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com