FDA Waves a Big Stick

The US Food and Drug Administration is stepping up oversight and enforcement activity for medical products by advising industry to tighten its data integrity and quality-control measures to ensure compliance. A series of food-contamination crises (e.g., melamine in infant formula and salmonella in nut products) have raised charges of lax oversight of food quality and safety, and public polls indicate continued low confidence in the agency's ability to protect consumers from unsafe foods and drug products.

Jill Wechsler

FDA's new leadership wants to turn that around. Principal Deputy Commissioner Joshua Sharfstein, who was FDA's acting commissioner pending confirmation of Margaret Hamburg for the top spot, took highly visible enforcement actions to illustrate that a new sheriff is in town. Soon after coming to FDA at the end of March, Sharfstein initiated a fast and aggressive recall of pistachio products as soon as evidence of salmonella contamination appeared. He also responded to criticism of FDA's process for regulating medical devices by supporting a review of safety information required for device classes.

The global swine influenza outbreak provided another opportunity for Sharfstein to take a proactive approach. He authorized emergency access to antiviral drugs and diagnostics and established teams under Jesse Goodman, newly named deputy commissioner for scientific and medical programs and acting chief medical officer, to facilitate the development of new vaccines, antivirals, diagnostics, and other products needed in a pandemic (see sidebar, "Science & Swine Flu").

Science & Swine Flu

Last month, FDA approved sanofi-pasteur's new Swiftwater, Pennsylvania, flu vaccine manufacturing facility, which can produce a new swine-flu vaccine if needed. In addition, a swine-flu consumer-protection team threatened fines and criminal action against anyone marketing products that make unapproved claims about guarding against or curing swine flu and seeking to take advantage of public fears about the virus.

Another new face at FDA reflects the agency's newly aggressive regulatory and legislative approach. David Dorsey, former top aide to Sen. Edward Kennedy (D-MA) on the Senate Health, Education, Labor, and Pensions (HELP) Committee, was named senior counsel to Sharfstein. Dorsey was a lead negotiator on legislation authorizing user fees, pediatric studies, and the Food and Drug Administration Amendments Act (FDAAA) of 2007. He also worked closely with Kennedy on proposals for authorizing biosimilars and for regulating dietary supplements.

"Enforcement will increase," warned Deborah Autor, director of the Office of Compliance in FDA's Center for Drug Evaluation and Research (CDER), at the April annual meeting of the Food and Drug Law Institute (FDLI). She pointed to a rise in injunctions, investigator disqualifications, and Warning Letters and advised companies to avoid the big stick by "being proactive about compliance."

Attorney Jim O'Reilly predicted a visible shift from the "kinder, gentler" approach of the Bush administration to active monitoring of violative operations. Former FDA counsel Bob Spiller complained that "FDA civil enforcement was cuffed and curbed and starved over many years;" now he anticipates big changes with more resources available for enforcement efforts.

One sign of the times is an expansion in Autor's compliance office to 250 staffers from 150 five years ago. The growth increases FDA's ability to take regulatory action. CDER issued almost 40 Warning Letters between Jan. 1 and Apr. 14 of this year, nearly half of the 87 sent out in all of 2008. CDER's Division of Drug Marketing, Advertising, and Communications also sent notice-of-violation letters to 14 drug companies in early April charging that sponsored links on Internet search engines such as Google provide information about drug benefits without fully disclosing risks. Marketers objected that FDA was ignoring the communications capabilities of Internet technology, but consumer advocates supported the move as a way to ensure comparable disclosure of information on risks along with benefits.

Action on the Hill

Congressional leaders indicate high interest in bolstering FDA leadership and authority. The Senate HELP Committee and then the full Senate moved quickly last month to confirm Hamburg as FDA commissioner, stressing the need for a strong agency to deal with the swine-flu outbreak, as well as food and drug-safety issues.

Kennedy and Sen. Charles Grassley (R-IA) also reintroduced legislation authorizing added FDA user fees to support more inspections of drug and medical product manufacturers. The measure would give the agency authority to issue subpoenas and to detain suspect products. Domestic and foreign manufacturers, including producers of active pharmaceutical ingredients (APIs), would have to register with FDA.

The measure is similar to the drug section of legislation backed by Rep. John Dingell (D-MI), which, at press time, was pending before the House Energy and Commerce Committee. That committee's chairman, Henry Waxman (D-CA), has indicated interest in enacting only the food-safety portion of the bill, but even that would grant FDA subpoena authority for all regulated products.

Building on FDAAA

These legislative proposals would enhance the added enforcement powers under FDAAA, which boosted fines and criminal penalties for violative activity. FDA gained a "huge new arsenal" of enforcement tools under the act, noted attorney Marc Sheineson at the FDLI conference.

To date, FDA has not brought a case under these new authorities, added Autor, "but when we need to use it, we will." She pointed to the agency's speedy action to halt production of drugs by KV Pharmaceuticals (St. Louis, MO), which resulted in a recall of 175 products and blocked shipment of thousands of lots. Autor also emphasized that FDA is taking data integrity seriously, citing recent FDA action to invoke its Application Integrity Policy against Indian manufacturer Ranbaxy's Paonta Sahib facility.

Autor discussed FDA's campaign to remove unapproved drugs from the market as well. With action taken against 12 classes of drugs, numerous consent decrees and injunctions issued, and $24 million in drugs seized from one company, the campaign has affected more than 200 manufacturers and 500 products.

The latest crackdown came in March when FDA cited nine companies for marketing 14 unapproved narcotic therapies. The message to manufacturers, said Autor, is that important drugs must have FDA approval. "We still see industry as somewhat complacent" about this, she says, promising more aggressive action to show that the agency means business.

Stress on safety

In addition to waving a big stick, FDA is taking steps to enhance the safety of prescription drugs during development and following market approval. The agency's Safety First program aims to update agency operations to improve its ability to identify and track drug safety issues, explained Gerald Dal Pan, director of CDER's Office of Surveillance and Epidemiology (OSE), at the FDLI conference. This includes giving OSE an "equal voice" in evaluating and overseeing new drugs and expanding OSE operations. The office's staff increased from about 120 to 170 during the past year and may top 200 by the end of 2009.

A related but more externally oriented Safe Use initiative seeks to prevent misuse, abuse, and inappropriate use of drugs by patients and health professionals. OSE is implementing several key FDAAA programs, including the review of Risk Evaluation and Mitigation Strategies (REMS) in drug applications and efficacy supplements, which require additional postmarket studies and the negotiation of safety labeling changes.

FDA is upgrading its adverse event reporting system to gain more reports from health professionals and to improve its internal capacity for assessing such information. The upgrade involves establishing an FDA Adverse Event Reporting System to hold and analyze adverse-event data. The system will first test safety reports involving food, veterinary drugs, and pet food and then expand to include medical products.

OSE also is implementing a new drug proprietary-name review program with the aim of shifting this task to manufacturers during the next few years. A pilot program scheduled to launch this fall will weigh whether FDA can review name proposals within set timeframes. FDA has issued draft guidance on how to submit a name evaluation and is developing further guidance on best practices for naming, labeling, and packaging of drugs and biologics to reduce medication errors.

Global challenges

Legislative efforts and FDA initiatives reflect the effect of global drug manu-facturing on ensuring product safety and quality. Such "supply-chain fragmentation and geographic dispersion of drug manufacturing add new risks," said CDER Director Janet Woodcock at the FDLI meeting. Foreign drug-manufacturing sites now outnumber registered domestic facilities (an estimated 3700 overseas and 2500 in the US, according to 2008 figures), and the volume of drug products made overseas continues to rise. Registered drug manufacturers in India increased 25-fold from 2001 to 2007, and China has experienced a 7-fold increase during the same period.

Woodcock described many drug products as "world travelers," with the API made here, vials there, and labeling elsewhere. Autor advised manufacturers to look for red flags indicating problems such as the widespread swine flu and the heparin contamination crisis. These crises provide an "open invitation to dishonest activity," she said, emphasizing the importance of corporate responsibility to protect against product contamination and unethical behavior.

Adulteration. More cases of apparently intentional contamination of imported food and drug products involving melamine and heparin, respectively, have prompted FDA to focus on the factors behind incidents involving dilution or substitution of ingredients in food and drugs primarily to increase profits. At a public meeting last month, agency officials heard from manufacturers and other interested parties about ways to predict, prevent, and address economically motivated adulteration (EMA). Attendees discussed which types of products are most vulnerable, how manufacturers track and verify product components and ingredients, where supply chains are open to abuse, and what analytical methods can best detect contamination.

Randall Lutter, FDA deputy commissioner for policy, defined EMA as the "fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e., for economic gain." This action may involve diluting or watering down drugs, possibly by increasing the inactive ingredient in a product.

FDA noted that dramatic shifts in product supply, perhaps from the entry of additional companies or a shift of production to new regions could signal fraudulent activity. EMA may involve expensive biologics that are relatively easy to engineer, or less costly medicines that are widely used. Although Lutter wants manufacturers to report any signs of fraud or product adulteration, he noted that confidential information that might be useful to the adulterers should not be revealed.

At the public meeting, academic experts described models for detecting shifts in supply chains that can signal fraudulent activity. Roger Williams, CEO of the US Pharmacopeia (USP), urged broader FDA and industry support of efforts to update USP monographs that set drug quality standards. USP was in the process of revising its heparin monograph when the contamination crisis happened, he explained, noting that "that revision came too late."

Supply-chain validation. Manufacturers voiced support for wider use of accredited third-party inspectors to audit foreign producers of active and inactive ingredients, as well as required registration of all ingredient producers and stiffer penalties for drug counterfeiting and adulteration. Martin Van Trieste, vice-president for quality at Amgen and member of the Pharmaceutical Research and Manufacturers of America (PhRMA) Quality Technical Group, backed the development of a proposed Qualified Trusted Importer Program, a voluntary certification program for qualified and compliant importers.

Van Trieste also described industry efforts to form the Rx–360 consortium, which aims to develop best practices for supply-chain management and new approaches to supplier auditing and adulteration detection. The group is holding a launch meeting in Washington, DC, on June 5, to discuss audit models and methods for monitoring suspicious events. Such efforts, he noted, would benefit from assurance that manufacturers can share information on suppliers and other issues without running afoul of antitrust laws.

Criminal elements have entered into the drug supply chain, warned Van Trieste, and it's only a question of when and where EMA will occur again. The short supply of antivirals during a pandemic influenza outbreak, he said, provides the "perfect opportunity for someone to come in and make a quick buck." Industry and FDA, he said, need to think like the criminals to detect adulterated products.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com