GMP Compliance Becomes Prominent Enforcement Issue

Most high-profile legal cases involving pharmaceutical companies in recent years have targeted off-label marketing and related pricing and promotional activities. Now federal law enforcement officials and food and drug lawyers anticipate a rise in legal actions involving lax adherence to cGMPs that result in adulterated products. With manufacturing problems recently linked to disruptive drug shortages and deaths associated with contaminated compounded injectables, drug quality issues have moved on to the legal and enforcement radar screen.

Biopharmaceutical companies will continue to face violative marketing cases and multimillion-dollar fines brought by whistleblowers and raised by FDA enforcers. In an end-of-the-year flurry of settlements in December 2012, Pfizer agreed to pay nearly $100 million to resolve federal and state charges for illegal off-label marketing. Amgen paid $762 million to settle criminal and civil charges related to violative marketing of several leading therapies, and Sanofi agreed to pay $109 million to resolve kickback charges related to an injectable treatment. These payments, however, are paltry compared to earlier billion-dollar settlements by several prominent pharmaceutical manufacturers, with GlaxoSmithKline's $3 billion fine in July 2012 topping the list. Federal and state prosecutors and attorneys expect violative marketing cases to continue, but there may be a slow-down as lawyers and litigators digest the impact of the US vs. Caronia ruling on Dec. 2, 2012. That case has raised questions about FDA's authority to limit a marketer's ability to discuss off-label claims that are not false or misleading.

For all these reasons, enforcement officials are looking to bring more cases against manufacturers for failing to comply with GMPs and quality standards. There are more whistleblowers going to qui tam lawyers with evidence of violations related to GMPs for drugs and biologics, observed former Department of Justice (DOJ) official Eugene Thirolf at the December 2012 enforcement conference sponsored by the Food and Drug Law Institute (FDLI). Michael Blume, director of DOJ's consumer protection branch, reported that he and others are looking to assess the impact of GMP issues on consumers, while weighing the effect of litigating manufacturing compliance issues on drug production. His colleague, Jill Furman, explained that in selecting cases, DOJ asks how bad was the misconduct, if management condoned the misconduct, and if the alleged activity affects the integrity of the drug regulatory process.

Resources to carry out a case are an important consideration, Furman observed, but "resources are never the issue in taking on a drug company." Blume said he doesn't expect settlement payments in GMP cases to be as large as those from off-label marketing suits, yet manufacturing issues raise the possibility of charges against individual corporate executives, including penalties that exclude an individual from doing business with the government.

NEW AUTHORITIES

FDA enforcement action may gain from additional tools for monitoring manufacturing activities. The FDA Safety and Innovation Act (FDASIA) is "changing the enforcement landscape," said Douglas Stearn, deputy director for policy and analysis in the Office of Compliance of the Center for Drug Evaluation and Research (CDER) at the FDLI December conference. A key FDASIA provision (section 711) specifies that manufacturers must comply with cGMPs, including quality controls and assurance of raw material safety, to avoid product adulteration.

Added FDASIA provisions for dealing with drug shortages and other manufacturing issues are "a big deal for all of us," added Mary Malarkey, director of the Office of Compliance and Biologics Quality in the Center for Biologics Evaluation and Research (CBER), during the FDLI conference. Recent CBER cases have led to criminal charges against manufacturers of unapproved and adulterated HIV test kits and actions to halt production and sales of misbranded stem-cell products that provided little benefit to desperate patients.

FDASIA also requires manufactures to report to the agency if a drug is stolen or counterfeited and imposes stiffer penalties and jail terms for intentional drug adulteration or counterfeiting. And on the international front, the legislation authorizes FDA inspectors to access records at foreign plants prior to an inspection. Drug quality should be a corporate commitment and taken seriously by upper management, Stearn said, adding that FDA wants "companies to address these issues early."

The need for adequate controls to ensure quality production "is not a new concept," commented attorney Cathy Burgess of Alston and Bird, at the FDLI conference. Yet compliance with GMPs remains "the bane of every company's existence," she said, noting that drug shortages have been triggered by quality problems and that manufacturers often can't determine the root causes of stability failures. Under FDASIA, moreover, ensuring control of suppliers of raw materials is of particular importance.

Hospira's recent history was discussed at the FDLI conference to relate the challenges for a company under pressure to make dramatic changes in GMP compliance to address widespread quality failures at several production sites. Quintiles senior director Mike Leavitt, working as a consultant to Hospira, described how multiple warning letters and failed inspections have prompted a major remediation initiative at Hospira's North Carolina production plant under an approach somewhat like a "self-imposed consent decree." Yet despite new corporate management and an in-house quality team under recently appointed Senior Vice-President Zena Kaufman, Hospira continues to face compliance issues. It received a warning letter in August 2012 for problems at a medical device plant located in Costa Rica, and visible particulate matter in Carboplatin injection prompted a recall of three lots in November 2012. A formal consent decree is expected, despite outlays on remediation of nearly $250 million, with another $100 million in spending expected.

INTERNATIONAL COOPERATION

The visible rise in outsourcing of drug manufacturing and in foreign facilities supplying the US market is prompting FDA compliance officials to focus more on international and supply-chain issues. The agency is conducting more inspections of foreign producers that will increase with added resources from the Generic Drug User Fee Act (GDUFA), Stearn noted. He cited more warning letters involving cGMP issues at foreign facilities, many listing failures to maintain required reports and records and to establish appropriate production and process controls. FDA urges foreign manufacturers to create independent quality units and to do more to meet GMP standards.

FDA officials, however, realize they will never have enough resources to monitor all the manufacturers and suppliers to the US market and thus are looking to more collaborative enforcement efforts to extend their global oversight of manufacturing compliance. FDA, the European Medicines Agency (EMA), and other regulatory authorities are continuing a program to share information on inspections of API makers and have launched a project for exchanging reports to reduce overlapping inspections for finished drug products. A mutual reliance pilot with EMA and an initiative to share bioequivalence data are in the works, as are projects to establish a common regulatory database with China and a roadmap for global medical product quality and supply-chain integrity with other Asian nations.

These efforts will help FDA better target its inspection and compliance resources, while obtaining information needed to bring enforcement actions. FDA officials say that they much prefer that manufacturers comply with quality standards and meet reporting requirements without the threat of penalties, but they welcome the added tools to help compel compliance when necessary.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com Read Jill's blogs at PharmTech.com/wechsler.