Drug maker in FDA hot seat, COO steps down

Watchdog groups cry bureaucracy

Mark A. DeSorbo

KENILWORTH, NJ—Officials at schering-Plough Corp. refused to comment on whether the resignation of Raul Cesan, president and chief operating officer, was a result of the company's ongoing failure to comply with the U.S. Food and Drug Administration's (FDA) current good manufacturing practices (cGMPs).

But agency watchdog, Dickison's FDA Webview, citing inside-FDA sources, reports that Cesan's sudden departure is a punishment for “displeasing” the FDA. The Web-based newsletter indicated that Cesan's departure, “although overtly a corporate punishment for fiscal damage on Wall Street, is more fundamentally a penalty for failing to satisfy FDA.”

The FDA has recently handed down some of the stiffest fines in history to pharmaceutical companies that have failed to comply with cGMPs, a critical protocol that aims to keep drugs, surgical supplies, medical devices and even food ingredients free from bacteria and microbial contamination.

Schering-Plough faces hefty FDA fines, lawsuits by investors and delays in government approvals for repeatedly flunking inspections over a three-year period at plants in New Jersey and Puerto Rico. [See “Drug makers beware, FDA on the prowl,” CleanRooms, May 2001, p. 1]

Schering-Plough under watch
The FDA would not comment on Cesan's resignation, but the agency along with Schering-Plough issued reports in late June that indicated the FDA completed inspections of the company's manufacturing facilities in Kenilworth and Union, NJ, and Las Piedras and Manati, Puerto Rico, issuing new findings (Form FDA-483).

The reports outlined continuing and additional deficiencies concerning compliance with cGMPs, namely relating to production process, controls and procedures, some of which have strict contamination control protocols. FDA reports also indicate breaches in cleaning validation and instances of possible contamination to product lots.

“The company is engaged in a major effort to resolve these issues, meet the expectations of the FDA, and put in place the people, systems and equipment to assure sustained compliance,” says Richard J. Kogan, Schering-Plough's chairman and chief executive officer.

According to Schering-Plough, the company spent more than $50 million on new equipment process and system improvements. In addition, the company hired some 500 people to bolster quality control, recruited several senior-level executives and formed a GMP review board, which includes three former FDA officials.

“Our highest priority is—and always has been—the well-being of patients who use our products,” Kogan says. “I am taking full responsibility for resolving these matters in a timely manner and securing FDA's confidence in the quality and reliability of our manufacturing system and control.”

According to FDA Webview, the strategy was devised by Cesan, who resigned on June 27, just five days after the FDA concluded its inspections of Schering-Plough facilities.

“It was Cesan who engineered the inadequate and overly bureaucratic strategy in February of hiring new vice presidents to overhaul Schering's approach to manufacturing and quality problems that FDA had been repeatedly condemning for over three years without meaningful result,” according to FDA Webview.

Schering-Plough spokesperson Denise Foy refused to comment on FDA Webview reports, and referred to a statement made in prior by CEO Kogan, in which he says, “We understand his decision and respect it. We are grateful to Raul for his many contributions to Schering-Plough. His many accomplishments are not overshadowed by the company's current challenges.”

John Scharmann, a consulting editor with FDA Webview, claims that the strategy “also failed to give sufficient attention to an underlying theme in most of the company's complex and diverse GMP problems: staff training.”

In the inspection of Schering-Plough's Manati, Puerto Rico, facility, the FDA determined there was no evidence that the drug maker took any action to ensure the safety and efficacy of Gentocin otic solution (ophthalmic solution) and continued to distribute the product with a label that caused contamination.

And inside sources told FDA Webview that Schering-Plough's escalating problems will “go down as a case study in deficient corporate culture, in which those with the greatest amount of authority to effect meaningful change in regulatory response (e.g., Cesan) do not have sufficient knowledge of the specifics to know in a timely manner which measures are the most likely to succeed with FDA.”

Furthermore, Cesan's departure, according to the FDA Webview represents a failed strategy, which places in question the fate of four new vice presidents, Merck executive Richard Bowles III; former Warner Lambert executive Louise S. Kaufman; Steven C. Chellevold; and vice president for quality Maurice Green, who were hired to help prevent repeated noncompliance with cGMPs.

“While time and the corporate culture may not have allowed them to be fully effective, a reality of the corporate world is that a new COO may want to install a new regime to finally begin impressing FDA,” according to the Web site.

Despite the challenges of meeting FDA demands, Schering-Plough continues to forge on. In a June 28 press release, Kogan reported that research and development expenditures are expected to top $1.4 billion, slightly higher than last year's $1.3 billion budget.

FDA also under fire
And while the FDA may be whipping shoddy drug manufacturers into shape and enforcing cGMPs, the agency is still getting bashed, most recently by the London-based medical journal, The Lancet, which says the agency caters to the pharmaceutical industry.

Moreover, the agency is being asked where compliance falls on the list of priorities of pharmaceutical companies.

Crystal Rice, an FDA spokesperson, says the agency cannot generalize about how drug manufacturers prioritize cGMPs over marketing and research and development, nor does it have any data to indicate what precedence compliance is given by the pharmaceutical industry or if there were frequent problems with cleaning validation.

“We cannot accept the premise that the FDA is having a hard time cracking down on shoddy manufacturing practices. We do, however, acknowledge that additional resources would be welcomed,” Rice says, adding that the lack of FDA inspectors and budgetary constraints needs to be addressed by Congress.

But according to Richard Horton, editor of The Lancet, Congress is part of the FDA's problem.

“The FDA is not only compromised because it receives so much funding from the industry, but because it comes under incredible Congressional pressure to be favorable to the industry,” Horton wrote.

Horton noted the FDA's handling of GlaxoSmithKline Plc's Lotronex, a controversial gastrointestinal drug that led to the deaths of five people.

Approved by the FDA in February 2000, Lotronex was removed from the market nine months later after the deaths of the five patients who were taking it as well as reports of severe side effects. The drug was developed to treat irritable bowel syndrome, but soon after its launch reports of side effects such as ischaemic colitis, a restriction of blood flow to the colon, began to surface.

Now, Horton says, the FDA is negotiating with GlaxoSmithKline on how to reintroduce the drug to the market.

“This story reveals not only dangerous failings in a single drug's approval and review process but also the extent to which the FDA, its Center for Drug Evaluation and Research, (CDER) in particular, has become a servant of the industry,” Horton wrote.

Charges refuted
Horton's characterization of the negotiations occurring between the FDA and GlaxoSmithKline over the potential reintroduction of Lotronex to the market is “completely misrepresentative and is entirely inaccurate,” Rice says.

“The FDA must make a singular organizational decision, taking into consideration the totality of the scientific evidence available,” she says. “The review process for this drug has been no different than that of any other review process. The FDA's safety concerns will have to be adequately addressed before the drug can be reintroduced.”

To Horton, however, it is an “impossible conflict for safety to be overseen by a center that receives funding from the industry to review and approve drugs.”


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