Last year, Virginia Behr, the ombudsman for FDA's Center for Drug Evaluation and Research, dealt with the usual consumer and industry complaints about off-label drug promotion, marketing of unapproved drugs and unethical research conduct. But she also played a greater role mediating scientific disputes between FDA staff.

The ¹ CDER ombudsman's annual report for 2009 cites the most common complaints the office received from industry, law firms, researchers, consumers and health care professionals. It also notes a new development within the agency: more CDER employees are turning to the ombudsman for help in resolving scientific differences of opinion.

"This trend is possibly attributed to greater staff awareness of the ombudsman's role and CDER's policy regarding resolution of differences of opinion," the report stated. "The increased awareness occurred because of presentations to staff during CDER Town Hall meetings and in other forums."

Serving As Mediator and Advisor

Behr said in an interview that procedures to resolve individual differences of scientific or regulatory opinion have been in place for more than a decade. People who disagree with someone else's view first voice their opinion and if the issue affects an application or agency decision they document their concerns to show there is a significant controversy or difference of opinion and the basis for resolution. Disagreements are then taken up the management chain.

As ombudsman, Behr serves as a facilitator, mediator or adviser to those who disagree with an agency position. "I talk with them about what their options are, encouraging discussion and making sure the right people hear their argument," Behr said.

While internal disputes are confidential, in recent years a few have become public. Most notably, disagreements between the Office of New Drugs and the Office of Surveillance and Epidemiology over Avandia's cardiovascular risk were aired at an FDA advisory committee meeting in 2007.

Last month the Senate Finance Committee released a report criticizing GlaxoSmithKline's handling of Avandia safety issues. The report included analyses by Office of Surveillance and Epidemiology staff citing strong evidence the drug increased the risk of heart attacks and heart failure compared to Takeda's Actos (pioglitazone). They also complained that the current TIDE trial comparing the two drugs is "unethical and exploitative" (² Also see "FDA Oversight Of Clinical Trials Could Be Strengthened After Avandia Report" - Pink Sheet, 1 March, 2010.).

Finance Ranking Member Chuck Grassley, R-Iowa, is advocating a solution to safety conundrums that would presumably reduce the number of internal safety disputes that the CDER ombudsman, at least, would have to field. The senator wants FDA to create a whole new center focused on drug safety. Disputes between the two drug centers would then be handled at the commissioner level.

Splitting CDER seems extremely unlikely, especially in the near term, but internal scientific disagreements seem likely to continue. The Pharmaceutical Research and Manufacturers of America, for one, is emphasizing the need for clear lines of authority in comments on a draft guidance describing what post-marketing studies FDA can require.

Patient Complaints Change FDA Policy

The CDER ombudsman post was created in 1995 to handle all complaints that come into the center. The ombudsman makes recommendations to the center director but cannot require action or mandate change. While other FDA centers have their own ombudsmen, at CDER Behr is a one-person shop. In her role she has a unique view of what FDA actions generate the most reaction from the public.

Since the ombudsman's interactions are confidential, the report provides few details about the 764 communications the office fielded last year. However, in at least one instance, consumer complaints appear to have prompted the agency to change its position.

Last year patients with amyotrophic lateral sclerosis, Lou Gehrig's disease, pleaded with FDA to be able to use Insmed's Iplex (mecasermin rinfabate [rDNA origin] injection), which is only approved for the treatment of growth failure in children. The agency initially denied requests from physicians for compassionate use of the drug in ALS patients, saying it was not aware of any data suggesting Iplex was beneficial in treating the fatal neurodegenerative disease.

"A lot of ALS patients were understandably clamoring for FDA to allow them to be able to try the drug," Behr said. She gathered the initial facts and brought the issue to the attention of CDER management, which subsequently brainstormed with others about what the agency could do.

FDA was concerned that compassionate use would deplete the limited supply of the drug, making it virtually impossible to conduct a controlled clinical trial. So it came up with a unique two-tiered approach to provide access. ALS patients could request compassionate use under a single-patient investigational new drug application. Others could participate in an Insmed clinical trial through a lottery system (³ 'The Pink Sheet,' March 18, 2010).

Concerns About Drug Supplies

The ombudsman also received communications from patients taking Vicodin (hydrocodone/acetaminophen) and Percocet (oxycodone/acetaminophen) who were worried that the drugs might be removed from the market after an FDA advisory committee recommended a ban on prescription painkillers that contain a narcotic and acetaminophen.

In July, a joint advisory committee voted to remove acetaminophen from combination prescription products to prevent liver injury (⁴ Also see "Acetaminophen May Get Pulled From Rx Combo Products After Narrow Vote" - Pink Sheet, 6 July, 2009.). CDER is still considering the panel's recommendations.

Many consumers also complained about the limited availability of desiccated natural thyroid, which is not approved by FDA. Consumers said they preferred this thyroid replacement medication over FDA-approved synthetic versions.

Another major complaint in 2009 came from companies attempting to import and sell electronic cigarettes, battery-operated devices that contain cartridges filled with flavoring, nicotine and other chemicals. FDA has detained shipments at the border and in July it issued a warning that lab analyses of samples found they contain carcinogens and toxic chemicals such as diethyl glycol.

The agency has said that thus far electronic cigarettes, which are generally marketed as smoking cessation products, meet the definition of a combination drug-device. Smoking Everywhere Inc., a marketer and importer of the devices based in Sunrise, Fla., filed suit against FDA last year challenging its authority to regulate electronic cigarettes. The case is pending in the U.S. District Court for the District of Colombia.

The agency also continued to receive complaints about the painkiller OxyContin (oxycodone). The report notes that consumers, advocacy groups and health care professionals requested that it be removed from the market because of its potential for abuse. Complaints about OxyContin were also cited in the ombudsman's annual report for 2007 (⁵ Also see "Consumers Complain To FDA About Albuterol Inhalers, Oxycontin Abuse" - Pink Sheet, 23 June, 2008.).

FDA Actions On Unapproved Drugs

Other perennial complaints from industry concern enforcement actions taken against marketed drugs that FDA has not approved. In 2009, the agency sent 13 warning letters to firms that marketed unapproved drugs and took action on four classes of unapproved drugs, including codeine sulfate tablets and narcotics containing morphine sulfate, hydromorphone or oxycodone.

Since FDA launched a new drug safety initiative in 2006 to remove unapproved drugs from the market, it has ordered more than 500 unapproved drugs to be removed from the market, which has impacted 275 firms. Since then 70 products have received FDA approval.

Behr also dealt with a surge of complaints about FDA's new requirement for manufacturers to electronically register their drug establishments and drug listings. Upon first engaging in the manufacture or preparation of drugs, owners and operators must register their establishments and submit listing information for all drugs in commercial distribution.

FDA stopped accepting paper registration and listing as of June 1, 2009. The ombudsman report said many companies, especially small businesses, complained that the 13-step electronic process was too complicated and lengthy.

The report also noted that the agency received fewer complaints about delays in responding to Freedom of Information Act requests. Behr said that may be because the center got rid of some pending requests. In 2009, there was a 12.4 percent reduction in the backlog from the previous year.

- Brenda Sandburg ( ⁶ b.sandburg@elsevier.com )

CDER Ombudsman Referees Increasing Number Of Internal Scientific Disputes

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