The Office of New Drugs' authority over FDA advisory committees creates a bias in industry's favor, Office of Drug Safety Associate Director for Science David Graham said March 21 during a National Press Club "Newsmakers" conference in Washington, D.C.

"The Office of New Drugs picks the members of the committees, and this maximizes the pro-drug bias and regulatory conflicts of interest," Graham said.

The Office of New Drugs "controls the entire advisory committee process," he asserted. "The decision to hold an advisory committee meeting on a drug safety question is primarily that of OND."

If the Office of New Drugs decides to solicit the input of an advisory committee, it also has authority over the conduct of that meeting, Graham said.

The Office of New Drugs "decides which committee will hear each safety issue, as well as what consultants will be involved, what safety data can or cannot be presented, who will or will not present, and what questions will be posed to the committee," he said.

"The same committee weighing in on the safety issue is almost always the same one that originally recommended approval of the drug."

As a result of Office of New Drugs's influence, "the flavor of the committees overall is weighted toward the drug," Graham argued. This produces an attitude toward safety issues that says "there's no problem that we can't fix, and no problem that's bad enough that we should curtail the marketing of a drug," he said.

Graham gained national prominence when he appeared as a "whistleblower" at a Senate Finance Committee hearing on FDA drug safety issues. Graham advocated implementing structural changes at FDA to separate drug safety and new drug review functions - an idea that has garnered the support of several lawmakers, including committee Chairman Charles Grassley (R-Iowa) (¹ Also see "“Independent” Drug Safety Office Is Goal Of Senate Vioxx Investigation" - Pink Sheet, 22 November, 2004., p. 3).

FDA Commissioner-designee Lester Crawford said at his March 17 confirmation hearing that he is willing to discuss creation of a more independent drug safety office, but he asserted that ODS is already acting independently (² Also see "FDA’s Crawford Open To Discussing Independent Drug Safety Office" - Pink Sheet, 21 March, 2005., p. 5).

HHS Secretary Michael Leavitt has maintained that an overhaul of FDA's internal structure should await completion of the Institute of Medicine's review of the agency's drug safety system (³ Also see "Drug Safety Changes Should Await IoM, HHS Secretary Tells Congress" - Pink Sheet, 7 February, 2005., p. 5).

In the meantime, HHS has unveiled plans for a Drug Safety Oversight Board to provide a higher level of drug safety review; the panel will be composed of advisory committee chairman and officials from the Center for Drug Evaluation & Research, among others (⁴ Also see "FDA Drug Safety Oversight Board May Include Advisory Committee Chairs" - Pink Sheet, 7 March, 2005., p. 10).

Graham, however, maintained that the planned makeup of the oversight board suggests it will exhibit the same pro-drug biases that are found among advisory committees and CDER.

Graham had strong criticism for CDER, reiterating his position that the Center is an inappropriate venue for post-approval oversight of drug safety.

Since "OND enables product marketing, while the ODS potentially restrains product marketing," tying together safety oversight with approval authority poses an unavoidable conflict, Graham said.

"These are inherent cross-purposes, and to insist that they be in the same center really is asking for disaster."

Graham pointed to the Centers for Disease Control & Prevention as another federal agency that "has learned this lesson."

The CDC "has restructured its vaccine program in order to free vaccine safety from domination by the group that promotes vaccine use," he noted.

Far from being independent, FDA's drug safety office is currently viewed within CDER as a "consultant" for the Office of New Drugs, Graham argued. "They occupy a position that is subordinate to OND. It's not a position of equality."

That relationship has resulted in the suppression of safety data, he said. "In the past several years, I know of multiple examples in our office where safety information was suppressed, including a number of occasions where information was withheld from advisory committees that were hearing drug safety questions," he declared.

"In each instance, OND ordered the suppression, and in each instance management from ODS supported OND over its own scientists."

In the run-up to the Feb. 16-18 meeting of the Arthritis Drugs and Drug Safety & Risk Management Advisory Committees on COX-2 inhibitor safety, Graham alleged that he had been "ordered" not to present unpublished data; he was later explicitly authorized to present the results (⁵ Also see "Graham Meta-Analysis Ultimately Positive For Celebrex, Bextra" - Pink Sheet, 7 March, 2005., p. 21).

FDA's handling of findings by Office of Drug Safety Medical Officer Andrew Mosholder regarding a link between antidepressants and pediatric suicidality has been a source of controversy as well (⁶ Also see "Antidepressant Fallout Includes Change In FDA Pediatric Study Procedure" - Pink Sheet, 4 October, 2004., p. 12).

Graham criticized the overall emphasis placed on drug safety with CDER, stating that "the common sentiment at the center is the rights of drugs take precedence over the rights of humans."

"New prescription drugs are not kept off the market until proven safe; instead they are presumed to be safe," he said.

CDER's focus on efficacy does not include due sufficient regard for safety issues, Graham asserted. "The center and OND's main considerations are effectiveness....Safety is secondary," he said. "There are rigorous standards for efficacy and very lax standards for safety."

Graham also complained that CDER does not consider the risk-benefit profile of drugs. "Not only does CDER presume that a drug is safe, it also presumes that the benefits exceed the risks," he declared.

"OND has never to my knowledge formally assessed the population benefit of Vioxx , or any other drug for that matter."

"Efficacy is not the same as benefit. The benefit in a population is how many lives are saved by the use of the drug. Efficacy is, does it lower your blood pressure, does it lower your cholesterol."

Graham also was critical of FDA's disclosure policy for advisory committee members. The policy has come under fire after the February advisory committee meeting on COX-2s.

That meeting is indicative of FDA's "lax" rules on financial conflicts of interest and a resulting pro-industry bias, he said, repeating allegations from the Center for Science in the Public Interest that 10 members of the COX-2 panel had ties to industry (⁷ Also see "COX-2 Advisory Cmte. Was Unbiased Crawford Says; Conflict Policy To Stay" - Pink Sheet, 7 March, 2005., p. 17).

"Ten committee members with financial ties to industry were responsible for majority votes in favor of continued marketing of Bextra and Vioxx ," Graham said.

He asserted that the panel's votes in favor of continued marketing of the COX-2s would have been vastly different if not for members with conflicts of interest.

"For Vioxx, the results would have switched from a 17-15 in favor of continued marketing to 14-8 in favor of withdrawing the drug," he said. "For those of you who are statistically inclined toward p-values, that is 0.007. That is highly statistically significant."

"For Bextra, the vote would have switched from 17-13 for continued marketing, to 13-7 against marketing. The p-value of that is 0.001."

"There is a clear association between having a conflict of interest and voting," he said. "If FDA is evidence-based...they should pay attention to that evidence."

Speaking at a generic pharmaceutical industry meeting in late February, Crawford said that only five members of the joint committee had fiduciary or financial ties to the pharmaceutical industry, and that he was confident the panel was unbiased.

During his confirmation hearing, the Acting Commissioner conceded that "there should be easier disclosure" for advisory committee members to improve transparency.

Graham, however, indicated that disclosure is not enough. "It's important to minimize, if not completely do away with, conflicts of interest," he said.

Graham rejected the argument that FDA cannot avoid enlisting advisory committee members who have some sort of conflict of interest, remarking that "you don't necessarily have to have the chairman of the department sit on your advisory committee."

He added that if Congress were to create a separate center for drug safety oversight, it would need its own independent advisory committee structure.

Office Of New Drugs Oversight Of Advisory Committees Creates Bias – Graham

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