Forbes: Judgment Day for the FDA, Pfizer

Wed, 9 Feb 2005

On Feb. 16-18 COX-2 Inhibitor Safety Issues will be the focus of an FDA Advisory Committee and (simultaneously) the European Medicines Agency (EMA).

The entire drug industry will be watching with bated breath. Which causal explanation will be offered for the demonstrable increased heart attacks linked to these drugs? Two possible explanations–increased blood pressure or increase blood clots?

Forbes notes that if the FDA advisory committee and its ultimate recommendations are to have any credibility the committee must not only be perceived as unbiased–it must include scientists who recognized Vioxx safety issues early on–and were critical of the FDA’s handling of the matter.

” It is the presence of such critics that will make the panel’s judgments stick in the minds of the skeptical. It’s not as if it will be hard to find them. Cox-2 skeptics such as Wayne Ray of Vanderbilt University, Steven Nissen of the Cleveland Clinic and Curt Furberg of Wake Forest University have served honorably on FDA panels in the past, as have drug safety experts such as Vanderbilt’s Alastair Wood, who was at one time mentioned as a potential FDA head.”

Last month, Thomas Longren, the director-general of the European Union’s Medicines Agency (representing 25 member states) called for a “radical shake-up” in drug safety monitoring:

“The detection of dangerous side-effects long after drugs have been introduced has led to renewed discussion about the need for greater efforts by regulators to identify problems with medicines once they have been authorised.”

“We have to find alternative methods to detect the safety of medicines.”

FDA’s failure in recent years to take action to protect the public from widely marketed harmful drugs –even when signs of danger have been detected in post-marketing adverse event reports–has led to an erosion of public trust.

FDA’s inaction when signals were detected, resulted in preventable loss of lives: Heart attacks have been linked to COX 2 inhibitors; Life-threatening muscle-wasting side effect (rhabdomyolysis) has been linked to cholesterol lowering statins, Baycol and Crestor; Suicides have been linked to SSRI antidepressants, the acne treatment,accutane, and the anti-malaria drug, Lariam.

Failure to warn about severe aggressive psychiatric/ behavioral drug side effects, including homicidal ideation–linked to SSRIs and Lariam–may have led to homicide.

Contact: Vera Hassner Sharav
212-595-8974

http://www.forbes.com/sciencesandmedicine/2005/02/07/cx_mh_0207fda.html

FORBES
Pharmaceuticals
Judgment Day For The FDA, Pfizer
Matthew Herper, 02.07.05, 11:10 AM ET

Next Wednesday, Feb. 16, painkillers go on trial. The big question: Will the jury be tough enough?

A panel of academic scientists–who have not yet been publicly named–will meet to advise the U.S. Food and Drug Administration on the safety of Cox-2 inhibitors such as Celebrex, Bextra and the withdrawn Vioxx. They will also delve into the safety of older anti-inflammatory medicines such as Aleve and Motrin. The task is so difficult that the FDA has allotted three days for the work, a clear sign of controversy. The last similar meeting was on the safety of breast implants. The three-day discussion will provide a climax to a debate about drug safety that began when Vioxx was pulled from the market for doubling the risk of heart attacks and strokes at high doses over long-term use.

It will be an especially important meeting for Pfizer (nyse: PFE – news – people ), which makes Celebrex and Bextra. The meeting is likely to determine the future of those drugs–including whether they have a future at all. The discussion may also have an impact on Pfizer’s potential liability.

Even if Celebrex and Bextra don’t make it through the meeting, Pfizer could look like a winner to investors as long as it doesn’t face a massive liability cloud like the ever-ballooning diet-drug litigation that has weighed on smaller rival Wyeth (nyse: WYE – news – people ) for years.

But for the meeting to save Pfizer–or to settle the public’s fears about Celebrex, Bextra, or Aleve–it needs to be credible. That means that the FDA advisory panel needs to be composed of people who are not merely unbiased, but even a little critical of the drugs. There is a real risk that the FDA could field a weak team and fail to settle the considerable public safety arguments about these drugs.

Here’s a worst-case scenario: The data are analyzed by the FDA’s standing arthritis advisory committee, composed of well-intentioned doctors who desperately need painkillers to give their patients. They don’t worry enough about the side effects, and after the meeting, drug safety experts and cardiologists go back into an uproar. Instead of starting to cool, the drug safety firestorm becomes blinding.

To prevent this from happening, the FDA actually needs to put together the toughest panel it can. Drug safety experts–who understand how even a small increase in risk for a common problem like heart attacks can have massive effects–need to be there. So do cardiologists, who will be as focused on the heart as rheumatologists are on the joints.

Even harder for the agency: The panel must contain people who saw the Vioxx risk early on, and it must also contain researchers who have been critical of the FDA’s handling of the matter. It is the presence of such critics that will make the panel’s judgments stick in the minds of the skeptical. It’s not as if it will be hard to find them. Cox-2 skeptics such as Wayne Ray of Vanderbilt University, Steven Nissen of the Cleveland Clinic and Curt Furberg of Wake Forest University have served honorably on FDA panels in the past, as have drug safety experts such as Vanderbilt’s Alastair Wood, who was at one time mentioned as a potential FDA head.

On Friday, briefing documents prepared by FDA staff for the panel were made public on the FDA Web site. So far, they are critical, seeing potential for heart risk in unapproved Cox-2 drugs developed by Novartis and Merck . One of the panel’s toughest decisions will be to say what is causing such heart risks. One possibility is that it is due to the fact that many of these drugs raise blood pressure slightly, a theory that might exculpate Celebrex, which seems to have less of an effect on blood pressure.

But another theory, put forth by University of Pennsylvania pharmacologist Garret FitzGerald six years ago, argues that all the Cox-2 drugs make blood more likely to clot, thereby increasing the risk of heart attack and stroke.

If this second theory wins the day, Pfizer will be in the position of trying to use its vast database of Celebrex data to prove that Celebrex is a very special case. The entire drug industry will be watching with bated breath.

EU drug chief urges shake-up
By Andrew Jack in London
Published: January 28 2005 02:00

The European Union’s top medicines regulator has called for a radical shake-up in drug safety with greater monitoring and independently-funded research to identify problems with treatments in use by patients. Thomas Lönngren, director-general of the European Medicines Agency (EMEA), said although the agency relied on a network of regulators and medical researchers across the EU’s 25 member states, it lacked an intensive drug monitoring system.

“We have to find alternative methods to detect the safety of medicines,” he said.

Mr Lönngren’s comments, in an interview with the Financial Times, will spark debate at a time of growing controversy on both sides of the Atlantic following health scares with authorised drugs including the SSRI class of anti-depressants and the anti-inflammatories, known as cox-2 inhibitors. He said: “There is an urgent need to build up independent networks of intensive drug monitoring … If we had had better follow-up already in place, we might have discovered problems earlier.”

The EMEA does not yet have the power of the Food and Drug Administration, its US counterpart, but its authority is increasing and in November it will be responsible for giving approval to drugs conditional on the completion of more detailed studies on potential health risks.

Mr Lönngren added: “From a safety viewpoint, we are keen to have a slower release [of new drugs].

“There is a conflict, because the company wants the biggest exposure immediately.”

The detection of dangerous side-effects long after drugs have been introduced has led to renewed discussion about the need for greater efforts by regulators to identify problems with medicines once they have been authorised.

Mr Lönngren said since last year drugs companies had had to submit their own “risk management plans” on products as a condition for EMEA approval. But he pointed to the inadequacies of today’s system – under which the industry and doctors take it upon themselves to identify side-effects.

The EMEA was drawing up its own enhanced risk-management plans for safety, he said.

It was necessary to provide both private and public funding for additional research into the safety of medicines already in use, alongside resources from drug companies.

“Depending on the financial capacity, we have to set up independent studies, probably selecting a number of products that reach a great part of the population [with] chronic well-known diseases, such as cardiovascular problems and diabetes.”

The EMEA has to negotiate a sometimes cumbersome process of authorisation via the European Commission, and to steer carefully between national medical regulators across the EU. But it is gradually taking on a stronger co-ordinating role.

Mr Lönngren’s comments came as Sir Tom McKillop, chief executive of AstraZeneca, the Anglo-Swedish pharmaceuticals group, warned that regulators might come under excessive political pressure over the safety of new drugs. Sir Tom feared this might discourage the development of future innovative treatments.

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