Week-in-Review editorial: Whatever happened to Post-marketing Surveillance?

The lead story this week was UK-based GlaxoSmithKline's (GSK) announcement it would cut jobs to make annual savings of around GBP 700m by 2010.

The cutbacks come as no surprise to the industry, especially since GSK reported a two per cent fall in Q3 FY07 pre-tax profits to GBP 1.9bn on nearly flat sales of GBP 5.5bn.

The main factor causing the sales drop was Avandia (roseglitazone). The diabetes drug was GSK's second-best selling product in FY06, with sales of over USD 3.2bn, or seven per cent of total sales for the company. Prescriptions have fallen massively, and now Takeda's Actos (pioglitazone) is the market leader.

Avandia was linked to heart problems in an article by Doctor Steven E Nissen of the Cleveland Clinic published in the Journal of American Medical Association (JAMA) back in May 2007, and the FDA asked GSK to change the labelling to warn of the dangers.

Again this week, more bad news came in the form of an article in the Wall Street Journal which revealed that the FDA was seeking a "black box" warning for Avandia. This type of warning is the strongest the FDA can give, short of banning the drug from the market. If approved, the labelling change would be the final nail in the coffin for the product.

So what happened to post-marketing surveillance for Avandia? Did GSK just forget about Merck & Co's Vioxx (rofecoxib) experiences in the rush to get the drug out on the market? Was the threat of imminent generic drug competition and pipeline gaps anticipated for 2010-12 too much to bear?

Are longitudinal studies long enough?
All possible side effects of a drug cannot be anticipated by pre-approval studies alone, as they only involve several hundred to several thousand patients. So how much active post-marketing surveillance of Avandia was performed?

The JAMA article mentioned above involved a meta-analysis of post-marketing studies for Avandia, which is how the author arrived at his conclusions. GSK defended itself by saying that a meta-analysis was not as scientifically rigorous as its own large-scale, long-term clinical trials. But how large should sample sizes be? How long should a study run in these cases? There is very little consensus on the matter in industry or among the regulatory bodies.

In the US, the FDA maintains a system of post-marketing surveillance and risk assessment programmes to identify adverse events which did not appear during the drug approval process. The agency has, however, been under significant pressure from the US federal government to increase its own evaluations of drug safety.

Regulatory agencies criticised
In a July 2007 speech to Congress, Senator Chuck Grassley criticised the FDA's handling of Avandia and expressed his concerns similar to those seen in the Vioxx case, where the FDA ignored its own post-marketing safety experts and once again left the public in the dark regarding health risks

Grassley said: "Not only did the FDA disregard the concerns and recommendations from the office responsible for post-marketing surveillance, but I have found that it also attempted to suppress scientific dissent. As I've said many times before, FDA employees dedicated to post-marketing drug safety should be able to express their opinions in writing and independently without fear of retaliation, reprimand, or reprisal."

"I expressed concerns about the FDA's treatment of the former deputy director of the division of drug risk evaluation [who] had been verbally reprimanded because she signed off on a recommendation that a black box warning be placed on Avandia for congestive heart failure," Grassley added.

The senator concluded: "I then wrote to the commissioner about a senior medical officer in the Office of New Drugs who was removed from the review of potential cardiovascular safety problems associated with Avandia. The medical officer also believed that there was enough evidence to support a black box warning regarding congestive heart failure."

Where these internal pressures come from is debatable, but the pharmaceutical industry is a very powerful group and actively lobbies governments, backed up by large budgets and spurred on my massive potential profits to please investors. Last week, for example, US-headquartered Bristol-Myers Squibb (BMS) revealed it had spent over USD 2.8m in H1 2007 to lobby government.

Risk is now being spread among the public, instead of being contained within the laboratory. Again the image of Big Pharma continues to be sullied by a lack of transparency, which, of course is key to accountability.

Effectively, rushing a drug to market is no dissimilar to a car company producing a product which falls apart at 90 mph on a busy motorway. The resultant deaths from toxic drugs are no less spectacular.

Look out for the Hot Topic feature on Post-marketing Surveillance in the upcoming December 2007 issue of Communiqué.