In mid July 2012, the Food and Drug Administration approved two new diet pills. No drugs in the class have been approved in the past 13 years. There has been (pardon the pun) an enormous groundswell of demand for anti-obesity drugs, both from medical professionals and from the public, as the BMI of Americans has climbed to unprecedented highs in recent years. Obesity is not a uniquely American problem. Australia has a similar incidence of obesity now. And in virtually every corner of the globe, as the quintessential American export, fast food, percolates through the borders and saturates the arteries of the inhabitants, they too become part of the obesity epidemic. You might say that obesity has become an extraordinarily successful American export.
It is not my intent in this posting to debate, discuss or deconstruct the causes of obesity—is it nature or nurture, is it excess intake or inadequate energy expenditure? I have decided that my own weight management hassles, with a BMI just edging over the upper threshold of normal into the overweight range, is due to the epigenetic effects of being born with severe intrauterine growth retardation, and that my body is constantly seeking extra calories to sustain catch up growth. And my body intuitively knows that the best physiology has determined that the best fuel for this catch up is massive amounts of frozen tart yogurt. Yum! The only problem now is that the growth is all lateral!
Given the abysmally rate of success for weight loss programs and other calorie restriction approaches, there is a concentrated effort to develop drugs that either suppress appetite or increase satiety or both.
So how will diet pills be used in the war on obesity? The FDA acknowledges on their website that many, if not most, persons with weight problems are likely to be taking diet drugs for their entire lives, since the drivers for obesity are powerful and redundant.
Past experience with diet pills has been disappointing, if not disastrous. Fenfluramine (Pondimin) , used in combination with phentermine, in the so called “Fen Phen” weight loss method, was approved in 1973. Over 18 million prescriptions for fenfluramine were written. It was taken off the market in 1997 after being linked to cardiac valve damage. The manufacturer agreed to a 3.75 billion dollar structured settlement rather than litigate thousands of claims. An analogue, dexfenfluramine (REDUX), approved in 1996, was also withdrawn in 1997 after increased risk of pulmonary hypertension was identified. A third diet pill, sibutramine (Meridia) appeared to increase the risk of cardiovascular events, including heart attack and stroke, and was voluntarily withdrawn in 2010.
It would seem that the history of this entire class of drugs, spanning more than 40 years, has been one of disappointment, disillusionment, disability and death after products were brought to market.
Over the counter diet pills have also been problematic. Dexatrim (original formulation), containing phenylpropanolamine, also commonly used in cold and flu treatments, was linked to hemorrhagic strokes and was banned in 2000. Ephedra, a “natural” botanical with adrenergic activity was promoted to boost energy and weight loss. Known as Ma Huang, and used in traditional Chinese Medicine for colds, flus and other respiratory disorders for thousands of years, ephedra was banned in the U.S. in 2004 because of an “unreasonably high risk of injury or illness.” At least 900 cases of ephedra related toxicity were uncovered including strokes and heart attacks. At least 37 deaths were attributed to the use of ephedra.
Increases in rare events are difficult to detect during clinical development, when a few hundred (or at best, a few 1000) persons are exposed to the drug for a relatively short periods of time, perhaps one year. Even a huge increased risk in a very rare event may be difficult to detect. For example, if a serious adverse event occurs in 1 in 1700 users, a practitioner will have to write a new prescription every day for 20 years to see two cases. Doctors or nurses working in isolated private practice settings cannot readily perceive patterns of adverse events.
In my own practice, I had two patients experience deep venous thrombosis (DVT) on birth control pills, as it happened both within the same month. I did an estimate of the probability of this occurring, using the incidence of DVT for women taking birth control pills and an estimate of the number of prescriptions I had written during my years in practice. The incidence of DVT is estimated to be 15 per 100,000 users. I figured that I had written 2 prescriptions a day for 50 weeks a year over 20 years period (10/wk x 50 weeks x 20 years = 10,000 prescriptions). Given the incidence of 2 DVT events per 100,000 users, indeed, I should have seen approximately 1.5 cases of DVT. Got ‘em.
The burden for post market drug monitoring falls to drug manufacturers and to the FDA. New surveillance and oversight mechanisms are being designed and developed now. The ones currently in place include:
- The product’s pre-approval safety profile
- The product’s current FDA-approved label
- Reports made to FDA’s Adverse Event Reporting System (AERS)
- Reports made to the Vaccine Adverse Event Reporting System (VAERS)
- Manufacturer-submitted periodic safety reports
- Medical literature
- Drug utilization databases
- Risk Evaluation and Mitigation Strategy (REMS)
- Controlled substance designation w/ special prescribing regulations (e.g. narcotics)
- Data from post-approval clinical trials and other studies, when applicable
FDA analyses for the safety evaluations include:
- Data mining analysis of all adverse event reports in the AERS or VAERS databases
- Review serious adverse event reports
- Medication error analysis
- Product utilization analysis
- Risk management review
- Analysis of post-approval safety data from clinical trials and other studies, when applicable
According to some HR experts, there is a low supply and high demand for qualified drug safety personnel. (http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2009_03_13/science.opms.r0900068)
Safety jobs have expanded beyond traditional toxicology. Pharmacometrics, pharmacogenomics, and simulation and modeling are just a few of the newer dynamic areas being developed to help monitor adverse events associated with drugs pre and post launch. These jobs offer engaging and challenging opportunities for life science students.