What’s Up with the FDA? Part 4

June 10th, 2011 by MorganDowney Leave a reply »

Previous posts have focused on the FDA’s actions regarding drugs to treat obesity or drugs which can cause weight gain. But what about all the other prescription drugs which are used by persons who are overweight or obese? Are they tested in this population? Do physicians have adequate information to understand how to adjust dosages? Are they effective in larger bodies? Are they safe?

The authors, all from the Food and Drug Administration, looked hard at this issue and have come up with some disturbing but important findings.

They note at the outset that the physiological properties of persons with obesity differs from that on the non-obese population in several aspects. “Obesity as a disease state,” report the authors, “ is also associated with changes in plasma protein constituents; decreases in tissue perfusion and increases in adipose tissue mass, lean body mass, cardiac output, and splanchnic blood flow, as compared with normal weight individuals.”  These changes can alter how the body processes drugs, via absorption, distribution, metabolism and excretion.

The authors looked at three sources: FDA regulatory guidances, a survey of labels of approved new Molecular Entities (NMEs) from 2004-2010 and a survey of drug product labels in the Physician’s Desk Reference (PDR), a widely used reference book for physicians.

Looking at the regulatory guidances, they found “only a few regulatory guidances/guidelines for medical product development recommend the inclusion of obese persons or analysis of the impact of obesity in drug development.”

Regarding, the labels of New Molecular Entities,  they found, “ Among the product labels of the 137 NMEs approved between 2004 and 2010, there was no meaningful efficacy and safety information in the clinical trial sections of the labels with respect to obese patients, except in two of the labels.”

Regarding the PDR, they found 72 drugs had obesity as a key word. For 44 drugs, obesity was described as a risk factor for cardiovascular adverse events and metabolic disorders such as lactic acidosis and diabetes. “In particular,” they note, “regarding cardiovascular adverse events, many drug labels did not make clear whether obesity was merely a risk factor per se or whether is should be considered a risk factor related to the specific drug product. In addition, obesity was labeled as a risk factor in many drug products, simply because the warning was cacommon to a class or a combination of products.”

A somewhat surprising finding was that obesity was not listed as a specific inclusion/exclusion criteria in many pivotal clinical trials supporting applications for drug approvals. Most patients were in class I obesity with fewer in class II and almost none in Class II. The mean weight of subjects in these clinical trials was closer to 80kg than 70kg which had been the standard weight of adults in drug development and closer to the mean adult body weight in the U.S. (81.5kg or 179.7 lbs) Nevertheless, the trials “have not been including sufficient numbers of patients in the different categories of obesity. Therefore, unless more patients with different categories of obesity are included in drug development, identifying the optimal drug dosages in obese patients will remain a challenge.” They state, “In conclusion, we found from our drug product labeling survey that specific dose adjustment was seldom recommended for obese patients. Where mentioned, this adjustment was often only an extrapolation of dose scaling based on the results of clinical trials conducted without obese patients.

Specific areas of concern identified by the authors included, oral contraceptives where consistent effectiveness data is lacking  even in products approved as recently as 2010 as well as serious safety concerns. “As a disease in itself, obesity is a risk factor for thrombosis. The use of oral contraceptives by obese women further increase risk several-fold. These risk factors should be considered when prescribing oral contraceptives with women with BMI>25kg/m2 .” Other areas of concern are managing postmenopausal issues for women and potential sub-therapeutic doses of anticicorbials.

Their conclusion is especially important. “Although the FDA encourages the enrollment of obese patients in clinical trials so as to collect sufficient information for dosing recommendations, there are few guidances or guidelines recommending active recruitment of obese patients. Meanwhile, there is no evidence that registered trials in support of a drug’s product approval are excluding obese patients. However, the inherent limitation with regard to the numbers of subjects enrolled in different categories of obesity restricts the potential to suggest specific dosing recommendation for obese patients.”

Coming from FDA employees these are pretty strong words. While I have been critical of the FDA, this self-examination (unofficial as it is) is an important contribution to the health of the population. On the other hand, it also connotes a certain neglect of 33% of the population whose poor health status has been well documented for years. It is time for the FDA to take these recommendations to heart and adjust regulatory guidances to include sufficient numbers of persons with obese in various categories to establish safe and effective dosing information. Implications of Obesity for Drug Therapy: Limitati… [Clin Pharmacol Ther. 2011] – PubMed result