For those not familiar with the concept or countries other than the US where laws may differ, generic drugs are those with the same active chemical as the originally-approved “brand name” drug. The original drug manufacturer is the one that conducts all of the preclinical and clinical safety and efficacy testing, natural product isolation and/or chemical synthesis, formulation with inactive ingredients to assure dissolution and reproducible release of the drug, etc. In return for all this work and an investment of about $800 million, the company produces a “brand name” drug for which they have a period of marketing exclusivity of roughly 17 years from the date the drug was first patented (in some cases this can now be extended another 5 years). While that sounds like a monopolistic proposition, many drugs take up to 12 years from patenting to be approved by the US FDA, meaning that the company has to recoup its investment in a rather compressed time period.
When a drug patent is about to expire, companies specializing in the manufacture of drug products compete to gain FDA approval to market a generic version of the drug without all of the huge investment made by the brand name developer of the drug. Hence, generic versions of brand name drugs are priced much lower. However, the generic company[ies] must demonstrate the so-called bioequivalence of their drug, meaning that the active component must be absorbed into the bloodstream within 80% to 125% that of the brand name drug, without any regard for the time course of that process. These studies rarely require more than a few dozen patients given a single dose of a drug. In many cases, this is adequate.
However, there are some situations in which generic drugs are not the same as brand name drugs, even when manufactured according to FDA tolerances. And while the initial approval process for generic drug manufacturers may be reasonably stringent, the follow-up monitoring of such companies is often less than ideal primarily because of short-staffing of this part of the FDA.
Joe and Teresa Graedon are consumer health advocates who write a syndicated drug-focused newspaper column called The People’s Pharmacy and air a NPR radio program of the same name. For over 30 years, they were strong supporters of generic drugs over brand name drugs until readers and listeners increasingly reported problems or lack of effectiveness when switching from a brand name drug to a generic formulation. While these were technically anecdotes, the volume of the case reports suggested that there may be more to the story than just patient perception (as has been reported recently in a study where a higher-priced placebo medication exhibited effects superior to that of a low-priced placebo).
Together with the independent testing laboratory, ConsumerLab.com, the Graedons commissioned an analysis of the Wellbutrin XL brand name version of the antidepressant bupropion versus three generic versions of the active component. From the ConsumerLab.com report:
Analyses of all four products showed that each contained its claimed amount of bupropion hydrochloride. However, the rates at which the products released their ingredient were quite different, raising concerns about their equivalency. A second laboratory repeated the dissolution tests on all of the products. Results from the second lab confirmed the major differences found in the first lab which are described below.
I have not yet requested permission to post their graphic results but here are some of the details:
[T]he Teva product released much of its drug earlier than Wellbutrin. Wellbutrin (shown in blue) released ingredient into solution slowly over the first several hours of the dissolution test, with only 8% dissolved at two hours and 25% at four hours. In contrast, Teva’s pill released ingredient rapidly at first — delivering over four times as much drug as Wellbutrin in the first two hours (34% vs. 8%). Within the first four hours, nearly half the drug in the Teva product had gone into solution, almost twice as much as Wellbutrin. At eight hours into the test, results for Teva and Wellbutrin began to even out, with each about three-quarters dissolved. By the end of the test, both products had fully released their expected amounts of drug.
As noted earlier, the FDA has hidden from online viewing the specific dissolution requirements for generic forms of Wellbutrin XL. So it’s not clear if the above results for Teva meet the FDA’s requirements for bioequivalency.
Drugs like antidepressants must be kept at a minimum threshold blood concentration over a long period of time and Wellbutrin has been formulated to release its active ingredient over an extended time frame. The generic version released much more of its drug earlier – how this relates to effectiveness is not yet clear since the ConsumerLab study was not a clinical efficacy trial.
However, the disturbing statement in their report was that FDA did not make available “the specific dissolution requirements for generic forms of Wellbutrin XL.” In fact, this difference would not have been publicly released if not for the joint People’s Pharmacy/ConsumerLab testing. From the update on the ConsumerLab website:
The Director of the Office of Medical Policy of the FDA’s Center for Drug Evaluation and Research, Dr. Robert Temple, has acknowledged that TEVA Budeprion XL 300 releases drug at a different rate than the brand name Wellbutrin XL 300, consistent with ConsumerLab.com’s findings in this report. Dr. Temple’s remarks were made during a radio broadcast on Southern California Public Radio station KPCC on December 19, 2007. He noted that the FDA was aware that bioequivalence studies in people showed the once-a-day generic to release drug sooner than its brand-name counterpart but that the FDA “thought that that wouldn’t make any difference.” He admitted that the once-a-day generic “had an early release pattern that was a little closer to the original [three-times-a-day] product” than to once-a-day Wellbutrin XL. The FDA approved the once-a-day generic without mention of this difference, further clinical testing or special follow up.
Two weeks prior to Dr. Temple’s remarks, on December 1, 2007, the United States Pharmacopeia (USP) officially released information indicating that the dissolution of the Budeprion XL 300 varied significantly from the original drug. According to the USP, tablets of Wellbutrin XL release only a small amount (less than 20%) of drug during the first two hours of dissolution. In contrast, the Budeprion XL releases at least 25% and as much as 50% of its drug in that period. These USP dissolution standards are based upon performance characteristics that the FDA approved for the original and generic drugs, respectively, and were provided to USP by the manufacturers.
The new information from the FDA and USP corroborate ConsumerLab.com’s findings for the Budeprion XL 300 product in this report which show it to release four times as much drug as the original Wellbutrin XL 300 — 34% versus 8%, respectively — in the first two hours of a dissolution test. The Generic Pharmaceutical Association questioned ConsumerLab.com’s findings. It is now clear that ConsumerLab.com’s findings were consistent with differences well known to both the manufacturer and the government but not disclosed publicly. [emphasis mine]
Generic drugs have great promise for reducing health care costs but should not be forced upon patients by insurers and/or the government if the drugs are substandard. Hiding this information undermines the public’s confidence in these products. FDA clearly needs to invest in more staff and laboratory resources to assess and monitor generic drug formulations as their use is now often required by insurers.