When patients are faced with the choice between a branded drug and a generic one – or find themselves put on a generic because their insurer is trying to save money – they are often reassured that the two medications are the same.
But the remarks this afternoon at the AAPS conference in Baltimore of Gerard Sanderink, Director of Metabolism and Pharmacokinetics at Sanofi-Aventis, brought into relief the question of exactly how different drugs can be and still pass the FDA’s current standards for bioequivalence.
And it’s a troubling picture.
Dr. Sanderink described how when Sanofi-Aventis decided to create an extended release version of Ambien that would work for an additional 3 to 5 hours in order to help patients remain asleep, the company tested 8 bi-layer formulations, comprising different proportions of the two included medications and different total doses.
Critical to Sanofi-Aventis was that the new pill would have three essential properties. It would offer patients the same quick absorption to help them get to sleep, it would offer medication to keep them asleep, and it would not leave any residual impairment in the morning.
One of the eight formulas “won” the aptly named Scheherzade trial and became what we now know as Ambien CR but what is interesting is what the other seven variations can tell us about the inadequacy of the FDA’s present procedure for approving generics as bioequivalent.
The winning formula took the crown in part because it left no lingering effects in the morning when compared to placebo. This was not true of some of the other formulas, which in some cases continued to have a residual impact long after the subject had woken up. As Dr. Sanderink’s presentation today showed, the pharmacodynamic profiles of the eight versions differed quite widely.
Yet, under the current FDA rules, all of the alternative Ambien formulations would pass a bioequivalence test against the chosen version. Right now, the agency only tests drug concentrations at 1.5 hours and then 1.5 hours to infinity.
That means that drugs that leave a lot more impairment in the morning can be sold as if they are identical to the original. And so can drugs that lack the properties of sleep initiation and sleep maintenance that make physicians and patients alike turn to Ambien CR.
Instead, Sanofi-Aventis wants the FDA to look at 0-3 hours, 3-6 hours, and 6 hours plus, covering the three important phases of the drug’s operation, initiation, maintenance, and wake-up.
I must agree with Dr. Sanderink: Classical bioequivalence criteria are insufficient, at least for this type of drugs, and the FDA should move to a more nuanced and tailored approach to evaluating whether generic drugs are sufficiently similar to the originals. To do otherwise is to do harm to patients, the companies that made the innovator drugs, and the agency’s own reputation.
