FDA standards are questioned

Times Staff Writer

In carrying out its mission to ensure that generic drugs are “the same medicine” with “the same results” as the pioneer drugs they follow, the Food and Drug Administration rigidly applies a standard of what is called “bioequivalence.” Measured in laboratories and in simple, small-scale human trials, a generic must deliver the same active ingredient to the bloodstream of patients in virtually the same amount at virtually the same rate as the pioneer drug.

The FDA considers “bioequivalence” a good surrogate for “therapeutic equivalence” -- the equal ability of two drug formulations to ease symptoms or cure disease. Physicians and pharmacologists say that for some copycat drugs, showing bioequivalence to the original is not proof enough that the “same medicine” will yield “the same results.”

There are several potential flaws in the FDA’s standards of comparison, drug experts say.

First, the agency’s tolerance for variance in the content and release of a drug’s active ingredient -- the healing compound -- may be too broad.


Second, the FDA does not demand realistic trials of different formulations in large patient populations.

And third, by measuring a generic medication’s ability to deliver a drug compound to the bloodstream, the FDA may be looking in the wrong place. Most drugs work their magic not in the blood but in organs, cells or tissue elsewhere, and the agency does not insist on proof that a generic formulation delivers its active ingredient effectively to the same sites that pioneer drugs do.

In fact, a brand-name drug’s generic counterpart is rarely an exact replica. Though the two share equal amounts of the same active ingredient, they generally look different. And those differences, say some pharmacologists, can result in small variations in how they work in patients.

A brand-name drug and its generic in most cases are formulated with different colorants, fillers and binding materials. Though all of those must come from an FDA-approved list of pharmaceutical ingredients, they are, in most cases, assembled differently in each manufacturer’s product. One version of a drug might use lactose or sugar as an inactive ingredient; another might not. But incidental ingredients like these can affect the way patients dissolve and metabolize a drug’s active ingredient -- faster or slower. And that, in turn, can result in variations in the two formulations’ effects.

In almost all cases, the FDA permits a generic drug to release 80% to 125% of an active ingredient into the bloodstream, compared to that released in a single dose of the original medication. That range would make little practical difference in the effect that most drugs have. And the FDA and generics manufacturers defend the allowable range of variance as the same that is permitted among “batches” of brand-name drugs.

But medical and pharmacology specialists warn that the FDA’s range may be too broad for some drugs, especially in cases where a drug has a “narrow therapeutic index” -- the fine line between an ineffective dose and a dangerous one.


Variations in the rate at which a brand-name and its generic (or two different generics) release their active ingredient could court disaster with some drugs, as well. On this front, experts said “extended release formulas” -- doses that usually are taken no more than once a day -- can pose particular problems.

If one formulation releases its therapeutic agent evenly over 20 hours and another releases a large percentage in the first five hours and very little in the final five, a patient might get a toxic concentration of drug in the morning and limp along with a dangerously ineffective dose late in the day. In lab tests and in small samples of human subjects, FDA measures release rates at periodic intervals. But pharmacologists warn that those intervals may not always be fine enough.

“Bioequivalence and therapeutic effectiveness are not necessarily the same,” wrote neuropsychiatrist Dr. Giuseppe Borgheini in a 2004 article published in the journal Clinical Therapy. Borgheini reviewed the medical literature documenting differences in the clinical effects of generic psychoactive drugs and their brand-name counterparts. In the case of three anti-seizure drugs -- phenytoin, carabamazepine and valproic acid (marketed under the commercial names Cerebyx, Tegretol and Felbatol, respectively), studies found that generic formulations either failed to release the correct dose to patients’ bloodstreams or eventuated in higher rates of “breakthrough seizures.”

Finally, the agency demands little clinical evidence that a proposed generic drug will work the same as a pioneer drug in a broad cross section of real patients. The agency conducts quality-control tests on generic samples periodically after marketing begins, and patients and physicians can report problems with a generic drug to the FDA’s adverse-event monitoring system. But neither generic-drug manufacturers nor the FDA does post-marketing studies that might indicate patients are responding differently to a generic than to its brand-name counterpart.

In the generics approval process, the FDA typically requires a manufacturer to administer a single dose of its proposed product to a group of 24 to 48 healthy volunteers, then to sample their blood levels periodically to gauge concentrations of the active ingredient. The generic’s performance is then compared with the pioneer drug in the same group.

But that may not be a good gauge of how large populations of sick patients will tolerate or respond to a variant of the medication they’ve already been on, say critics of the approval process. “We don’t use these medicines in normal volunteers: our patients are old, their hearts, their livers, their kidneys don’t work so well,” said Pennsylvania State medical center cardiologist Dr. Gerald Naccarelli. “They test these generics on a healthy 30-year-old and test his blood levels and say, ‘OK, close enough.’ And they translate that into an 80-year-old-guy who’s on nine different meds? I would suggest that someone who knew nothing about medicine would say that’s problematic.”