The Corpus Callosum

When generic drugs started to become popular, many people were skeptical.  Many people got switched from brand name to generic products, and complained that the generic did not work as well.

These complaints often were treated with skepticism.  After all, generic drugs contain the same active ingredient(s) as the brand-name product, but cost less.  Plus, the FDA assured us that they were bioequivalent.

Over the past decade or so, public acceptance of generics has increased.  Many people want to get the generic equivalent.  But now there are questions about the validity of the testing done to ensure bioequivalence.  As reported in the LA Times:

FDA standards for generics are questioned
By Melissa Healy, Los Angeles Times Staff Writer
March 17, 2008

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."...

The authors point out that the testing done to ensure bioequivalence tends to be very limited: only a small population of persons are studied, and that population tends to be composed of young, healthy persons.  Plus, a drug is considered to be satisfactorily bioequivalent if the absorption of the drug is within 80 to 125% of the original.  

The article is pretty good, as far as it goes.  But there are some points that they fail to mention.

Often, the main differences between brand name and generic medications are matters of convenience.  The brand name product may be film-coated, making it easier to swallow, or less bitter.  They may dissolve in the mouth, making it unnecessary to swallow.  They may be slow-release preparations, allowing for fewer doses during the course of a day.  They may be enteric-coated, causing less stomach irritation.  They may have more distinctive markings, making it easier to identify, harder to mix up with another drug.  

All of those things are nice.  Some people might think the niceties are worth a higher price, while others might prefer to dispense with the niceties in favor of a lower price.  

The real controversies, though, is whether the things work, and whether they pose any safety problems.

The article quotes a researcher, Giuseppe Borgheini MD, PhD, mentioning that he wrote an article in the journal "Clinical Therapy" in 2004.  (Actually, it was published in Clinical Therapeutics, in 2003; there is no journal called "Clinical Therapy")

Specifically, l study found that plasma levels of phenytoin were 31% lower after a switch from a brand-name to a generic product. Several controlled studies of carbamazepine showed a recurrence of convulsions after the shift to a generic formulation. After a sudden recurrence of seizures when generic valproic acid was substituted for the brand-name product, an investigation by the US Food and Drug Administration found a difference in bioavailability between the 2 formulations.

For many drugs, the exact blood level is not important in most situations.  In other cases, the drug is titrated to effect, so the bioequivalence is not an issue -- assuming that the patient stays on the same formulation that was used during the titration.  

In actual usage, though, there can be a problem.  What if a person is stabilized on a formulation that happens to be absorbed to 125% of the extent of the original drug, but then switches to a different generic that is absorbed to only 80% of the original extent?  That is a pretty big difference.  It could make the difference between doing well, and relapsing.  If the switch is made the other way, a person may suddenly develop adverse effects, or outright toxicity.

Pharmacies may switch suppliers at any time.  Sometimes this is obvious, if the pills are different colors.  But if they are both, say, little round whit things, it may not be obvious.  

The take-home message for patients is that generics usually are fine, but it is good to check each time a prescription is filled, to see if the new supply is made by a different manufacturer.  If so, ask you doctor if the change might be significant.  This is true especially if the drug is one that is monitored with periodic blood levels.  Lithium is a good example.  

The other situation where it might be important is with those drugs that are not monitored with blood levels, but are monitored for their biological effects.  Thyroid medication, diabetes medication, and anticoagulants are obvious examples.