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Approval of Generic Biologics: Why We Can't Afford a Dangerous Shortcut

Charles, David MD

doi: 10.1097/01.NT.0000281160.93957.79

Dr. Charles is associate professor of neurology at Vanderbilt University and chairman of the Alliance for Patient Access.

As both the cost and the impressive results of biologic drugs become more widely understood, there is growing interest in finding shortcuts that will speed the approval of potentially cheaper generic versions.

Biologics — therapies created using biotech science instead of traditional pharmaceutical chemistry — are some of the most effective and most expensive drugs available today. As their patents begin to run out, some policy-makers believe they can be replaced by interchangeable, less costly generic versions without the need for clinical trials.

Congressional legislation has been proposed that would create a fast-track approval path for new generic biologics, a path that does not include a stopover for clinical trials. A bill titled the Access to Life-Saving Medicine Act (H.R. 1038) was introduced in the House by Rep. Henry Waxman (D-CA) in February with a companion Senate bill (S- 623) introduced by Sen. Charles Schumer (D-NY).

The stated purpose of the legislation is to improve patient access to life-saving medication and to save costs for the Medicare program. These are worthy goals. But we won't achieve them with a policy based on the fallacy that biologics in the same generic category are essentially identical. Approving a new generic biologic without clinical trials is a high-risk /low-reward proposition. In terms of patient safety, this is a shortcut the medical community cannot afford to take.

The science involved dictates that no two biologic drugs are completely interchangeable. Even biologic drugs in the same FDA category designed to treat the same disease or condition have unique characteristics. This is because the performance characteristics of an injected biologic drug are largely determined by the manufacturing process, not by a chemical formula as they are in conventional or “tablet” drugs.



Conventional pharmaceuticals are generally small chemical molecules produced with different ingredients added under tightly controlled conditions. By contrast, biologic medicines are often large protein molecules manipulated through complex methods. It's a long, complex, scientifically exciting but expensive process with significant variations from manufacturer to manufacturer.

It's those manufacturing variations that make it impossible to predict the patient effects of one biologic drug on the basis of our experience with another. Without the benefit of controlled clinical trials, predictions are at best difficult, at worst dangerous.

Immune reactions among different versions of the same biologic drug can differ with an intensity that goes well beyond the immune reactions associated with conventional drugs. The immune reaction concern, however, is overshadowed by the challenge of finding the proper dosage levels.

As neurologists know from experience, finding the therapeutic dosage level for a substitute version of conventional drugs is a challenge. A patient taking one generic preparation of phenytoin prescribed at 100 mg. three times daily to control seizures, for example, might maintain a blood level of 15 and get relief. Put that same patient on a different generic substitute and the blood level of the medicine could fall to 11, within the therapeutic window but possibly low enough for the reoccurrence of seizures.

I don't want to disparage the use of generics. In the more familiar world of chemically-based tablet drugs, some generics do provide an economic and clinically effective substitute for the original or “brand name” version. Due to wide variation in dosage levels, though, pharmacies should not be permitted to arbitrarily substitute a generic version for the drug prescribed by a physician. This decision must be made by physicians and explained to patients.

The challenge of setting proper dosage levels for generic versions of conventional medicines is magnified a hundred-fold on the high-tech frontier of biologics. Not only do safe and effective dosage levels for biologics differ from version to version, there are no hard and fast conversion numbers (dosage equivalents) to translate proper dosage from one biologic to another.

Under one set of circumstances, the equivalent dosage ratio between biologic A and biologic B might be 4:1. Change the circumstances and the ratio could jump by a factor of three. Drastic swings in dosage equivalents among theoretically equivalent biologic drugs have been well documented. Predicting the performance of one biological on the basis of comparison with another is simply not possible without specific clinical testing. The well-documented variation in dosage levels among biologics makes a compelling case for trials.

A recent report comparing two preparations of botulinum toxin type A (Botox in the US, and Dysport in Europe), should be required reading on Capitol Hill.

That study evaluated the dosage utilization of the two preparations when used to treat cervical dystonia and blepharospasm (Mov Disord 2005;20:937–944). To me, the most striking aspect of the study was the sharp variation in equivalent dosage levels. The levels ranged from a ratio of Dysport to Botox of 2:1 all the way up to 11:1. A range that wide should close the interchangeability argument.

The lesson for US policy-makers is clear. If it's in the public interest to expedite introduction of generic versions of any biologic drug, let's do it right from the beginning. We need to recognize that generics in the biotech sphere will never be safe, effective, and prescribed with confidence unless we have an understanding of their performance variations available only through clinical trials.

Those trials should not be seen as a delay in introducing new drugs, but as an investment in their safety and effectiveness.

©2007 American Academy of Neurology