Generic drugs Part 1

The New England Journal of Medicine provides a look at the future of generics here:

Today, generic drugs account for 63% of all U.S. prescriptions for drugs (see Figure 1). Since generic drugs sell at substantially lower prices than their brand-name counterparts, they save consumers and purchasers of prescription drugs tens of billions of dollars per year. Moreover, their expanded role has been linked to an attenuation of overall price increases for prescription drugs. Between 2007 and 2010, roughly 110 drugs will lose their patent protection — including well-known products such as Norvasc (amlodipine), Imitrex (sumatriptan), Fosamax (alendronate), and Risperdal (risperidone). Estimates suggest that these 110 drugs are currently responsible for $50 billion a year in sales — so competition from generic drugs could generate large additional savings.

The FDA Orange Book has a listing of brands and generics.

This website carries a lot of good information.

However, it should be noted that current regulations permit a variation of approximately 20% either way in the bioavailability of the active ingredient. (The specifics of the permitted variation in bioavailability hinge on the FDA’s technical definition of bioequivalence, which requires that there be no statistically significant difference in bioavailability. For the FDA’s definition, see the agency’s Guidance for Industry document, which sets out guidance on confidence intervals for test to reference comparisons across different types of medications, as well as the FDA’s Code of Federal Regulations 320 document on bioavailability and bioequivalence requirements. Also see this 1999 Food and Drug Law Institute overview of the Hatch-Waxman Act of 1984.) In one study (Borgheini 2003), a full 31% variation was found in the blood plasma levels of a particular medication after a patient switched from a branded to a generic product. (Why does this happen? It may be accounted for by differences in the manufacturing process yielding different particle sizes that are absorbed at different rates, as well as other factors.)

This does NOT necessarily mean that purchasing generic medications in preference to branded counterparts is a bad idea — in fact, in most cases it is probably still a very good idea! — but this does mean that the issue is not quite as clear cut as it might otherwise seem as a medical issue, if not price for the end user.

The FDA describes it stats creation thusly:

The statistical methodology for analyzing these bioequivalence studies is called the two one-sided test procedure. Two situations are tested with this statistical methodology. The first of the two one-sided tests determines whether a generic product (test), when substituted for a brand-name product (reference) is significantly less bioavailable. The second of the two one-sided tests determines whether a brand-name product when substituted for a generic product is significantly less bioavailable. Based on the opinions of FDA medical experts, a difference of greater than 20% for each of the above tests was determined to be significant, and therefore, undesirable for all drug products. Numerically, this is expressed as a limit of test-product average/reference-product average of 80% for the first statistical test and a limit of reference-product average/test-product average of 80% for the second statistical test. By convention, all data is expressed as a ratio of the average response (AUC and Cmax) for test/reference, so the limit expressed in the second statistical test is 125% (reciprocal of 80%).

For statistical reasons, all data is log-transformed prior to conducting statistical testing. In practice, these statistical tests are carried out using an analysis of variance procedure (ANOVA) and calculating a 90% confidence interval for each pharmacokinetic parameter (Cmax and AUC). The confidence interval for both pharmacokinetic parameters, AUC and Cmax, must be entirely within the 80% to 125% boundaries cited above. Because the mean of the study data lies in the center of the 90% confidence interval, the mean of the data is usually close to 100% (a test/reference ratio of 1). Different statistical criteria are sometimes used when bioequivalence is demonstrated through comparative clinical trials pharmacodynamic studies, or comparative in-vitro methodology.

Generic drug manufacturing is the predominate method of saving money in the market for pharmaceutical drugs. As the market changes we have to consider trends.

1. Many insurance companies mandate the use of the generic form of a drug, with the user picking up the cost of using a brand name. Hence it appears to be a quick remedy and will continue to be a force in this market.

2. When manufactured in the US, quality control was excellent. Any run in production that did not meet specs was sold overseas. That did not mean it was a bad run necessarily, but did not meet specs. I do not know what was done with product that simply was medically sub-par.

3. Currently there are few drugs manufactured in the US anymore, generic or brand name. There are more than a couple dozen countries that have manufacturing facilities in their jurisdiction.

4. For different reasons sometimes generic drugs are not the equivalent to the brand name for a patient. In MA generic drugs are mandatory unless specifically requested by the doctor, and in MA have tripled in co-pay from Dec 2007, and will continue to rise.

The FDA has turned to hiring private inspectors that are certified by them in the country of origin to inspect manufacturing plants. The same is true for medical devises, where few are made in the US.

Given this basis, part 2 will develop the theme.