Treat Patients, Not Statistics

To the Editor:

It was with great interest that I read the responses to my recent editorial regarding generic immunosuppression (1) by Dr. Latran (2) and Drs. Trofe-Clark, Gabardi, McDevitt-Potter and Alloway (3).

Having attended the meeting of the Food and Drug Administration (FDA) Advisory Committee for Pharmaceutical Science and Clinical Pharmacology on Narrow Therapeutic Index Drugs on July 26, 2011, I recognize the arguments levied by the pharmaceutics, chemists and statisticians. The individual patient does not exist, but only large groups represented by statistics. The individual patient responses to the drug switch in the Momper study (4) illustrated the wide variation between patients; figure 2 shows that the drugs levels of one of three liver transplant patients decreased at least 25%, and the drug levels in one of 10 increased by 50%. This is the raw data, not statistics. To treat individuals as if they all respond as the statistical mean is like saying that there will be one size suit for all US males, at a mean height of 5 feet 9 inches, ignoring that Bill Shoemaker (a jockey) was 4 feet 11 inches and Shaquille O’Neal is 7 feet 1 inch.

The blood level variation in the Momper study shows the individual effect of changing from brand to generic tacrolimus. Indeed, there are always other variations caused by food and other factors that were not studied. However, clinicians have seen and handled the daily variations since 1988, when we first started using tacrolimus. I suspect we will never see a scientific report on this phenomenon for any of the generics.

Those of us who actually monitor and direct immunosuppressive therapy know that changes such as those shown in figure 2 are very significant and can cause major and permanent harm. Surgeons and physicians caring for and treating both liver and kidney transplant patients know that there are major differences in the drug requirements in the two-patient populations to reach similar drug levels. Hence, there are reasons to use the target population for testing of new generic drugs. This may yield substantially different results than those obtained after the testing described in detail by the authors (2,3) for FDA approval of a generic drug, which is done in healthy volunteers as a single-dose administration. The drug interval of 80–125% does not even have to include 100% of the brand name concentration.

The fact is that today we have to monitor drug levels and organ chemistries every time a patient refills a prescription. Thus, generic drugs are not, by definition, equivalent to the brand drug. On July 12, 2011, the Danish Medical Agency concluded that “monitoring at more frequent intervals typically involves the taking of extra blood samples to measure the concentration of the medicine in the blood. Such intervention is not considered compatible with generic substitution” (5).

Negative reactions including rejections and side effects, seen in our clinics in patients on generic medication, have not been scientifically collected and for the sake of this discussion are dismissed as anecdotal.

Again, surgeons and physicians responsible for the well-being of our patients must have a drug supply that we rely on, regardless from where the pharmacy gets the immunosuppressive drugs. Today we do not have that.

Disclosure

The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.