current bioequivalence standards are not sufficient for narrow therapeutic index (NTI) drugs,
Currently, the “sameness” of a brand product and a generic version is evaluated based on a two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent.
This allows for a variability of 45%, which will definitely affect the medication’s effects, both good and bad.
It’s too simplistic to call these “quality” problems. There’s a range from sub-standard Active Pharmaceutical Ingredient (API) and manufacturing issues, to excipient changes (excipients are the substances other than the pharmacologically active drug contained in a pill) and, most importantly, bioequivalence and bioavailability standards.
“Now, when a patient comes in who is not doing well, the first thing I do is look at their drugs and find out who makes it.”
Not all doctors would be so vigilant, so this is something we should look into ourselves if the pharmacy switched generics, which can be the start of troubles for many of us due to wide efficacy variability of generics.
requiring patients to use these follow-on products is an enticing, but incorrect and dangerous policy option
Placing short-term budgetary considerations before long-term patient well-being is pennywise and pound foolish, and is deleterious to both the public purse and public health.
The bioequivalence issue is clearly rising up the list of FDA priorities
Consider the agency’s action last week when it informed Mallinckrodt its methylphenidate hydrochloride tablets might not be therapeutically equivalent to Concerta
the drug produced by Mallinckrodt may deliver the drug at a slower rate than another generic version of Concerta
no longer recommends them as an automatic substitution for Concerta.
As my friend and colleague, Dr. Scott Gottlieb has written:
FDA has tried to retrofit the “Hatch Waxman” generic drug law and policies that govern approval of small molecule drugs to these complex drugs, with sometimes troubling results
The problem is that FDA has refused to define these complex drugs as distinct from normal, small molecule medicines.
The agency’s desire to try and squeeze these complex drugs through its existing generic law approval pathway may have as much to do with political expediency as with good science
The good news is that the FDA recognizes the need for more specific, regular, and predictable standards
We must think differently about bioequivalence on the front end and pharmacovigilance on the back-end.
SPEs occur when a product does not perform as expected—perhaps because of API or excipient issues – or too broad of a bioequivalence range and issues relating to therapeutic interchangeability.
we must also strive to capture Substandard Pharmaceutical Events (SPEs)
Outcomes is so much more than a value-based reimbursement issue.