Generics, Bioequivalence, and Justice

By Matthew L Baum

I have written previously on this blog about morally modifying technologies (here and here), which by definition work no better than existing technologies but enable the side-stepping of a moral tension associated with the first technology. Generic pharmaceuticals are a particularly well-known and widely endorsed form of morally modifying technology: they have no therapeutic advantage over name-brand drugs, but by costing less enable the sidestepping of some of the difficult moral issues involved in rationing healthcare.   With the current public focus on limiting the rising cost of healthcare, moreover, there is increasing emphasis on the development and use of generics as a cost-saving measure. Jonathan J. Darrow has already written on this blog questioning whether we should celebrate increasing public endorsement of the development of these drugs that bring with them no new therapeutic benefit. But I would like to highlight in this post a different challenge to the responsible pursuit of a golden age of generics: bioequivalence.

Helping the development costs of generics to stay low, the FDA has an abbreviated approvals process that hinges on the generic being shown ‘bioequivalent’ to the name-brand drug (on top of requiring the generic to contain the same active chemical and be taken by the same route and dosage form) [See here and here]. Bioequivalence may sound reasonable, but many would be surprised to learn that it does not mean therapeutic equivalence.

As I learned upon attending a recent talk on general pharmacology, a generic is considered to be bioequivalent if 1) the highest concentration the drug reaches in the blood is 20% above or 20% below that of the brand name and 2) the amount of drug in the blood over time is +/- 20% of the brand name (i. e. area under a curve of serum concentration of drug plotted vs time); the estimates must both fall within the 90% confidence interval. The study to show bioequivalence is carried out in a small sample of healthy individuals (which may raise concerns about the generalizability of the measures to the target population of sick individuals); there is no requirement to investigate whether the product in its generic formulation produces an equivalent therapeutic effect.

Five factors come together to make this standard of bioequivalence problematic:

  1. While the brand-name manufacturer is required to specify the exact process by which they make the drug, this is not required for generics and differences in production can introduce considerable variability in cases where a popular drug is produced by multiple manufacturers.  Since two generics may vary from the brand-name in different directions, a generic that is 20% above the brand name and a generic that is 20% below could each be considered by the FDA “bioequivalent” to the brand name and approved for use but at the same time would be far from “bioequivalent” to each other; this is especially complex with generics of drugs like Percocet, which are combinations of several active molecules.
  2. Pharmacies usually dispense the generic that is currently the cheapest (they are sometimes required to do this), which leads to generic-generic switches that are often unknown to the prescribing physician; this practice would be reinforced if insurers reimburse for only the cheapest generic or in the case of pharmacies that are part of larger organizations that make “package” purchases from a single supplier (like getting a discount if you buy cable, phone, and internet from the same company).
  3. As a greater number of generics become available for each name-brand and competition rises, the frequency of switches may be likely to increase.
  4. While in many cases patients can tolerate variations in drug concentrations, there are times when they can’t. If the drug has a narrow therapeutic window, i.e. a little too much can mean terrible side effects or too little can mean it is ineffective, then +/-20% may be too much room for error. This is the case for drugs to control seizures, to treat cancer, or to maintain tolerance of transplants.  The risk for complication is also greater in particularly vulnerable patient populations like the very elderly or those with multiple significant medical problems; since bioequivalence is shown on the young and healthy, the variability of drug exposure might be especially large in these vulnerable populations.
  5. With Wyeth v. Levine, 555 U.S. 555 (2009), and PLIVA, Inc. v. Mensing, 131 S.Ct. 2567 (2011), patients who are injured as a result of generic-generic variations may have no recourse to recover damages under state tort law.

The EU and more recently the US have taken measures to address the risks to those on drugs with narrow therapeutic indexes: a) narrowing the percent variation in drug concentrations that is accepted as bioequivalent, b) recommending careful monitoring for complications/loss of efficacy (at not-insignificant cost) of brand-name to generic and generic to generic switches c) and physician notification of any changes in medication.

To prevent reaping the cost savings of generics at the expense of increased risk to our most vulnerable patients, we could consider extending these sorts of measures of therapeutic monitoring and decreased accepted variability to generics more broadly or to generics with multiple manufacturers. But, of course, each of these new measures comes at a cost to the health-care system and thereby diminishes the core benefit of developing generics.

mbaum

mbaum

During his fellowship, Matthew Baum was a second year MD-PhD student in the Health Science and Technology (HST) combined program of Harvard and MIT where he integrated his interests in clinical, scientific, and ethical aspects of mental health. He holds a DPhil at the Oxford Centre for Neuroethics where his doctoral work, supported by a Rhodes Scholarship, concerned the ethical implications of the development of predictive biomarkers of brain disorders. Matthew also completed an MSc in Neuroscience at Trinity College Dublin as a George Mitchell Scholar and holds a BS and an MS in Molecular Biology from Yale. During his medical and neuroscience training he maintained a strong engagement with neuroethics; he has acted as the student representative to the International Society for Neuroethics. During his time at the Petrie-Flom Center, Matt researched the intersection of biological risk and disorder.

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