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Are Generic Drugs Really Inferior Medicines? N Moore1, D Berdaï1 and B Bégaud1 In this issue Gagne et al. report an elegant case-crossover study of seizures in patients on antiepileptic drugs. They found that a dispensation episode approximately triples the risk of having a seizure within 21 days, but the risk is not statistically different whether the dispensation was of the same brand-name or generic drug as previously used or a switch from brand-name to a generic or from a generic to a brand name. The cause of the seizure might be a delay in taking medication or late redispensation, among others, but apparently the nature of the product dispensed is not relevant in this study; this may alleviate some of the concerns about generic drugs and epilepsy.
Generic drugs raise many interesting questions, some of which are scientific and medical, others more metaphysical, theoretical, or emotional. Beyond purely economic or marketing considerations, they can sometimes generate strong passions. Generics are used to contain pharmaceutical costs in health care by introducing an element of price competition once the patent on the innovator-branded or reference-listed product has expired, generally after a dozen years or so on the market. The pharmacist can or must substitute a cheaper generic for a prescribed branded product. The introduction of generics will often seriously reduce the drug’s cost to consumers and health-care systems, and the innovator company’s profits. This is often not a trivial reduction. For a generic to be approved, the manufacturer must provide proof that
the generic product can be manufactured with consistent high quality, and for systemically acting drugs the generic must provide systemic exposures (two one-sided 95% confidence intervals (CIs) around maximum concentration (Cmax) and area under the curve) that are within the prespecified equivalence boundaries (80–125%). For some drugs, there may be more latitude concerning Cmax, depending on the type of drug, the therapeutic ratio, or the need for strictly controlled plasma concentrations such as for antiepileptics or immunosuppressants, where over- or underdosing might result in serious toxicity or lifethreatening treatment failure. For drugs used essentially for long-term prevention such as treatment of hypertension or hyperlipidemia, or drugs with a wide therapeutic margin, the dose–response relationship is less marked and strict
plasma concentration control may be less important. The precise recommendations for development of generics can be found on the US Food and Drug Administration and European Medicines Agency websites, including for specific drugs or drug families (http://www.fda. gov; http://www.ema.europa.eu). There may be a risk of treatment failure or toxicity because of the differences in pharmacokinetics between the princeps (the originally patented formulation) and the generic, or between generics. Even though the quantity of active ingredient in each tablet is determined within strict limits so that there are exactly the same quantities of active products, the individual absorption characteristics of each tablet might differ by as much as 40%, which is the range between the allowed upper and lower limits of the CI of the mean concentration ratios. However, the probability of one drug being at the upper limit of the CI and the other being at the lower limit is less than 0.0025 (1 in 400), which for an individual patient might occur once in 33 years’ continuous treatment while switching drugs every month. It has been argued (usually by experts or representatives of the innovator drug companies) that this could be a major public health problem. Indeed, many cases have been reported of patients who had unsatisfactory disease control after being switched to a generic. However, such a loss of disease control might be reported if it occurs after switching but not reported when the same drug is pursued. There may be other reasons for differences between generics and branded drugs. If, for instance, the drug is a racemic with isomers that have different potencies, and the generic has an isomer distribution different from that of the
1Department of Pharmacology, University of Bordeaux, Bordeaux, France. Correspondence: N Moore (
[email protected])
doi:10.1038/clpt.2010.168 302
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perspec tives innovator, the result might be a different activity profile with the same pharmacokinetic profile in plasma concentrations measured using methods that do not differentiate isomers.1 Pharmaceuticals containing different excipients having influence on safety (e.g., allergy) or pharmacokinetics (e.g., slow-release formulations) are less common. Finally, there may be an issue of patient confusion over different drug names, appearances, or colors when switching between innovator and generic presentations, resulting in overdose when both are taken, or mistrust, noncompliance, and inefficacy when neither is. These patient errors might contribute to reports of generic failure or toxicity. Of course, the generic may actually be substandard. This has been shown with generics produced in countries that may not have the same quality control as mainstream industrial countries. This has also been the case for drugs produced in the mainstream countries. 2 Most branded drugs are now manufactured in the same countries and often in the same factories as their generics, and the biggest producers of generics are often the makers of the original drug. Regulators have significant issues with the quality of products coming from manufacturers in the developing world, and this applies to innovator drugs as well as generics. “Gray market” imports and counterfeit medicines, usually sold over the Internet, are also a real concern. Even though they may be confused with generics, these fake medicines are outright fraudulent, and this is a different issue.3 On the other hand, there is no requirement to test bioequivalence between batches of innovator drugs coming from the same or different factories, even in different countries. In fact, generics might well be better characterized than different batches of the innovator drug. The field is very complex; real concerns about drug quality and patient safety interact with potentially huge financial consequences and very real conflicts of interest both for and against generics. There are many reports of treatment failures with generic drugs in which improvement occurred when
the patient was switched back to a brand-name medicine.4–6 Experts have expressed opinions against switching to generics and made recommendations to request nonswitching by prescribers. However, there are few formal, scientifically sound studies of the effects of switching from brand-name to generic drugs and back. Kesselheim et al.7 carried out a meta-analysis of clinical trials comparing brand-name and generic versions of cardiovascular drugs such as β-blockers, diuretics, calcium channel blockers, antiplatelet agents, statins, angiotensin-converting enzyme inhibitors, warfarin, and α-blockers. They found no evidence of any negative consequences of using generic rather than brand-name drugs. The same authors also did a meta-analysis of studies comparing brand-name antiepileptic drugs to generic drugs. They found no clinical difference in randomized clinical trials, although observational studies indicated differences in health services utilization.8 Other studies found no difference between brand-name cyclosporine and a generic, even with a complex formulation in high-risk patients,9 or for highly active antiretroviral therapy.10 The study by Gagne et al.11 adds to the scientific arguments against an added risk of generic drugs. In this study of more than 1,700 cases of seizures requiring hospitalization, the refill-adjusted odds ratio of seizure after switching from a branded to a generic drug had a point estimate of 1.04 to 1.19. Because of the relatively small number of seizures occurring after a switch (15–19), the power was not sufficient to formally exclude a two- or threefold increase in the risk. On the other hand, the risk concerned about 1% or less of all hospitalized seizures. Like most observational studies, this one is not definitively conclusive but adds to the amount of scientific data for or against increased risk associated with generics. Larger studies and similar studies in various settings should progressively make the image clearer. In conclusion, the use of generics raises many real or perceived problems in clinical practice because of possible quality defects or specific ingredients
not included in the branded medicines and because of patient confusion with drug names and physical aspect, especially in the elderly. Quality issues must be constantly monitored and addressed, but this is a purely technical problem and pertains to both generic and branded drugs. The relevance of pharmacokinetic or other nonqualitative differences to patient health is uncertain. Finally, the magnitude of the economic stakes adds to the importance of collecting objective medical data. Clearly it is time to step back from anecdotal case reports and expert opinion and move instead to evidence-based judgment using clinical trials and metaanalyses, in addition to well-designed pharmacoepidemiological studies— such as the one presented here by Gagne and colleagues—to monitor the real impact of generics on patient health care and safety. There is still not much real evidence, but for the moment it is in favor of generics. CONFLICT OF INTEREST The authors declared no conflict of interest. © 2010 ASCPT
1. Mattar, M. Failure of copy Imatib (CIPLA, India) to maintain hematologic and cytogenetic responses in chronic myeloid leukemia in chronic phase. Int. J. Hematol. 91, 104–106 (2010). 2. FDAnews. FDA considers further regulatory action against McNeil (6 May 2010). 3. Lon, C.T. et al. Counterfeit and substandard antimalarial drugs in Cambodia. Trans. R. Soc. Trop. Med. Hyg. 100, 1019–1024 (2006). 4. Rascati, K.L., Richards, K.M., Johnsrud, M.T. & Mann, T.A. Effects of antiepileptic drug substitutions on epileptic events requiring acute care. Pharmacotherapy 29, 769–774 (2009). 5. Rodriguez, C.A., Agudelo, M., Catano, J.C., Zuluaga, A.F. & Vesga, O. Potential therapeutic failure of generic vancomycin in a liver transplant patient with MRSA peritonitis and bacteremia. J. Infect. 59, 277–280 (2009). 6. Armstrong, T.S., Choi, S., Walker, J. & Gilbert, M.R. Seizure risk in brain tumor patients with conversion to generic levetiracetam. J. Neurooncol. 98, 137–141 (2010). 7. Kesselheim, A.S. et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA 300, 2514–2526 (2008). 8. Kesselheim, A.S. et al. Seizure outcomes following the use of generic versus brand-
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perspec tives name antiepileptic drugs: a systematic review and meta-analysis. Drugs 70, 605–621 (2010). 9. Al Wakeel, J.S. et al. Six-month clinical outcome of cyclosporine microemulsion formulation (Sigmasporin Microral) in stable renal transplant patients previously maintained on sandimmun neoral. Transplant Proc. 40, 2245–2251 (2008).
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10. May, S.B. et al. Effectiveness of highly active antiretroviral therapy using non-brand name drugs in Brazil. Braz. J. Med. Biol. Res. 40, 551– 555 (2007). 11. Gagne, J.J., Avorn, J., Shrank, W.H. & Schneeweiss, S. Refilling and switching of antiepileptic drugs and seizure-related events. Clin. Pharmacol. Ther. 88, 347–353 (2010).
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CYP2D6, serotonin, and suicide—a relationship? L Bertilsson1 Early studies showed that the concentration of the serotonin metabolite 5-hydroxyindole acetic acid in cerebro spinal fluid was decreased in patients who had attempted suicide. 1 Lester 2 later performed a meta-analysis of 27 research reports and found strong evidence for the involvement of the serotonin system in suicidal behavior, especially in patients using violent methods. Isacsson et al.3 demonstrated a substantial decrease in suicides in Sweden during the years 1995–2005 in parallel with an increased use of antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs). These authors discuss the evidence that treatment of depression with antidepressants prevents suicide. These data seem to indicate that serotonergic mechanisms are involved in etiology of suicidal behavior. Suicide is a very serious condition not only for those committing it and for society, but also for relatives and friends. It is therefore important to gain more knowledge about its etiology and prevention. In this issue of Clinical Pharmacology & Therapeutics, Zackrisson et al.4 describe the very interesting result that in 262 cases of suicide, the frequency of the cytochrome P450 CYP2D6 gene duplication is 10-fold higher (P = 0.007)
than in natural death cases used as controls. CYP2D6 gene duplication causes ultrarapid metabolism of drugs such as antidepressants (tricyclics as well as SSRIs) and neuroleptics.5 What is the relationship to suicide? The relationship might have a very simple explanation—that the suicide cases had been depressed and were treated with antidepressants unsuccessfully as a result of ultrarapid metabolism. Data on diagnosis and drug treatment were not available from the article by Zackrisson et al. We have previously shown that in depressed patients who failed to respond to antidepressants (known to be substrates of CYP2D6), the frequency of CYP2D6 gene duplication is 10-fold higher than in healthy Swedes.6 Rau et al.,7 in Germany, came to a similar conclusion. However, for the suicide cases examined by Zackrisson et al., no information is available on therapeutic failure of antidepressants. Therefore, an alternative explanation to the overrepresentation of CTYP2D6 gene duplication among the suicide cases was touched on by these authors. We found in 1989 that the personality of poor metabolizers of debrisoquine was significantly different from that of extensive metabolizers.8 This difference in personality between CYP2D6
1Division of Clinical Pharmacology at Karolinska Institutet, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden. Correspondence: L Bertilsson (
[email protected])
doi:10.1038/clpt.2010.144 304
phenotypes and/or genotypes has been confirmed in some, but not all, publications (see the discussion in a recent article on the personality of Cubans by Gonzalez et al.9). A relationship between personality and the drug-metabolizing CYP2D6 enzyme, with its main action in the liver, seems at first difficult to understand. However, CYP2D6 is also—but at a lower activity—present in the human brain,10 where its distribution follows that of dopamine nerve terminals. Siegle et al.11 clearly demonstrate that CYP2D6 messenger RNA and protein are expressed within different regions of normal human brain. As discussed in an editorial by Eichelbaum,12 several endogenous substrates of CYP2D6 have been demonstrated. Of special interest for personality and suicidal behavior is the fact that 5-methoxytryptamine is O-demethylated by CYP2D6 to serotonin.13 Serotonin might then be synthesized in dopaminergic neurons by CYP2D6 and acts as a false transmitter in “wrong” (inhibitory?) neurons. Although a link between CYP2D6 activity and serotonin or dopamine action might be a farfetched speculation, the observation of different platelet serotonin concentrations in subjects with different CYP2D6 genotypes14 gives further support for this. The results of Zackrisson et al.4 are very interesting, but a full explanation why CYP2D6 gene duplication is related to suicidality cannot yet be provided. In one way or another, serotonin seems to be involved. CONFLICT OF INTEREST The author declared no conflict of interest. © 2010 ASCPT
1. Träskman, L., Åsberg, M., Bertilsson, L. & Sjöstrand, L. Monoamine metabolites in CSF and suicidal behaviour. Arch. Gen. Psychiatr. 38, 631–636 (1981). 2. Lester, D. The concentration of neurotransmitter metabolites in the cerebrospinal fluid of suicidal individuals: a meta-analysis. Pharmacopsychiatry 28, 45–50 (1995). 3. Isacsson, G., Holmgren, A., Osby, U. & Ahlner, J. Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995– 2005. Acta Psychiatr. Scand. 120, 37–44 (2009). 4. Zackrisson, A.L., Lindblom, B. & Ahlner, J. High frequency of occurrence of CYP2D6 gene
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