Black-box safety warnings and the future of generic drug liability

Generics/Research | Posted 07/12/2012 post-comment0 Post your comment

Generic medicines currently have no responsibility for adding warnings about adverse effects of their medicines. Despite the US Supreme Court ruling that it was ‘impossible’ to force generics manufacturers to update their labels with the latest warnings, many feel that they have an ethical responsibility to do just that [1].

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Although black-box safety warnings are routinely added to drug labels after approval [2], they have occasionally been based on adverse effects data that come to light only after there is generics competition, as was the case with metoclopramide, see Table 1. In many cases, such safety information did not emerge because of vigilance by the manufacturer or FDA, but owing to evolving litigation, publicly funded research or studies of competing products.

Table 1: Drugs with black-box warnings added after generics entry

Drug Approved (year) Warning content Warning added (year) Reason
Promethazine* 1956 Severe tissue injury, gangrene 2009 Litigation
Indomethacin 1965 Death from cardiovascular causes 2005 Results from randomized trials of cyclooxygenase-2 inhibitors
Haloperidol 1967 Increased mortality among elderly patients with dementia-related psychosis 2008 Canadian and US government-sponsored observational studies
Droperidol 1970 QT-segment prolongation, torsades de pointes (a specific, rare variety of ventricular tachycardia) 2001 Accumulated spontaneous reports
Disopyramide 1977 Increased mortality with class IC anti-arrhythmics 1996 Results from NIH-funded trial of other anti-arrhythmics
Metoclopramide 1980 Tardive dyskinesia (a difficult-to-treat form of dyskinesia, a disorder resulting in involuntary, repetitive body movements) 2009 Litigation
Fluoxetine 1987 Suicidal thinking and behaviour in children and adolescents 2004 Litigation that revealed suppressed clinical-trial findings
* Warning applies to injectable form only; NIH = National Institutes of Health.

And what if the originator stops marketing a drug? Even if production continues, the brand-name manufacturer usually sharply reduces the resources committed to that product, including support of ongoing safety assessments. Few generic drug firms routinely conduct rigorous post-marketing safety evaluations. Although some have grown into sophisticated multinational corporations, others are small, local firms by comparison. It is hard to see how they might cooperate equably in collecting, verifying and disseminating adverse effect reports.

A bipartisan group of lawmakers has introduced legislation seeking to make generics manufacturers responsible for updating their labels just as brand-name drug companies are. The legislation remains under consideration in both Congress and the Senate.

No-fault compensation
Alternatively, a system like that for vaccine-related injuries is proposed. A no-fault system operates in which injured parties receive compensation from a fund created by levying a small fee on each dose of vaccine administered. In the case of generic drugs, patients could qualify for similar compensation by demonstrating that they had been harmed by a generic drug side effect that was not properly addressed in the product information. Generics manufacturers that join the programme would only bear additional liability if their labels do not match a consensus version [3].

Collection of adverse reaction data and additional research, if necessary, could be managed by FDA or another government body with appropriate expertise. FDA would be responsible for overseeing the integration of new findings into a centrally-written consensus label. With generic drugs now accounting for more than 75% of US prescriptions, imposing a minimal fee on each prescription would provide the revenue for an important investment in pharmacovigilance.

Such a database would make it possible to pool adverse event reports. It would also be more sensible than the current approach, in which so much research on the risks posed by approved drugs is funded by the manufacturers – a situation that can lead to problems with the collection, analysis, and reporting of safety data [4]. Finally, this alternative approach would be in keeping with a stronger, better-managed role for FDA in monitoring drug side effects.

Editor’s comment
Please feel free to share your thoughts via email or in the comments section below. What are your views on this issue? Would an approach like that used for vaccines work for generics?

Related article

The ethics of generic drug liability

References

1.  Kesselheim AS, Avorn J, Greene JA. Risk, responsibility and generic drugs. N Engl J Med. 2012; 367(18):1679-81.

2.  Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:2215-20.

3.  Duke J, Friedlin J, Li X. Consistency in the safety labeling of bioequivalent medications. Pharmacoepidemiol Drug Saf. 2012 Oct 8. doi: 10.1002/pds.3351. [Epub ahead of print].

4.  Madigan D, Sigelman DW, Mayer JW, et al. Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies. Am Heart J. 2012;164:186-93.

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