US scientists reviewing 20 years of research and expert opinion on generic versus brand name drugs in the treatment of cardiovascular diseases found no clinical evidence showing brand names were superior to generic versions even though a substantial number of experts writing editorials advised against interchanging them.
The study was the work of Dr Aaron S Kesselheim, of Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues, and is published online in the 3rd December issue of the Journal of the American Medical Association, JAMA.
When two drugs are bioequivalent it means that to all intents and purposes after they have been given to the patient they are biologically equivalent to each other, for example the composition, rate and extent to which their active ingredients are present at the target site inside the body are so similar that you can’t tell the difference between them.
And yet there appears to be a general opinion among doctors and patients that despite the fact generic drugs are bioequivalent to brand name drugs, the brand names are clinically superior. But generic drugs are much cheaper, so Kesselheim and colleagues decided to investigate the available clinical evidence on generics versus brand names and the views of editorial writers on the subject with respect to cardiovascular treatments.
For the study, the researchers systematically searched for peer reviewed studies published between 1984 and 2008 and listed in a number of well known databases, including MEDLINE, EMBASE, and International Pharmaceutical Abstracts.
They selected those studies that compared the clinical effectiveness and safety of generic versus brand name cardiovascular drugs. In a separate exercise they also identified editorials that wrote about substituting brand names with generic versions.
Kesselheim and colleagues then used techniques commonly used in research that reviews other studies, whereby the design, setting, participants, results and funding of each study is extracted and put through a test that assesses the quality of the trial, whilst the results are pooled in such a way that they can then be viewed as if they had come from one giant trial (meta-analysis).
As a separate exercise they reviewed the editorials and classified them as negative, positive or neutral, depending on the authors’ view on generic substitution.
They found a total of 47 clinical trials covering 9 subclasses of cardiovascular drugs, and established the following results:
- 38 of the 47 (81 per cent) trials were randomized controlled trials (considered to be higher quality).
- For beta-blockers, 7 out of 7 randomized controlled trials (100 per cent) found generics to be clinically equivalent to brand names.
- For diuretics, the figure was 10 out of 11 (91 per cent).
- For calcium channel blockers it was 5 out of 7 (71 per cent).
- For antiplatelet agents it was 3 of 3 (100 per cent).
- For statins it was 2 out of 2 (100 per cent).
- For angiotensin-converting enzyme inhibitors it was 1 out of 1 (100 per cent).
- And for alpha-blockers, 1 out 1 randomized controlled trial (100 per cent) found generics to be clinically equivalent to brand names.
- In drugs that have a narrow therapeutic index (where you have to be really careful to give the right dose so as not to injure the patient), clinical equivalence was found in 1 out of 1 randomized controlled trial (100 per cent) for class 1 antiarrhythmic agents, and in 5 out of 5 (100 per cent) for warfarin.
- Pooling the results of all the trials gave a total of 837 participants and an aggregate effect size of -0.03 (95 per cent confidence interval of -0.15 to 0.08), meaning that across the studies as a whole, there was no statistically significant evidence that brand names were superior to generic drugs.
Reviewing the material from 43 editorials, the researchers found that:
- 23 of them (53 per cent), expressed a negative view about whether generic drugs could replace or be used instead of brand names.
- This compared with 12 (28 per cent) that encouraged substitution.
- The other 8 editorials did not reach a conclusion on interchangeability.
- Among editorials covering narrow therapeutic index drugs, 12 (67 per cent) expressed a negative view compared with 4 (22 per cent) in favour generic substitution.
Kesselheim and colleagues concluded that:
“Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.”
They wrote that the rising cost of prescription drugs is a critical policy issue: it strains the budgets of patients and insurance providers, and leads to poorer health as it works against helping everyone to make sure patients can complete their medication schedules.
“The primary drivers of elevated drug costs are brand-name drugs, which are sold at high prices during a period of patent protection and market exclusivity after approval by the Food and Drug Administration (FDA),” they added.
The idea of generics is to help people afford drugs, and these become available after the brand names have had their period of being the only ones on the market, the so called exclusivity period. Many doctors and payers encourage this.
However, some patients and doctors have been concerned that the generic versions may not be as effective. As Kesselheim and colleagues explained:
“Brand-name manufacturers have suggested that generic drugs may be less effective and safe than their brand-name counterparts. Anecdotes have appeared in the lay press raising doubts about the efficacy and safety of certain generic drugs.”
Kesselheim and colleagues suggested that one explanation for the discordance between the clinical evidence and the opinion expressed by experts in the editorials could be that:
“Commentaries may be more likely to highlight physicians’ concerns based on anecdotal experience or other nonclinical trial settings.”
Another explanation they suggested was that the:
“Conclusions may be skewed by financial relationships of editorialists with brand-name pharmaceutical companies, which are not always disclosed.”
Nearly half the trials (23 out of 47) and nearly all the editorials and commentaries they reviewed did not reveal where the funding came from, noted Kesselheim and colleagues, who also wrote that:
“We identified numerous studies that evaluated differences in clinical outcomes with generic and brand-name medications. Our results suggest that it is reasonable for physicians and patients to rely on FDA bioequivalence rating as a proxy for clinical equivalence among a number of important cardiovascular drugs, even in higher-risk contexts such as the NTI drug warfarin.”
“These findings also support the use of formulary designs aimed at stimulating appropriate generic drug use. To limit unfounded distrust of generic medications, popular media and scientific journals could choose to be more selective about publishing perspective pieces based on anecdotal evidence of diminished clinical efficacy or greater risk of adverse effects with generic medications. Such publications may enhance barriers to appropriate generic drug use that increase unnecessary spending without improving clinical outcomes,” they added.
“Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease: A Systematic Review and Meta- analysis.”
Aaron S. Kesselheim; Alexander S. Misono; Joy L. Lee; Margaret R. Stedman; M. Alan Brookhart; Niteesh K. Choudhry; William H. Shrank.
JAMA. Vol 300, No 21, pp 2514-2526, December 3, 2008.
Written by: Catharine Paddock, PhD