Generic drugs now comprise approximately 90 percent of all prescription drug purchases in the United States, while accounting for only 20 percent of all prescription drug spending.1 These statistics result from the statutory, regulatory, and biomedical research efforts of diverse stakeholders. For its part, the FDA has streamlined its oversight of generic drug development through modernized processes related to bioequivalence study design and data review. In addition, the agency’s research capabilities have been broadened to advance the standards upon which generic drug products can be assessed for efficacy, safety, and quality. Collaboration with industry, lawmakers, and patient advocacy organizations has been essential to improving marketing practices and competitiveness in generic manufacturing.2
The benefits of a robust national generic drug program are clear, both in terms of patient health and the economic sustainability of our national healthcare system more broadly. Still, we continue to face challenges particular to the generic drug landscape. Some of these arise from the scientific and regulatory complexities essential to the products themselves, whereas others appear to stem from societal perceptions of drug development and regulation that we are still working to appreciate.3 We have learned, for example, that differences in the appearance of generic pill products, despite their established bioequivalence, may be associated with the failure of certain patients to adhere to evidence-based therapeutic regimens.4 We also have seen, particularly for drugs that manifest a narrow therapeutic window (i.e., drugs where small differences in dose or blood concentration may lead to serious therapeutic failures or adverse drug reactions), that physicians may be more likely to prescribe brand-name products over approved generic products.5
In this Spotlight on CDER Science, we review recent FDA-sponsored research that looks retrospectively at the clinical dynamics related to the therapeutic use of levothyroxine, a drug that not only has a narrow therapeutic window, but that also is one of the most widely prescribed drugs in the United States. The research, published in JAMA Internal Medicine,6 capitalizes on the use of health records to identify patients (anonymously) who have switched in their use of generic manufactured thyroxine products while being monitored for thyroid function over time. The focus on levothyroxine allowed the researchers, first, to execute a real-world clinical review (within limitations dictated by available claims data) of an FDA-approved therapeutic available from several alternative generic manufacturers. Second, the investigators’ analysis extends to a consideration of whether social or institutional concerns, rather than potential evidence-based issues related to generic product performance, may ultimately place limitations on the uptake and prescribing practices of approved generic drug products.
Another reason for focusing on levothyroxine is that the generic prescription rate observed for the drug, relative to brand-name prescription rate, is much lower than the value of 90% cited for approved prescription drugs in general.6 Prior to initiating their study, the researchers had noted, in fact, that the American Thyroid Association (ATA) had questioned the FDA’s methods for determining bioequivalence between levothyroxine products,6 which measured levels of thyroid hormones directly and compared them among volunteers taking different levothyroxine products. The ATA guidelines recommended using thyrotropin levels as the biomarkers for evaluation of therapeutic equivalence. In the absence of such evidence, the ATA recommended that prescribers avoid switching between levothyroxine products in the treatment of hypothyroid patients. As a result of that recommendation, brand-name levothyroxine was preferentially prescribed over generic levothyroxine products.
The FDA-sponsored study found that, for a population of patients (N > 15,000) undergoing properly monitored levothyroxine treatment over time, those who switched among generic drug products maintained the same level of thyroid function (as indicated by average serum thyrotropin level) as those who consistently used a single levothyroxine product. These results establish evidence that should mitigate concerns such as those raised by the ATA over levothyroxine product switching.
The researchers were careful to point out that their study was not designed to assess the therapeutic equivalence of levothyroxine products. Rather, by meticulously culling through a national administrative claims database that linked laboratory test measures of thyroid function of patients undergoing treatment with levothyroxine products, the investigators identified and matched two patient populations to compare the effects of product switching to single-product use over the course of treatment. Their conclusion is that switching among different generic levothyroxine products was not associated with clinically significant changes in thyroid function (as indicated by subgroup average serum thyrotropin level). The researchers’ conclusion—although fully consistent with FDA precepts of bioequivalence and, at the pharmacy level, product interchangeability itself—conflicts with current ATA guideline recommendations that warn clinicians about potential changes in thyroid function associated with levothyroxine product switching.
The impact of our nation’s generic drug program has been immense, with generic drugs having saved our healthcare system upwards of $2.44 trillion dollars in the past decade. Improving drug competition and boosting patient access to innovative and affordable treatments remains a priority for the FDA. As science and evidentiary standards are strengthened to further this success, it becomes equally important to identify factors—scientific or otherwise—that may limit our full potential to realize benefits in the generic/interchangeable product space. The CDER-sponsored research discussed here suggests that there may be institutional resistance among some stakeholders that may not be supported by real-world evidence.
1Association for Accessible Medicines. The U.S. Generic & Biosimilar Medicines Savings Report. October 2021. https://accessiblemeds.org/sites/default/files/2021-10/AAM-2021-US-Generic-Biosimilar-Medicines-Savings-Report-web.pdf. Accessed April 22, 2022.
2US FDA. FDA drug competition action plan. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/fda-drug-competition-action-plan. Accessed April 22, 2022.
3Deloitte. Will more generic drug approvals push prices down, or push manufacturers away? https://www2.deloitte.com/us/en/blog/health-care-blog/2020/will-more-generic-drug-approvals-push-prices-down.html. Accessed April 22, 2022.
4US FDA. From our perspective: The importance of the physical characteristics of generic drugs. https://www.fda.gov/drugs/news-events-human-drugs/our-perspective-importance-physical-characteristics-generic-drugs. Accessed April 22, 2022.
5Kesselheim AS, Misono AS, Lee JL, et al. Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease: A Systematic Review and Meta-analysis. JAMA. 2008;300(21):2514–2526. doi:10.1001/jama.2008.758.
6Brito JP, Deng Y, Ross JS, Choi NH, Graham DJ, Qiang Y, Rantou E, Wang Z, Zhao L, Shah ND, Lipska KJ. Association Between Generic-to-Generic Levothyroxine Switching and Thyrotropin Levels Among US Adults. JAMA Intern Med. 2022 Apr 1;182(4):418-425. doi: 10.1001/jamainternmed.2022.0045. PMID: 35226058; PMCID: PMC8886450.