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FDA Suggests ‘Institutional Resistance’ To Levothyroxine Generics Is Misplaced

American Thyroid Association Caution ‘May Not Be Supported By Real-World Evidence’

Executive Summary

Following the publication of a real-world case-study of levothyroxine use that included switching between different versions of the product, the FDA has suggested that “institutional resistance” to generics – including from American Thyroid Association guidance that warns against switching – “may not be supported by real-world evidence.”

Data provided by a new real-world case study of levothyroxine use – that included switching between multiple generic versions of the hypothyroidism treatment – effectively addresses “institutional concerns about generic product interchangeability,” according to commentary published by the US Food and Drug Administration.

Based on the FDA-sponsored comparative effectiveness research study – which was recently published in JAMA Internal Medicine – the US agency has suggested that “institutional resistance” to generics, including from American Thyroid Association guidance that warns against switching between versions of levothyroxine, “may not be supported by real-world evidence.”

The study itself concludes that “switching among different generic levothyroxine products was not associated with clinically significant changes in serum thyrotropin (TSH) level,” acknowledging that “these findings conflict with the current guideline recommendation that warns clinicians about potential changes in TSH level associated with switching among levothyroxine products sourced from different manufacturers.”

FDA Continue To Face Generic-Specific Challenges

Moreover, the agency has used the study as an opportunity to emphasize the benefits of generics more broadly, and to push back against elements that continue to restrict the uptake of bioequivalent off-patent alternatives.

Noting that generics account for around 90% of US prescription drug purchases at just 20% of the cost, the FDA said “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,” the agency pointed out, as well as broadening its research capabilities “to advance the standards upon which generic drug products can be assessed for efficacy, safety, and quality.”

“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,” the agency maintained, adding that “collaboration with industry, lawmakers, and patient advocacy organizations has been essential to improving marketing practices and competitiveness in generic manufacturing.”

“Still,” the FDA conceded, “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.”

“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.”

And “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.”

“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.”

Focusing on the levothyroxine study specifically, the FDA acknowledged that the product is “a drug that not only has a narrow therapeutic window, but that also is one of the most widely prescribed drugs in the US.”

However, at the same time “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.”

Noting that the research “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 agency explained that the researchers had been able 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.”

Moreover, “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.”

Prior to initiating their study, the agency indicated, the researchers had noted that the American Thyroid Association “had questioned the FDA’s methods for determining bioequivalence between levothyroxine products, which measured levels of thyroid hormones directly and compared them among volunteers taking different levothyroxine products.”

American Thyroid Association guidelines recommended using thyrotropin levels as the biomarkers for evaluation of therapeutic equivalence. But “in the absence of such evidence,” the agency noted, “the American Thyroid Association 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.”

But pointing to results of the study – which 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” – the FDA said “these results establish evidence that should mitigate concerns such as those raised by the American Thyroid Association over levothyroxine product switching.”

Switching Among Different Products Produced No Significant Changes

The researchers “were careful to point out that their study was not designed to assess the therapeutic equivalence of levothyroxine products,” the FDA highlighted.

“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 agency underlined that this conclusion was “fully consistent with FDA precepts of bioequivalence and, at the pharmacy level, product interchangeability itself,” even if it conflicted with the current American Thyroid Association guideline recommendations that warn clinicians about potential changes in thyroid function associated with levothyroxine product switching.

Concluding that “the impact of our nation’s generic drug program has been immense, with generic drugs having saved our healthcare system upwards of $2.44trn in the past decade,” the FDA said that despite this success “improving drug competition and boosting patient access to innovative and affordable treatments remains a priority for the FDA.”  (Also see "US Savings Top $338bn In 2020" - Generics Bulletin, 22 Sep, 2021.)

“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.”

And according to the FDA, the levothyroxine research “suggests that there may be institutional resistance among some stakeholders that may not be supported by real-world evidence.”

Association Says Study Is ‘Reassuring’

Responding to the study and FDA comments, a spokesperson for the American Thyroid Association told Generics Bulletin that the association “finds this study reassuring for patients and clinicians,” adding that the body “will include this study in the systematic review they conduct in preparation for their next update of their hypothyroidism guidelines.”

However, the association cautioned, “not all levothyroxine products (all brands and all generics) have been compared with each other in rigorous bioequivalence testing. So it remains reasonable for clinicians to be alert for altered thyroid status in individuals who have their levothyroxine products switched, and consider re-checking a patients thyroid function tests if the clinical situation suggests that the patient may have developed symptoms of either undertreatment or overtreatment of their hypothyroidism.”

Editor’s note: this story was updated on 10 May 2022 to include comments from the American Thyroid Association.

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