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Evaluating Truth in Off-Label Marketing

How can lawmakers promote safer COVID-19 treatment?



By: Shivan Lala


The race to find an effective COVID-19 treatment has extended beyond the development of novel therapies, as many look to existing antiviral medications as a promising option. Off-label drug use is commonplace in cancer research, and a US District Court ruled in Amarin Pharma, Inc. v. FDA that marketing such use is permissible under the First Amendment. However, this ruling relies on assumptions of scientific integrity that do not exist in off-label drug research. Future policy aimed at effective and safe COVID-19 treatment should instead apply a heightened level of scrutiny to off-label drug use to ensure rigorous scientific testing.

A central aspect of upholding off-label marketing via the First Amendment is the assumption that the manufacturers’ statements are “truthful”. As demonstrated in Amarin, allowing such marketing promotes increased transparency regarding both consumer choice and education, promoting freedoms that are not constitutionally regulated by a government agency. However, these arguments rest on a faulty foundation that assumes the scientific “truth” (namely efficacy and safety) of off-label pharmaceutical treatments. While the FDA standards for researching and producing a drug are notoriously high, the same level of scrutiny is not required in exploring off-label effects on other disease models. The standard practice of promoting off-label pharmaceutical uses is much less empirical and scientific than perceived in Amarin, which fundamentally undermines the idea that it can be used to inform “decision making in an open marketplace”.


When treating cancer, clinical oncologists rely on off-label prescriptions an estimated 50% of the time, primarily based on a physician’s experience with the drug. While this number may seem promising, allowing this standard of care de-incentivizes pharmaceutical companies from subjecting their drugs to scientifically rigorous testing to validate their off-label claims. According to Jonas de Souza, a Hematology and Oncology professor at the University of Chicago Pritzker School of Medicine, “…if the drug is already widely adopted in practice, there is no financial incentive for the drug company to pursue [off-label testing]”. He further recognizes that “very few studies that assess the use of off-evidence drugs in oncology”, contradicting the idea that current regulatory standards can accurately deem an off-label marketing effort “truthful”. Without a rigorous testing method of these claims, it is nearly impossible to decide if cases of off-label marketing can be upheld under the First Amendment.


A topical example of this issue arises with the use of Chloroquine/Hydroxychloroquine to treat COVID-19. While this has been touted as an example of effective off-label drug use, a simple inquiry into its efficacy as a COVID-19 treatment immediately raises concerning questions. A recent preprint of a Chloroquine clinical trial noted that “no published reports of robust clinical studies on the safety and/or efficacy of chloroquine (CQ) and/or hydroxychloroquine (HCQ) for the treatment of COVID-19 during the recent 2020 pandemic”. More recently, The Lancet conducted a study involving over 96,000 COVID-19 patients and was “unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with

a macrolide, on in-hospital outcomes for COVID-19”. Another off-label antiviral, Remdesivir, demonstrated effective COVID-19 treatment in early in vitro (in a test tube) and mouse models and was thought to be a promising option. However, human testing conducted by Gilead lacked important experimental conditions such as placebos and was still unable to find significant effects of the drug. Overall, off-label drug marketing demonstrates a systemic lack of accurate testing, the validity of which is paramount to many of the First Amendment criticisms leveled against regulation.


The potential harm of promoting an ineffective or unsafe drug during this pandemic is immeasurable, causing both unintended side effects and premature reopening and restriction easing. If off-label drug use contributes to major COVID-19 public health decisions, their efficacy and safety must undergo the same level of robust testing as the original drug. Many of the arguments that call for unregulated/deregulated off-label marketing operate under the assumption that these off-label uses are backed up by sound science, which has not been demonstrated in practice. Instead, lawmakers should advance legislation that promotes thorough vetting of off-label claims before they can be introduced to the general public.

References

1. Avorn, J., Sarpatwari, A. & Kesselheim, A. S. Forbidden and permitted statements about medications - Loosening the rules. N. Engl. J. Med. 373, 967–973 (2015).

2. de Souza, J. A. Off-Label Drug Utilization in Oncology – Hematology & Oncology. Clinical Advances in Hematology & Oncology https://www.hematologyandoncology.net/archives/june-2011/off-label-drug-utilization-in-oncology/.

3. Off-Label Drug Use in Cancer Treatment - National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/drugs/off-label.

4. Gabriela Silva Borba, M. et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study) CloroCovid-19 Team (in alphabetical order). doi:10.1101/2020.04.07.20056424.

5. Mehra, M. R., Desai, S. S., Ruschitzka, F. & Patel, A. N. Articles Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19 : a multinational registry analysis. Lancet 6736, 1–10 (2020).

6. Goldman, J. D. et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N. Engl. J. Med. NEJMoa2015301 (2020) doi:10.1056/NEJMoa2015301.

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