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The COVID-19 Crisis Casts More Light on Non-traditional Evidence in Biopharma

CiTRUS Market Access Practice 

May 2020

Johann Odermann - VP, Payer Strategy


One of the more noteworthy developments of the last few weeks has been the discussion and indeed controversy around the off-label use of a previously approved, widely available generic medication, hydroxychloroquine, and to a lesser extent azithromycin. Hydroxychloroquine as Plaquenil was first marketed by Sanofi Aventis in April of 1955 and is indicated for malaria prophylaxis and acute treatment, acute and chronic treatment of rheumatoid arthritis, and chronic discoid and systemic lupus erythematosus. Azithromycin, first approved in 1988, is indicated for a variety of bacterial infections including certain skin, sinus, lung, middle-ear, throat, and genitourinary infections. Azithromycin prevents bacterial growth via inhibition of protein synthesis, and as an antibacterial, azithromycin has no direct anti-viral effect. Azithromycin’s is thought to work on coronavirus infectionsby suppressing inflammatory processes via certain immune responses contributing to airway inflammation.


The pandemic has exposed a number of issues related to public health, supply chain management, and hospital / provider preparedness. One of the most prominent has been the search for effective treatments and expanded use of existing biopharmaceuticals that may prove effective in treating COVID-19 patients. The shift of healthcare systems in adjusting to the urgent need to identify and treat patients has created a number of issues in the near term that may have lasting changes in healthcare in the US – either due to their persistence beyond the immediate pandemic, or through lasting changes to themarkets and stakeholders as a result of the collective response. What follows below are some thoughts on off-label use of medicines, real-world evidence, and the potential for market change as a result of the pandemic and government response to the threat of widespread morbidity and mortality associated with COVID-19.


FDA Approval and Off-Label Use


Use of prescription medicines “off label” commonly refers to the act of prescribing or taking currently marketed medication for an indication other than that for which it was FDA approved. Off-label use isn’t restricted to anti-infectives, anti-virals, or acute medical conditions. Off-label prescribing may involve use in a different populations or age ranges than that in which it was clinically tested and approved. Contrary to what patients might assume, off-label drug use is not synonymous with experimental or research use - once a drug is FDA-approved it can be legally used for any indication with a valid prescription. Though more common in certain patient population such as children or elderly, off-label prescribing accounts for 10 to 20% of all prescriptions written in the US.

An FDA approval may imply that available, rigorous clinical evidence shows a drug is safe and effective for the specific indication, disease, or symptom for which it was tested. Approval is based on available evidence of effectiveness and safety however it is not a guarantee.  There are many notable examples of safety risks emerging after more extensive real world use, including Bextra, Vioxx, Omniflox, Cylert, Accutane, Seldane, Propulsid, and Rezulin. This reminds us that study and monitoring of medicines outside of drug manufacturer registration trials is essential.


The FDA does not prohibit physicians from prescribing drugs off-label and The United States does not require physicians to record the purposes for which they prescribe drugs. Indeed, Congress has taken steps to prevent the FDA from interfering with the practice of medicine. The law and courts have generally sided with physicians in finding doctors lack legal duty to inform patients of a drug’s regulatory status (FDA approved uses vs. off-label); The physician’s duty has been deemed that of providing clinical information, not informing patients of the legal complexities of FDA approval. Given the clinically complex presentation of many patients, physicians work to balance individual patient needs and characteristics with available scientific evidence in deciding whether to prescribe medications off-label.


There are many reasons why existing products are often prescribed off-label. The pace of medical practice innovation often outpaces the FDA’s ability to approve new drugs or relabel products previously approved. In disease where patient unmet medical needs outpace the ability for pharma companies to invest, off-label use is common, for example in cancer there is often evidence from academic physicians and researchers about the use on patients not listed in the label.


The FDA approves only 40 to 60 percent of drugs submitted for review, with the approval process often taking six to eight years and an average of $1.7 billion per approved product. The marginal increase in revenue associated with relabeling a drug with a supplemental indication consequently might not offset the added expense and time incurred in conducting necessary clinical trials. Another reason for common off-label prescribing is often a paucity of evidence regarding effectiveness of “on-label” use in certain patient populations especially those frequently excluded from clinical trials – e.g. children, pregnant women, elderly, and psychiatric patients. Finally there are cases where physicians have found, personally or anecdotally, that a particular treatment works despite not having an indication.


Recent News Updates


Within the last week Novartis announced that it will sponsor a Phase III trial assessing hydroxychloroquine as a treatment for hospitalized patients with COVID-19 having reached agreement with the FDA to launch the randomized, double-blind, placebo controlled study. Sandoz, Novartis’ generics and biosimilars division will donate hydroxychloroquine to be used in the study of approximately 440 patients. Trial enrollment will begin within the next few weeks in the US and will be conducted at more than a dozen sites. Novartis also stated it will make any intellectual property within its control related to the use of hydroxychloroquine to treat or prevent COVID-19 widely available “through non-exclusive voluntary licenses, appropriate waivers, or similar mechanisms.”


On March 28, FDA issued an emergency use authorization while also stating “FDA encourages the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of these products in treating COVID-19.”


In an April 13 article published in GEN online (Genetic Engineering & Biotech News) “Vanquishing the Virus: 160+ COVID-19 Drug and Vaccine Candidates in Development” the combination of hydroxychloroquine and azithromycin is listed prominently in the over 160+ drug and vaccine candidates now in development. The combination of hydroxychloroquine and azithromycin has shown positive results in some studies including the March 17th edition of The Journal of International Antimicrobial Agents where “100% of patients treated with hydroxychloroquine and azithromycin combination were virologically cured comparing with 57.1% in patients treated with hydroxychloroquine only, and 12.5% in the control group.”


Other studies that will be enrolling patients include Gilead Sciences’ Remdesivir, AbbVie’s Kaletra, ruxolitinib and canakinumab for hospitalized patients, Imatinib mesylate, (Gleevec), secukinumab (Cosentyx) and valsartan (Diovan).



The seemingly effective use of Plaquenil and Zithromax, above and beyond issues related to the manufacture and sale of PPE, masks, and various diagnostics may spur new thinking by patent holders and regulators as companies face risks for asserting patents and those developing treatments seek ways to limit potential liability. The increased scrutiny and outcry associated with patents in the face of COVID-19 will likely grow to a fever pitch if patents are seen as a hinderance to effective treatments.

In March a medical testing company that had acquired patents from Theranos created an uproar after filing suit against another company developing COVID-19 tests – leading to a subsequent pledge to offer royalty-free licenses for corona virus pandemic related uses. Later the same month, Gilead dropped it’s “orphan drug” bid for an experimental treatment that, had it been approved, would have added seven years of exclusivity and tax credits, after encountering criticism and allegations of trying to profit off the pandemic. Issues such as these, within the previously established Administration and Congressional focus on drugs and drug pricing may serve as another source of pressure on pharma pricing and patent strategies by legislators, regulators, and payers. Establishing data support as well as sharing best practices are both areas where pharma can assist payers and providers.


Therapeutic Interchange

Utilization of drugs off-label isn’t the only market response to clinical practice needs. Increases in drug prices and payer price sensitivity have precipitated increases in therapeutic interchange (TI), the practice of switching a prescribed drug for another in the same therapeutic class believed to be therapeutically similar though perhaps chemically different. TI exists in contradistinction to generic substitution in that therapeutic interchange does not occur between therapeutically equivalent products. In a study from 2016, implementation of therapeutic interchange yielded projected savings of $73 billion in excess branded drug overuse. In 2016, 89 percent of all prescriptions dispensed in the U.S. were filled with a generic drug. Given high generic utilization rates, and increased awareness of and comfort with off-label prescribing, one area where we might see change post COVID-19 is an increased interest on the part of payers and institutions in more TI programs, as well as increased patient comfort with Therapeutic Interchange.

Therapeutic interchange has been quite common in institutions and has been practiced at more than 80% of hospitals since 2002. Once P&T consensus is reached on formularies and which medications are appropriate for interchange, institutional pharmacists can freely interchange products in accordance with the formulary. Therapeutic interchange in community pharmacy is less common - community pharmacies lacking the closed formularies and formulary committees that would allow them to leverage therapeutic interchange. To affect interchange, community pharmacists must contact the original prescriber to request a new prescription, resulting in delayed patient care and increased systemwide cost and administrative burden. Prescribers may, however, be able to authorize community pharmacy therapeutic interchange on a patient-by-patient basis by allowing pharmacists to leverage the patient’s health plan formulary. To date, 3 states have legislatively enabled this practice. Several organizations have published position statements outlining under what circumstances therapeutic interchange should take place. These organizations represent patient and disease advocacy groups and pharmacy, physician, and managed care organizations. Although each position statement was published separately, a consensus appears to have been independently reached among multiple organizations around the following points:

  • Therapeutic interchange should only be used for medications expected to provide a substantially similar benefit to those expected from the originally prescribed medication.

  • Therapeutic interchange is appropriate where there is some type of evidence-based formulary.

  • Interchange should be considered in light of therapeutic benefit first, followed by cost and other considerations.

  • Patients should be notified of and agree to any change before medication is dispensed.

  • Physicians should be notified of interchange within a reasonable time period after the change occurs.

  • Pharmacy record retention should be part of any interchange performed.

  • There should be some mechanism in place to exclude patients and medications from interchange when clinically inappropriate.



In the search for additional treatment options, as well as attempts to cut system costs due to decreased health system revenues as a result of focusing on the pandemic almost exclusively, therapeutic interchange may be an area that sees renewed interest. Likewise, a growth in evidence-based formularies may lead to more widespread TI in commercial and government payers. Trends and implications point to the need to have a cohesive and tight medical communications / publications plan and a coordinated payer value proposition.


Legislation Regarding Off-label Promotion


The FDA Modernization Act of 1997 allows pharmaceutical manufacturers to distribute peer-reviewed journal articles about off-label uses of medications to health care professionals upon request in addition to increasing patient access to experimental drugs. Off-label drug use publications must be accurate, unedited, and clearly disclose the relationship between information distribution and the sponsoring pharmaceutical company. FDA has continued to ban direct-to-consumer marketing
of off-label uses.


In a number of cases including those involving drug manufacturers like Caronia, Amarin, Pacira, and the medical device company Vascular Solutions, courts have concluded that if the speech at issue is found truthful and non-misleading, it may not serve as the basis for a misbranding action and that neither company nor representatives will be prosecuted for truthful and non-misleading promotion of outside of approved label uses in violation of the FD&C Act.




Given the need for up-to-date clinical information regarding real-world use of labeled products, opportunity may exist for biopharmaceutical manufacturers to assist in dissemination of sound clinical utilization information and scientific resources in areas that relate to currently marketed products as well as disease states within which manufacturers may have an interest and expertise. A strong scientific communications strategy and platform are vitally important in the ability to capitalize on market demands for sound, leading-edge information, operating in the role of strategic partner with payers and practitioners alike.


Real World Data and Real World Evidence

As the breadth and reliability of RWE increases, so do the opportunities for FDA to make use of this information.” Scott Gottlieb, Former FDA Commissioner.


In therapeutic interchange and off-label use, providers rely on real-world data and, where available real-world evidence to guide shared decision making. Real-World Data (RWD) is defined as data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources. Real-World Evidence (RWE) is the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD. It’s important to understand that RWD and RWE
are not synonyms. Under the 21st Century Cures Act, FDA’s RWE Program must evaluate the potential use of RWD to generate RWE of product effectiveness to help support approval of new indications for drugs approved under FD&C Act Section 505(c)
or to help to support or satisfy post approval study requirements. FDA’s RWE Program also applies to biological products licensed under section 351 of the Public Health Service Act.


Observational studies based on RWD have historically been used to support regulatory safety decisions as treatment assignment based upon physician judgment, rather than random assignment as in a tightly controlled clinical trial, create challenges for establishing causal inferences to support the acceptability of observational studies for decisions regarding product effectiveness.


In contrast to efficacy, FDA has a long history of using RWE to monitor and evaluate post market drug safety. FDA’s primary source for executing pharmacoepidemiologic queries and studies is electronic health data (medical claims and pharmacy dispensing data) in the Sentinel System (which includes data on more than 100 million individuals based on a network of 18 data partners). FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) perform safety monitoring studies through pharmacoepidemiologic research projects under the Sentinel Initiative. CDER and CBER also perform pharmacoepidemiologic studies in collaboration with other Federal partners including the
Centers for Medicare & Medicaid Services (CMS) and the Veterans Health Administration. In addition, CDER uses the Clinical Practice Research Datalink, which includes United Kingdom longitudinal patient-level EHR data. CDER uses RWD from the Centers for Disease Control and Prevention National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project, an active surveillance system operating in approximately 60 hospital emergency departments across the United States to specifically evaluate drug abuse, misuse, and the potential for self-harm.


Pharmacoepidemiology studies, observational studies that examine how drugs are used and their effects in populations, can be used to address the problems inherent in RWD and RWE reliance on physician judgement versus randomization as occurs in typical pivotal trials filed with FDA in support of labeling approval. Broadly speaking, pharmacoepidemiology focuses on selecting the appropriate data, design, and analysis to obtain a valid and unbiased answer to questions regarding the use of RWD. Adapting and building on the Pharmacoepidemiologic Guidance, FDA plans to issue guidance about observational study designs using RWD, including whether and how these studies might provide RWE to support product effectiveness in regulatory decision making.




Biopharmaceutical manufacturers can partner with providers, pharmacists, and payers in advance of acute RWD and evidence needs in assisting with tools ensuring data identified and captured are important to payers and robust, sound, and logged correctly so that regulators can effectively evaluate real-world effectiveness – not just product safety.


Payer Perspective on Off-Label and Therapeutic Interchange


Comprehensive therapeutic interchange programs (CTIP) are instituted as a method of controlling pharmaceutical costs as well as standardizing therapies. Payer policy differs based on whether the payer is in the commercial or government segment. CMS bases determination of reimbursement of off-label use of prescription drugs based on five approved compendia. In the case of oncology, if the off-label cancer drug is supported by at least one of the compendia CMS will provide coverage. Compendia therefore play a significant role in federal payment decisions for off-label cancer drugs and likewise have an influential role in the cost of cancer treatment and manufacturer product sales. However, due to limited transparency about how compendia are assembled and disclosure of conflicts of interest on the part of contributors, and substantial inconsistencies both between and within these resources, reliance on compendia is problematic.


In managing the member health populations, payers stipulate that drug or biological use must be safe, effective, and otherwise reasonable and necessary. Drugs or biologicals approved by FDA are considered to have met these stipulations when used for indications specified on approved product labeling. FDA approved drugs used for indications other than what appears in official labeling may be covered if the product use is determined to be medically accepted based on major drug compendia (e.g. the American Hospital Formulary Service Drug Information (AHFS-DI), NCCN Drugs and Biologics Compendium, Truven Health Analytics Micromedex Drug Dex, Elsevier/Gold Standard Clinical Pharmacology, Wolters Kluwer Lexi-Drugs), authoritative medical literature and/or accepted standards of medical practice.




Biopharmaceutical manufacturers seeking to maximize life-cycle management would benefit from implementation of sound strategy and tactics focused on accurately representing product efficacy and safety in various compendia, as well as including compendia links in product dossiers, publications, and payer related marketing materials.


CiTRUS Access is familiar with the unique characteristics of non-traditional evidence and the utility it provides in managed markets, medical communications, and brand life-cycle management. This report is not intended to provide exhaustive detail but rather to highlight potential considerations to bear in mind given recent domestic and global healthcare events.

To learn more about how these and other issues may affect your company, please contact Johann at

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