Denise Myshko is your editorial contact for the Formulary Watch. She joined Formulary Watch as editor is June 2021 from Oncology Live. Prior to that, she was managing editor of PharmaVOICE, a trade publication in the pharmaceutical industry. Email: dmyshko@mjhlifesciences.com

Denise Myshko

 two therapies from its Medicare formularies because generics are now available. Both changes impact Prime’s Ideal, Value, Value Plus & Essential Formularies Center of Excellence Formularies, as well as client specific formularies.

Vimpat (lacosamide), which is marketed by UCB, is used to treat epilepsy. Generics became available in March 2022 and are being manufactured by Camber Pharmaceuticals, Glenmark Pharma and Vista Pharm. The generic is available as 50 mg, 100 mg, 150 mg, 200 mg tablets and 10 mg/ml oral solution. This formulary change was effective April 26, 2022.

Combigan (brimonidine tartrate/timolol maleate ophthalmic solution) is approved for reducing elevated intraocular pressure in patients with glaucoma. It was developed by Allergan, which is now a part of AbbVie. A generic from Apotex was launched February 2022. It is available in 5 ml, 10 ml and 15 ml bottles. This formulary change was effective April 28, 2022.

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Generics are now available for the two drugs: Vimpat and Combigan.


 Prime Removes Two Drugs from Medicare Formularies

The FDA has recently modified the Dsuvia Risk Evaluation and Mitigation Strategies (REMS), eliminating the six-month healthcare setting audit requirement and reducing annual healthcare setting audits. Previously the FDA required the manufacturer, AcelRx Pharmaceuticals, to audit all healthcare settings within six months of an initial order, and to then continue to audit all such sites annually thereafter.

The FDA approved Dsuvia (sufentanil), a synthetic opioid, in November 2018 for the management of acute pain severe enough to require an opioid analgesic. It is a sublingual tablet that was designed to provide rapid pain relief and to eliminate dosing errors associated with intravenous administration.

Dsuvia was approved with a REMS program to ensure proper use and administration. The REMS required distribution through certified healthcare settings and required AcelRx to audit these facilities.

“We continue to work closely with the FDA on the Dsuvia REMS program and have established a track record of compliance and safety, including lack of accidental exposure,” Pamela Palmer, M.D., Ph.D., co-founder and chief medical officer of AcelRx, said in a 

. “We believe that it is this history of stewardship and responsibility, which is included in our latest three-year assessment REMS report as submitted to the FDA, that has resulted in the lowering of both the number and frequency of required site audits.”

In February 2021, the FDA had issued a warning letter to AcelRx about false and misleading advertising. The company’s “Tongue and Done” campaign, 

, minimized the risk of serious adverse events and undermined the conditions for safe use. The company in a 2021 earnings 

 said that it been notified by the FDA that AcelRx had met all requirements of the warning letter.

The FDA has changed how often AcelRx Pharmaceuticals is required to audit healthcare settings that administer Dsuvia, which is a synthetic opioid.



FDA Modifies Dsuvia REMS Program

 several new-to-market drugs to it precertification list for both commercial and Medicare members. This requires physicians to submit requests two weeks in advance for coverage review.

A spokesperson for CVS Caremark, said new treatments coming to market for chronic, often complex, specialty conditions, help expand options for people living with them. (Aetna was acquired by CVS Health in 2018.)

"However, utilization management plays an important role in helping to make these treatments affordable for employers and members," the spokesperson told

. "When a new high-cost specialty drug comes to market, it is part of CVS Health and Aetna’s standard process to evaluate available evidence for appropriate management, which may include a pre-certification requirement."

 (faricimab): The FDA approved Genentech’s Vabysmo in January 2022 to treat patients with neovascular or “wet” age-related macular generation and diabetic macular edema, two leading causes of vision loss worldwide. It is the first bispecific antibody for the eye. The list price for this therapy is $2,190 per treatment. Aetna says this is part of the ophthalmic medical injectables drug category.

 (sutimlimab-jome): Developed by Sanofi, Enjaymo was approved in February 2022 as the first treatment to decrease the need for red blood cell transfusion due to hemolysis in adults with cold agglutinin disease (CAD), a rare autoimmune disease. Enjaymo is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. The list price is $1,800 per vial. Aetna indicated precertification is required for the drug and site of care.

 (filgrastim-ayow): This biosimilar was approved in March 2022. Developed by Amneal Pharmaceuticals in collaboration with Kashiv Biosiences, Releuko is a biosimilar to Neupogen and is used to decrease infection after chemotherapy. Aetna indicated this is part of the granulocytecolony stimulating factor drugs category. GoodRx lists a price as low as $226.98, compared with $329.41 for Neupogen.

 (cilcabtagene autoleucel): Developed by Janssen, Carvykti is chimeric antigen receptor T-cell (CAR-T) immunotherapy approved by the FDA in February 2022. It is used to treat patients with relapsed or refractory multiple myeloma. Carvykti has a list price of $465,000 for a one-time infusion. It is only available in a limited number of hospitals that are certified to offer the treatment.

Aetna has made available four specialty drugs that were approved early in 2022 through prior authorization. These include a biosimilar, a CAR-T immunotherapy, and therapies for macular degeneration and a rare auto-immune disease.


Aetna Adds Recently Approved Drugs to Precertification List

Nearly half of the trials used to support novel drugs approved by the FDA in 2020 used a surrogate measure of outcomes, according to a new 

The 49 novel drugs approved in 2020 were supported by 75 pivotal trials. More than half of these drug approvals were supported by a single pivotal trial, and nearly half of the trials used surrogate measures as endpoints.

Investigators, led by Mayookha Mitra-Majumdar, MPH, a research specialist at Brigham and Women’s Hospital in Boston, noted that drugs for rare diseases require regulatory flexibility. Of the novel new drugs approved in 2020, 19 were first in class, and pivotal trials of oncology drugs had more flexible trial designs than approvals overall. In fact, pivotal trials supporting oncology approvals were much more likely to have historical controls and to use at least one surrogate measure as a primary endpoint.

The use of historical controls instead of placebo or active controls, investigators said, raised questions about the strength of the evidence. Investigators found that postmarket requirements were common and “take on increased importance in cases in which they are intended to fill gaps in efficacy and safety left by preapproval evidence limited in amount and/or quality,” the wrote.

This analysis of trials to support 2020 drug approvals follows a trend in the use of surrogate endpoints, especially in trials for oncology therapies. Between 1992 and 2019, the FDA issued 194 unique oncology drug authorizations for 132 drugs that were based on surrogate endpoints, according to a 

Progression-free survival is frequently used as a surrogate marker for regular and accelerated approvals, which requires limited patient numbers and shorter follow-up compared with overall survival, which IQVIA said is considered the gold standard for demonstrating clinical benefit.

 analysis noted that reduced requirements raise concerns about the impact on patient outcomes, and these surrogate endpoints may not accurately predict the benefit of a therapy.

“Without a reasonable likelihood that these drugs provide substantial clinical benefits, the argument for more rapid entry becomes less compelling,” investigators wrote. “The FDA and consumers may benefit from a reexamination of how the agency balances time to market with ensuring that approved drugs are sufficiently safe and effective.”

Once confirmatory trials are conducted, therapies may be found to not provide survival benefit. Last year, for example, several manufacturers withdrew indications that had received accelerated approval, including 

 who withdrew the indication of Tecentriq (atezolizumab) to treat metastatic breast cancer, and 

 who withdrew gastric cancer indication for Keytruda (pembrolizumab).

Investigators pointed that a limitation of their assessment is that the analysis was too recent to assess outcomes of the postmarket requirements, and whether the FDA takes appropriate action based on these confirmatory studies.

While regulatory flexibility is important for drugs for rare diseases, investigators are concerned the trend toward surrogate endpoints decreases confidence that new drugs can improve patient outcomes.

Analysis Finds 2020 Drug Approvals Based on Smaller, Less Rigorous Trials

 a request for an emergency use authorization made by a physician for the use of fluvoxamine to treat adults with COVID-19 to prevent hospitalization. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the FDA to treat patients with obsessive-compulsive disorder and depression.

The rationale for fluvoxamine’s use in patients with COVID-19 is based on models that found the drug binds to the sigma-1 receptor on immune cells, reducing inflammatory cytokines.

The EUA request was based on the results of several studies, including one 

 conducted in Brazil (the TOGETHER trial) and published in 

 that showed a 5% risk reduction in hospitalization. 

David R. Boulware, M.D., is an infectious disease physician with the University of Minnesota who submitted the EUA requestion, suggests in a 

 in the same publication that fluvoxamine seems an effective low-cost therapy that provides benefit.

“There are no FDA-approved or EUA authorized medicines which have shown benefit in vaccinated populations or who are not ‘high risk,' ” Boulware wrote in a letter to the FDA about the agency’s refusal to issue the EUA. “There remains a clinical need of effective medications and possible options. More horse memes by the FDA are not helpful for those of us who are serious clinical trialists,” he said, referring to a tweet the FDA issued last year about why ivermectin shouldn’t be used to treat COVID-19.

But the FDA in a memorandum explaining its decision said based on the available evidence, the data don’t support the use of fluvoxamine for treating non-hospitalized patients with COVID-19 to prevent hospitalization. The regulatory agency indicated that while the TOGETHER study met its primary endpoint, the results were primarily driven by a reduction in the emergency department visits lasting greater than six hours. Regulators indicated there are uncertainties about whether that is a meaningful threshold.

The agency pointed out that this endpoint has not be used to support regulatory decisions about other treatments for nonhospitalized patients with COVID-19. The endpoint used in other decisions about COVID-19 therapies include “proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28” and “percentage of subjects who were hospitalized or died through Day 29 due to any cause.”

The FDA wrote: "acknowledging that retention in an emergency setting for six hours or longer was intended to serve as a proxy for hospitalization in this study, it is uncertain how accurately the study captured recommended retention time for observation, who determined the length of observation, and whether the six-hour timepoint represents a clinically meaningful threshold.”

The FDA also questioned whether the results are generalizable to patients in United States.

Boulware, in a letter to the FDA about the agency’s refusal to issue the EUA, said progression to severe disease is a valid clinical trial endpoint that was used in vaccine trials. “The EUA application noted the 36% reduction in progression to severe Covid-19 as per FDA’s definition of severe Covid-19,” he wrote.

The FDA also pointed out that other studies, STOP COVID, STOP COVID 2, and COVID-OUT, did not demonstrate a benefit of fluvoxamine in adults with COVID-19. Two of those studies were stopped for futility.

“More guidance on the choice of clinical endpoints for outpatient trials in 2022 would be useful,” Boulware wrote in his letter. “As a clinical trialist, there remains a need for greater two-way communication between FDA and the research community. FDA’s current guidance for trial endpoints for outpatient early treatment of COVID-19 pretends as if it is circa 2020. A medication is beneficial for many reasons, including shortening duration of illness or preventing progression to severe Covid-19. Progression to hospitalization/death is substantially lower in vaccinated populations and/or those with prior infection. This is no longer a realistic trial primary endpoint.”

Additionally, regulators said there are limited 

 data to support the proposed mechanism of action of fluvoxamine for the treatment of COVID-19. “There is no evidence to date that an anti-inflammatory therapeutic would be beneficial at an early stage of infection when COVID-19 disease severity is mild and that anti-inflammatory therapies are currently recommended only for hospitalized individuals requiring supplemental oxygen,” the FDA said.


FDA regulators said the data to support the EUA, which was submitted by a physician, is not sufficient to support the use of the antidepressant fluvoxamine for the treatment of patients with COVID-19.


FDA Declines EUA for Fluvoxamine for COVID-19

Payers, regulators and clinicians are increasingly looking to health economics and outcomes research (HEOR) and real-world evidence (RWE) as a valuable source for patient-level data, and the demand for this information about patients and their medications will only increase, according to a 

 in which Trinity Life Sciences interviewed experts in the economics and outcomes field. The paper aims to better understand how these capabilities can be best leveraged across the life-sciences industry to improve patient outcomes.

The demand for outcomes research continues to grow. The growth not only comes from value, access and pricing teams, but from cross-functional teams across life-sciences companies, according to Trinity Life Sciences.

There is a focus on generating evidence, and this is both a top-down and bottom-up effort, Nandini Hadker, partner, evidence strategy at Trinity Life Sciences, said in an interview with 

“The FDA has embraced economics and health outcomes research. They have given the green light to not just use randomized clinical trials, but also to use real-world data and real-world evidence,” she said. “Pharmaceutical companies want to differentiate their therapies and show the value that they bring to the market and how they improve the clinical paradigm.”

At the same time, there has been an evolution in the health economics and outcomes research industry. The data and analytics industry has grown and matured, with new companies forming and new sources of data now available, as well as new methods for capturing data, such as wearable technologies, which track patient physiological measures over time. “There has been an evolution in evidence generation, moving from the slow and academic studies to a much more strategic, more real-time effort to assess value,” Hadker said.

Additionally, she said, the timeline for beginning to assess patient outcomes of new therapies has shifted. “Pharmaceutical companies are not waiting for the product to get market approval before doing these assessments. They are starting two years before approval, looking at unmet needs today to create a regulatory submission that includes real-world evidence,” she said.

Important elements of these studies now include quality of life, activities of daily living, pre- and post-therapy survey questions. “There is an economic angle to this,” Hadker said. “Patients who are doing better on therapy, that would show up in the system. Patients wouldn’t see doctors as much or go the emergency room.”

Payers, however, want these benefits to be quantified. “Health economics and outcomes research is here to stay. In the future, it’s going to be an integral part of decision making for pharmaceuticals, and even for devices and diagnostics.”

Over the next decade, the paper points out, there will be greater data availability and more high-quality data and will likely include more patient-specific and personalized value narratives. In addition, practices more common in Europe, such as health technology assessments, cost-effectiveness analyses and cost-utility analyses, will likely become more common in the United States and include impact on quality of life.

The role of health economic and real-world evidence has become, and will continue to be, an important aspect of healthcare decision-making.