Jennifer Gershman, PharmD, CPh

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There are a variety of medications being studied for the COVID-19, and the possible treatment landscape is rapidly evolving.

There are no FDA-approved medications for the treatment of COVID-19. Currently, medical management consists of infection prevention and supportive care, which includes supplemental oxygen and mechanical ventilator support when indicated. Based on a search of ClinicalTrials.gov, there are at least 181 clinical trials being conducted as of April 14, 2020, both studies at the recruiting stage and those that have already begun. The scientific community is coming together to find safe and effective treatment options to combat COVID-19, which include existing and novel drugs. 

Remdesivir is an intravenous (IV) drug with broad antiviral activity (for example, SARS virus and Middle East respiratory syndrome) that has been used for the treatment of Ebola virus, and it works by inhibiting viral replication through premature termination of RNA transcription. Additionally, remdesivir appears to have a favorable safety profile based on its having been used to treat approximately 500 individuals, including healthy volunteers and those with acute Ebola virus infection. Remdesivir is being studied by Gilead Sciences for the treatment of COVID-19 and evidence suggests that it is currently one of the most promising investigational drugs.  

On April 29, Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), announced positive interim results of an NIAID-sponsored study of remdesivir. Fauci said the time to recovery was shorter for COVID-19 patients randomized to the remdesivir arm of the study than the patients in the placebo arm (11 days vs. 15 days) and that difference was statistically significant. However, on the same day, results published in 

from a randomized, placebo-controlled trial of remdesivir conducted in the Hubei province in China showed no association between treatment with the antiviral and a difference in time to recovery. Results of a cohort study were published in the 

 on April 10, 2020, examining compassionate use of remdesivir in 61 patients hospitalized with COVID-19 with an oxygen saturation of 94% or less while breathing ambient air or who required oxygen support.

Patients received a 10-day treatment of remdesivir 200 milligrams (mg) IV on day 1 followed by 100 mg for the remaining 9 days of therapy. Fifty-three patients had data analyzed (seven lacked posttreatment data, one had a dosing error) and clinical improvement was seen in 68% of patients. A total of 32 patients (60%) reported adverse events (AEs) during follow-up. The most common AEs were increased hepatic enzymes, diarrhea, rash, renal impairment and hypotension. Twelve patients (23%) experienced serious AEs, including multiple organ dysfunction syndrome, septic shock, acute kidney injury and hypotension, with most occurring in those receiving invasive ventilation. The results are promising, but  more robust studies are needed to determine the safety and efficacy of remdesivir for patients with COVID-19. Study limitations included the drug not being randomized and lacking a control, missing data, and a short follow-up duration.

The Search is on For Treatment Drugs and a Vaccine

There are currently two phase 3 randomized clinical trials, known as the SIMPLE studies, for patients with severe COVID-19 symptoms (NCT04292899) and for those with moderate symptoms (NCT04292730). Gilead released topline results from the SIMPLE trial studying patients with severe COVID-19, which demonstrated similar improvement with the five- and 10-day treatment regimens of remdesivir.  Time to improvement for 50% of study participants was 10 days in the five-day treatment group, and more than half of patients in both groups were discharged from the hospital by 14 days. Results are expected by May 2020 for the study evaluating patients with moderate COVID-19.  Since January 25, 2020, as part of individual compassionate use protocols, Gilead has been providing emergency access to remdesivir for over 1,800 qualifying patients with severe COVID-19 symptoms who are unable to enroll in ongoing clinical trials. The company is currently working on transitioning to expanded access of remdesivir for patients with severe symptoms and will collect and analyze treatment data.  

Hydroxychloroquine, chloroquine and azithromycin

The FDA recently issued an emergency use authorization (EUA) for the use of the antimalarial drugs chloroquine and hydroxychloroquine (Plaquenil) for the treatment of hospitalized adult and adolescent patients with COVID-19 who are unable to participate in a clinical trial and who weigh 50 kg or more. These medications have immunomodulatory activity that could contribute to an anti-inflammatory response, which is the theoretical mechanism of action for the proposed treatment of COVID-19. The dosage of hydroxychloroquine recommended by the EUA is 800 mg on the first day of treatment followed by 400 mg daily for four  to seven days of total therapy, based on clinical evaluation. Chloroquine’s EUA recommends 1 g on day one followed by 500 mg daily for four to seven days of total treatment, based on clinical evaluation. However, there is controversy surrounding these drugs, as their safety and efficacy for the treatment of COVID-19 have not been established. Limited evidence suggests that these medications may have clinical benefits in patients with COVID-19.  

Hydroxychloroquine with azithromycin was examined in observational and nonrandomized studies in France for the treatment of COVID-19, but data were limited as many individuals were considered to be low risk and only a small number of patients were included. Azithromycin has immunomodulatory and anti-inflammatory properties, but there are currently insufficient data for its adjunctive use in the management of COVID-19. Both hydroxychloroquine and azithromycin are associated with QT prolongation, so patients with chronic medical conditions should be closely monitored to prevent drug-induced cardiac AEs. A jointly published guidance was released on April 8, 2020, by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society regarding possible serious health risks associated with hydroxychloroquine and azithromycin. Recommendations include QT interval monitoring, withholding hydroxychloroquine and azithromycin in patients with baseline QT prolongation or known congenital long QT syndrome, correcting hypokalemia and hypomagnesemia, and avoiding other QTc-prolonging medications. 

The safety and efficacy of hydroxychloroquine for the treatment of COVID-19 will be further evaluated in the ORCHID Study (NCT04332991)by the National Heart, Lung and Blood Institute. This phase 3 multicenter, placebo-controlled, randomized trial aims to enroll approximately 500 patients, and is estimated to have initial results by April 2021. There are also chloroquine studies underway in China and other countries, as there is currently limited evidence regarding the drug’s effectiveness for COVID-19. One randomized phase 2b clinical trial compared high-dose chloroquine (600 mg twice daily for 10 days) with low-dose chloroquine (450 mg for five days, twice daily only on first day) in 81 patients with severe COVID-19 in Brazil.All patients also received azithromycin and ceftriaxone. The fatality rate was 13.5%, with more deaths and QTc prolongation occurring in the high-dose treatment group.The study halted the high-dose treatment arm and results were posted to medRxiv, the preprint server for health sciences, but the study has not yet been peer reviewed. These results shed light on cardiac AEs potentially being dose dependent.  

One man in Arizona died and his wife was hospitalized after they both ingested chloroquine phosphate, commonly used at aquariums to clean fish tanks, in an attempt to prevent COVID-19.The American Association of Poison Control Centers released a statement about AEs relating to hydroxychloroquine and chloroquine, especially nonpharmaceutical formulations that can be particularly dangerous, as exposure to these drugs has increased.

Tocilizumab (Actemra), manufactured by Genentech, is a recombinant humanized monoclonal antibody that is an interleukin-6 (IL-6) receptor antagonist, with a proposed mechanism of action that combats cytokine release syndrome, or “cytokine storms,”  in some severe cases of COVID-19. The drug is currently approved to treat various conditions such as rheumatoid arthritis; however, there are limited data demonstrating that tocilizumab shows benefit for severe COVID-19 symptoms and results in fever reduction and a decreased need for supplemental oxygen. Because tocilizumab is an immunosuppressive drug, it can increase the risk of serious infections. 

A phase 3 randomized multicenter study is underway to evaluate the safety and efficacy of tocilizumab in hospitalized patients with severe COVID-19 pneumonia.

Articles

Remdesivir Leads the Pack of Possible Treatment Drugs for Covid-19 

Cancer is not quite the ferocious killer that it used to be. Millions of Americans are living with cancer, not just dying from it. Reasons for the diminishing death rate include lower smoking rates, earlier detection of some cancers, and advances in treatment.

But the treatment advances are coming at a high price. Treatment costs can easily exceed $100,000 a year. In response, CMS and commercial insurers are establishing alternative payment models, which, in theory, are supposed to slow down the stampeding costs while protecting, and perhaps even improving, the quality of cancer care. 

The Oncology Care Model (OCM) developed by CMS’s Center for Medicare and Medicaid Innovation (CMMI) is certainly the highest profile of these alternative payment model. In November, CMMI announced a successor program called the Oncology Care First (OCF) that for the most part builds on OCM and might push episode payment for cancer care more fully into the mainstream of healthcare. Importantly, OCF will most likely include two tracks that would include downside risk right from the start, and the third will be upside-only for a limited time. But some experts are arguing that value-based cancer care would be better served by a program involving just four of the most common cancers while also changing how costs are  gured so they would relate solely to cancer care.

OCM is a five-year pilot program that began in July 2016 and is scheduled to end next year. CMMI says 175 practices are currently participating Each episode is six months long and is triggered by a patient receiving either oral or intravenous chemotherapy. Under OCM, care has continued to be paid for on a fee-for-service basis: This is not a prospective payment program.

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But OCM has two types of payments that are supposed to serve as an incentive for controlling costs and improving care. Participating practices are paid a “monthly enhanced oncology services”-MEOS, for short- payment of $160 per patient for care coordination. They are also eligible for shared savings payments if they beat episode-based financial benchmarks and met quality improvement targets. OCM also requires participating practices to provide a number of services, including around-the-clock access to a specialist who has real-time access to patient medical records, care plan documentation, and pharmacotherapy based on nationally recognized clinical practice guidelines.

Views differ on OCM. Some see a well-intentioned start to episodic payment but also a work-in-progress.
	
	“The OCM is an attempt to enhance the oncology care, but I am not sure it’s accomplishing the goal yet,” says Luis Raez, MD, FACP, president of the Florida Society of Clinical Oncology, and chief scientificofficer and medical director of the Memorial Cancer Institute in Hollywood, Florida.
	
	Raez says OCM quality standards have led to improvements in care but that the program needs an upgrade. Enough time has passed-and data collected-for researchers to begin studying OCM. An evaluation of its first year that was commissioned by CMMI identified declines in the use of intensive care units and emergency departments by patients of OCM practices, but not much, if any, effect on the lowering of costs. CMMI gave some details about OCF when it unveiled the program with an “informal request for information” in November.

Here are some of the important diferences between OCF as proposed and OCM:

 OCM limits the MEOS payments to practices to patients who are receiving chemotherapy. OCF would expand that population to include patients receiving hormone treatment. Patients not getting any cancer-related drug but under active surveillance or whose care is being otherwise managed by an oncologist would also be counted. This proposed expansion pertains only to the monthly payments, not to the patient population assigned to practices for the purpose of possible performance-based payment.

 In OCF, practices could team up and pool their patients for the purposes of hitting benchmarks for the performance-based payments.

 Under OCM, the enhanced services were 24/7 access to a clinician, patient navigation, preparation of care plans, adherence to guidelines, use of certified electronic health record, and using data for continuous quality improvement. OCF adds electronic patient-reported outcomes, or ePROs, to that list. CMMI’s informal request for information says ePROS can be used to monitor patient symptoms and identify high-risk patients.

 Keely Macmillan, a senior vice president at Archway Health, a healthcare consultant that specializes in bundled payments, says that under OCM practices get claims data on a quarterly basis, which creates too much of a lag between when the care is delivered and steps that practices might take to address practice transformation issues. Macmillan says CMMI is committed to providing OCF participants claims data more frequently.

Expansion of care covered by monthly payments.

 As proposed, under OCF the monthly payment would include payment for enhanced services and an “administration component” that covers administration of drugs. OCM’s monthly payments are designed to cover just the enhanced services. Macmillan says it is still unclear whether additional services such as imaging or lab services will be included in the OCF monthly payments, but the intent is to make a greater share of the payments to practices prospective rather than fee for service.

 Under OCM, CMMI does not set monthly payments or novel therapy adjustments specific to cancer type. Macmillan says Archway’s analysis of data from 20 OCM practices revealed problems with lumping cancers together in that way. For example, lung cancer cases were strongly correlated with negative performance-based payments, an indication of a model that doesn’t properly take into account the care needed. Likewise, colorectal and small intestine cancer were correlated with positive performance payments. As proposed the OCF monthly payment would take into account the type of cancer and whether the patient received chemotherapy or hormonal therapy. The OCF informal request for information also floats the idea of dividing a subset of cancers (breast, bladder, prostate) into highand low-risk categories for the monthly payment “in recognition that spending patterns are significantly different for high-risk patients receiving chemotherapy and low-risk patients receiving hormonal therapy.” The informal RFI also suggests calculating novel therapies adjustments by the type of cancer.

The OCF would have three risk tracks, two with two-sided risk right off the bat. The upside-only track would be available only for two performance periods.

OCF has been characterized as a thoughtful upgrade of OCM-a tweaking that will solve some problems. Not everyone sees it that way.

“I like that OCF is moving to downside risk, but otherwise there’s not a lot I like about that program,” FranÃ§ois de Brantes said in an email to Managed Healthcare Executive.

De Brantes, a senior vice president at Signify Health, says that by emphasizing total cost, OCM and OCF mean oncology providers stand to gain (or lose) payment based on services that have nothing to do with their patients’ cancer care. He also said the programs don’t adjust enough for dierent types of patients and the dierent types of cancer.

An article published on the Health Aairs blog post in December, de Brantes and four colleagues argued that OCF could be improved by focusing on breast, lung, colorectal, and prostate cancer, partly because the treatment strategies for those cancers are well known and established. Limiting the program to those four cancers could also “sharpen the eorts to measure quality in a more meaningful way,” they wrote. De Brantes and his colleagues also made a case for focusing the model on the most eective, appropriate treatment for patients, not necessarily its price, which, they said, may be largely out of the providers’ control.

Jennifer Gershman, PharmD, CPh, is a pharmacist and medical writer residing in South Florida. 

The successor, Oncology Care First, will likely include two tracks with downside risk right from the start.

The Oncology Care Model and Its Heir Apparent

Pharmacists have an important responsibility not only to keep up with new drug approvals but also to stay abreast of the latest pharmacy regulations affecting the profession. The 

 states: “I will accept the lifelong obligation to improve my professional knowledge and competence.” Pharmacists can stay up to date by participating in continuing education (CE) programs, through various resources, such as professional organizations, and registering for email alerts with the Drug Enforcement Administration (DEA) and FDA.

Here are the new and proposed federal regulations, as well as state laws, that are trending across the United States.   

Proposed Laws Aimed to Reduce Opioid Abuse

 recently announced proposed regulations to further limit excess quantities of opioids amid the epidemic. According to the 

, more than 130 people in the United States die daily from an opioid overdose. Additionally, opioid abuse results in an U.S. economic burden of 

 a year, which includes healthcare costs, loss of productivity, addiction treatment, and criminal justice involvement. The DEA has issued a 

 to reduce the amounts of five Schedule II opioid-controlled substances manufactured in 2020 compared with 2019. The proposal includes reducing the production by these drugs by the following amounts: fentanyl (31%), hydrocodone (19%), hydromorphone (25%), oxycodone (9%), and oxymorphone (55%). This is expected to result in a quota that would be a 53% decrease in the amount of allowable production of these opioids since 2016. Comments were due by October 10, 2019 and will be reviewed by the DEA.

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“Reducing the amount of opioids of these Schedule II drugs that have the highest potential for abuse will hopefully help to combat the opioid epidemic,” says Fred Weissman, PharmD, JD, associate professor, clinical pharmacy, USC School of Pharmacy, Los Angeles. Weissman has also authored the book “A Guide to California Community Pharmacy Law” and discussed the importance of laws that are aimed to curb prescription drug abuse. Controlled substance prescriptions must be issued for a legitimate medical purpose by a practitioner. However, pharmacists have a 

 when filling and dispensing the prescription and must use their professional judgement. 

The DEA also announced additional proposed regulations for monitoring quotas for Schedule II controlled substances to help prevent prescription drug abuse as part of the Substance Use-Disorder Prevention that Promotes Opioid Recovery Treatment for Patients and Communities Act (

). The SUPPORT Act requires that appropriate quota reductions be made after estimating potential for diversion and would help to ensure that there are sufficient quantities of the medications for the medical, scientific, research, and industrial needs of patients in the United States. The notice of the proposed regulation was published in the 

, and the comment period ends December 23, 2019. The SUPPORT Act became law in 2018 and helped to establish more treatment programs for opioid abuse as well as strengthen monitoring of controlled substance prescriptions.

Most states and the District of Columbia have passed laws that allow pharmacists to dispense the emergency opioid overdose reversal treatment, naloxone, under a standing order, which takes the place of an individual prescription. Additionally, some states have given pharmacists direct authority to prescribe and sell naloxone to consumers. Weissman discussed that pharmacists can play an important role in dispensing naloxone to help prevent opioid overdoses. However, naloxone access can be limited in some communities. The 

 is currently working to ensure that this lifesaving drug is accessible, and one of the efforts is making it easier for companies to develop it as an over-the-counter (OTC) product. The FDA has designed, tested, and validated the key labeling requirements to approve an OTC naloxone product by developing a model Drug Facts Label (DFL) with pictogram instructions so that anyone with access to the drug can better understand how to administer it. Additionally, this is the first time that the FDA has proactively established and tested a DFL to assist with creating an OTC product. There are likely to be more laws and regulations in 2020 to reflect the expanded naloxone access and possible OTC availability. 

Certain aspects of the DSCSA will be implemented in 2020, which affects pharmacies. It was first enacted in 2013 and sets out serialization and track and trace requirements for the U.S. drug supply chain from the manufacturer to dispensers. “Every drug product should come from a legitimate source,” says Weissman. The DSCSA will enhance the FDA’s ability to help protect consumers from exposure to counterfeit, stolen, or contaminated drugs. Weissman discussed the importance of 

 understanding their responsibilities for protecting patients under the DSCSA, as many of the 

Pharmacists should check the following: registration of manufacturers and repackagers; licensing of wholesaler distributors and third-party logistics providers; and licensing of pharmacies through the state. Pharmacies should only accept prescription drugs that have the following three product tracing documentation: transaction information, transaction history, and transaction statement. The product tracing documentation must be stored in paper or electronic format for 6 years. Pharmacies must also ensure that they have a process in place to investigate and handle prescription medications that they believe are illegitimate, which include counterfeit, diverted, stolen, intentionally adulterated, or unfit for dispensing. Pharmacists must work with the manufacturers to ensure that appropriate measures are taken so that patients do not receive these illegitimate products, and the FDA, as well as trading partners they purchased the drug from and sold the medication to, must be notified immediately. Pharmacists should also check out the FDA’s free CE program that explains the DSCSA requirements.        

Pharmacists and Hormonal Contraception Prescribing

American College of Obstetricians and Gynecologists

 recently issued recommendations that hormonal contraception should be available OTC to expand access to patients without age restrictions. Evidence suggests that women want easier access to hormonal contraception. As of April 2019, 

 allow pharmacists to prescribe certain types of hormonal contraceptives, which is now a growing trend across the country. Weissman discussed that each of the states have different training requirements for pharmacists, which is implemented by their respective board of pharmacy. In order to switch from prescription to OTC status, drug manufacturers can submit a New Drug Application to the FDA. The FDA considers the following for a switch: consumer labeling; analysis of whether patients can adequately self-screen based on the label; and evaluation of actual-use to simulate how the products would be used by consumers. Additionally, the FDA must ensure that the label and package inserts are written so that important information is understood by the layperson. Pharmacists can help to play an important role in women’s health as access to hormonal contraception continues to expand in 2020.

Jennifer Gershman, PharmD, CPh is a pharmacist and medical writer residing in South Florida.

The new and proposed federal regulations, as well as state laws, that are trending across the United States.

Top Pharmacy Regulations for 2020: What Pharmacists Should Know

, 38 drugs have been approved in 2019 as of November 15, 2019, bringing more treatment options to the market for patients. 

, a healthcare performance improvement company, released its 2019 Drug Price Forecast for health systems, with an expected 4.57% increase for pharmaceutical purchases made from January 1, 2020 to December 31, 2020. 

Here are drugs in the pipeline expected to be approved in 2020 and their financial impact.

It can sometimes be difficult to predict which medications will be approved, as there can be drug safety issues that the FDA needs more clarification on and further studies may be warranted, says Erin Fox, PharmD, BCPS, FASHP, senior director, Drug Information and Support Services, University of Utah Health, Salt Lake City. Fox provides budget forecasting in her clinical practice setting and discussed that the budget is generally set after drugs receive FDA approval.

‘Encouraging’ COPD drug pipeline could ease symptoms, address root causes

According to Fox, the pharmacy and therapeutics committee reviews the medications, and drug monographs are created to determine whether the new drugs will be added to the hospital formulary. The FDA approved Eli Lilly’s 

 (lasmiditan) for acute treatment of migraine with or without aura, and it is expected to be available in January 2020. Reyvow is unique in that it is the first FDA-approved medication in a new class of acute migraine treatments known as serotonin (5-HT)1F receptor agonists. 

 (crizanlizumab-tmca) received FDA approval November 15, 2019, which is two months ahead of schedule. Adakveo is manufactured by Novartis and is the first targeted therapy to treat patients with sickle cell pain. Additionally, 

 received orphan drug designation, which provides incentives to the manufacturer. 

 submitted the Biologics License Application (BLA) for eptinezumab for migraine prevention, and the expected approval date is February 21, 2020. Eptinezumab is a monocloncal antibody that has demonstrated positive results for migraine prevention in the 

 phase 3 studies. Seattle Genetics and Astellas have submitted the BLA for 

 for advanced or metastatic bladder cancer, and the target approval date is March 15, 2020. Enfortumab vedotin is considered a novel investigational antibody-drug conjugate that targets Nectin-4, which is a protein that is prevalent in bladder cancer. The BLA submission was based on positive results from the first cohort of patients in the 

Merck received FDA approval December 19, 2019 for 

, the first FDA approved vaccine for the prevention of Ebola virus disease. Biohaven Pharmaceuticals is studying 

 for acute treatment and prevention of migraine. Rimegepant is a calcitonin gene-related peptide receptor antagonist with a long half-life and good oral bioavailability, and the New Drug Application (NDA) has been submitted to the FDA with an expected approval of early 2020. 

 presented at the International Headache Conference demonstrated that rimegepant decreased disability by about 41% and reduced lost productivity time by approximately 50% over a one-year treatment period. 

 was approved November 20, 2019, earlier than the expected date of February 4, 2020, for the treatment of acute hepatic porphyria, a rare genetic disease that can resemble other conditions and affect quality of life. Givlaari is the first drug approved for this rare disease, and it comes with a high wholesale price of $575,000. 

 plans to offer patient assistance and work with insurance companies to help provide coverage. The 

 phase 3 study demonstrated that Givlaari improved quality of life measures compared to placebo. 

 was granted priority review for patients with epithelioid sarcoma who cannot receive curative surgery, and approval is expected January 2020. Additionally, 

 marketing and education strategies are in place in anticipation of tazemetostat’s approval. 

Intercept has submitted an NDA for obeticholic acid for patients with fibrosis due to nonalcoholic steatohepatitis (NASH), a type of liver disease. Approval is expected in 2020 based on positive results from the 

 phase 3 study showing obeticholic acid improved liver fibrosis without worsening NASH at 18 months.         