Mary Caffrey

As the race heats up to create vaccines to halt the spread of coronavirus disease 2019 (COVID-19), two key federal agencies signaled this week that getting it right outweighs the need for speed.

First, on June 30, 2020, FDA issued released a 

 for industry outlining what data the agency will want to see before any vaccine is approved. The next day, leaders from the National Institutes of Health (NIH) vaccine working group, 

, concluded that “large, randomized controlled trials” of SARS-CoV-2, the virus that causes the disease, offer the fastest, safest way to a vaccine that will have widespread use.

In their message, the NIH authors said a research path that relies on purposely infecting healthy volunteers with the virus—known as controlled human infection models, or CHIMs—would still take one to two years, giving the protocols needed to reduce risk. However, the authors said this route may, at some point, have a limited role to “complement” large trials; the authors said this might help answer questions about seasonal coronaviruses, or to understand how long immunity lasts.

The trouble with using CHIMs at this point, they write, is that SARS-CoV-2 is too dangerous and too little is known about it. “Virtually all recent CHIMs have involved microorganisms that either pose minimal risk for causing severe disease in the enrolled population, have effective oral treatments, or both,” they wrote.

“Currently, we lack sufficient knowledge of SARS-CoV-2 pathogenesis to inform inclusion and exclusion criteria for a SARS-CoV-2 CHIM. A single death or severe illness in an otherwise healthy volunteer would be unconscionable and would halt progress.”

The quest for a COVID-19 vaccine has drawn entrants from across the pharmaceutical industry, including giants such as 

, which released a progress report this week with few details. Several phase 3 trials are set to start this month, with developers taking a range of approaches, including DNA, RNA, protein and viral vectored vaccines.

 on the guidance, FDA Commissioner Stephen M. Hahn, M.D., said the approval process must have the public’s trust. "While the FDA is committed to expediting this work, we will not cut corners in our decisions and are making clear through this guidance what data should be submitted to meet our regulatory standards. This is particularly important, as we know that some people are skeptical of vaccine development efforts," Hahn said.

"We have not lost sight of our responsibility to the American people to maintain our regulatory independence and ensure our decisions related to all medical products, including COVID-19 vaccines, are based on science and the available data. This is a commitment that the American public can have confidence in and one that I will continue to uphold."

FDA’s message offered the following to developers of any SARS-CoV-2 vaccine:

Given the “current understanding” of the virus, FDA would use its traditional approval process.

As more is known about how virus immunology, and about vaccine responses, FDA may consider its Accelerate Approval pathway; however, this would require “identification of an immune response or other measure that is reasonably likely to predict clinical benefit.”

Any use of the “emergency use authorization,” or EUA, would be made on a “case-by-case basis,” using criteria that include the available evidence and which population the vaccine would target.

FDA said it would want to see evidence that a vaccine would prevent COVID-19 or decrease its severity in at least 50% of those vaccinated. Thus, trials must be sufficiently large.

The agency called for developers to include “diverse populations” in clinical trials, especially minority groups that have been disproportionately affected by COVID-19.

Studies should include older adults and those with comorbidities, and “plan for” the vaccine to be evaluated in children.

As with all vaccines, FDA will require extensive monitoring once the product is available, and post-marketing studies may be required.

Articles

FDA outlines what it will take to get a COVID-19 vaccine approved, while NIH offers its research strategy.

Word From FDA, NIH on COVID-19 Vaccine: No Cutting Corners

 since March, when the nation went into lockdown because of  COVID-19. Experts are predicting that remote visits are likely to get woven into the routines of American healthcare delivery when the pandemic eases up, although how fully will depend on payment and regulations. The proposed 

that CMS put out last week could be a sign of things to come. If adopted, the rule would make permanent  changes introduced as part of the COVID-19 public health emergency: telehealth visits could be part of home health care plan although they can't replace an in-person visit and won't be paid for like one.  

One area where telehealth seems an obvious solution—treatment for patients with drug or alcohol addiction—still needs work, say authors of a 

. Authors from the University of Michigan—Lewei Lin, M.D.,M.S.; Anne C. Fernandez, Ph.D.; and Erin E. Bonar, Ph.D.—say that while legal and reimbursement barriers to telehealth have come down, doctors still lack guidance on how to serve these patients with electronic visits. They note that “telehealth” can mean different things, ranging from full-on from video conferencing to cellphone texts on.

Patients with substance abuse disorders, who may include up to 

, have distinct needs that can be hard to meet with remote visits, they note. How can clinics obtain urine screens? And will providers develop “therapeutic rapport” with patients in a remote visit?

These hurdles must be overcome, they say, because patients with addictions need more help than ever. COVID-19 creates “an unprecedented, unanticipated urgency and need” for services. Here are three of their recommendations for telehealth and treatmennt of people with substance abuse disorders:

“Most SUD treatment has relied on fairly intensive monitoring and treatment,” they write, but COVID-19 creates the need for alternatives, which will be useful after the pandemic. The field needs evidence-based guidelines that outline the frequency and means for obtaining toxicology screens, which could involve tools such as “apps, transdermal devices, and photo verification of mailed biological tests.”

Find new ways to deliver life-saving medications. 

Too few people were qualified to prescribe 

 for opioid use disorder before the pandemic, and the easing of regulatory and reimbursement hurdles that have allowed telehealth to flourish must extend to this area, too. Rural areas have particularly high need, but research is needed on “how we overcome limited infrastructure and patient acceptability,” the authors say. Studies are also needed to learn which forms of telehealth work best.

Add services, such as online group therapy. 

Many who live with addiction have other mental health disorders, and they need additional treatment, case management and community support services. More work is needed to address privacy issues when delivering care, however.

Most of all, the authors say, regulators must end barriers to telehealth for good. “Lifting of restrictions during COVID-19 is helpful, but many of these guidelines pertain to care only under the current public health emergency,” they write. “For lasting improvements to occur in treatment access, we need to make these changes permanent.”

3 Ways to Promote Telehealth During COVID-19 for Patients With Drug, Alcohol Addiction

Merck's checkpoint inhibitor Keytruda (pembrolizumab) has been approved for patients with hard-to-treat colorectal cancer if they have genetic mutations already known to respond well to the drug.

 presented a month ago at the annual meeting of the American Society of Clinical Oncology, which was held online. Scientists at ASCO said Keytruda, which cut the risk of death or cancer progressing by 40% compared with chemotherapy, would quickly become the new standard of care in certain patients.

Merck announced Keytruda's approval for use as a first-line, single-agent therapy in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mutations, who account for about 5% of metastatic colorectal cancer patients. Keytruda’s effectiveness when this mutation is present is well-recognized, and led to FDA’s first 

 approval for pediatric patients with these mutations last month.

FDA’s action is based on results from KEYNOTE-177, a phase 3 trial of 307 patients, which found that Keytruda doubled progression-free survival from 8.2 months to 16.5 months.

At ASCO, lead study author Thierry André MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said 

 would change the standard of care and that the results showed the value of biomarker-driven studies. Michael Overman, MD, of The University of Texas MD Anderson Cancer Center, a commentator at ASCO, said that going forward it would be “critical” to test every colorectal patient for the MSI-H/ dMMR mutations.

In its statement, Merck officials said the approval was handled under Project Orbis, an FDA initiative that allows for collaboration and a single submission with multiple international agencies; the new indication was also reviewed by regulators in Australia, Canada, and Switzerland.

“Today’s approval has the potential to change the treatment paradigm for the first-line treatment of patients with MSI-H colorectal cancer, based on the important findings from KEYNOTE-177 that showed Keytruda monotherapy demonstrated superior progression-free survival compared to standard of care chemotherapy,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer for Merck Research Laboratories, said in the statement.

FDA approves Merck's Keytruda for certain patients with metastatic colorectal cancer a month after study results were presented at ASCO.

Keytruda Approved for Early Treatment of Colorectal Cancer in Patients With Genetic Mutations

Nearly five years after results about the drug Jardiance stunned the diabetes world, the class called SGLT2 inhibitors continued to dominate discussion at the annual meeting of the American Diabetes Association (ADA), which wrapped up its five-day virtual meeting today.

Today, however, the endocrinologists are sharing the ADA stage with collaborators from cardiology, as the sodium glucose co-transporter 2 (SGLT2) inhibitors are proving to produce more profound results in preventing heart failure and renal decline than they did in controlling blood sugar in diabetes.

Results from a pair of SGLT2 trials - involving a mainstay, Farxiga (dapagliflozin, AstraZeneca) and a relative newcomer, Steglatro (ertugliflozin, Merck/Pfizer) - were the big news of the ADA meeting, but for different reasons. 

Merck had already announced that topline results from the VERTIS CV trial showing that Steglatro had not matched its SGLT2 rivals in meeting certain key targets, notably a measure that included whether the drug helps lower the risk of cardiovascular death.
	 
	But today offered better news about the relatively late entrant to the SGLT2 market - it was approved in December 2017,  more than four years after the FDA approved the first SGLT2 inhibitor, Janssen’s Invokana (canagliflozin). According to results from the VERTIS CV trial, Steglatro cut the risk of heart failure hospitalization by 30% among patients with diabetes and cardiovascular disease, which is similar to the results for its SGLT2 inhibitors rivals. Steglatro did not match the 2015 EMPA-REG OUTCOME results of Jardiance (empagliflozin, Eli Lilly/Boehringer Ingelheim) in reducing cardiovascular death.

But today’s presenters and a commentator did not focus on that shortcoming. Instead, they emphasized that the SGLT2 class is on firm footing in the treatment guidelines for patients with type 2 diabetes with cardiovascular or renal risk. 

, M.D., associate vice president of clinical research for Merck, said in an interview that the heart failure results from the VERTIS CV trial were “consistent with the class” and support other data that show SGLT2 inhibitors can benefit patients at risk for heart failure. 
	
	“We’ve been very excited in the medical community, because these are new opportunities for patients with diabetes who are at risk for hospitalization for heart failure,” he said. “We are looking forward to sharing these results with regulatory agencies around the world.”

Farxiga Shows Potential in Preventing Diabetes


	Results presented over the weekend from the DAPA-HF study of Farxiga point to the next wave of inquiry for the SGLT2 inhibitors - and a return to the roots as diabetes drugs. This time, though, the drug class might be taken to prevent the disease rather than treat it.

Results from DAPA-HF that were presented last year in Paris, broke new ground by showing that Farxiga, a drug developed for diabetes, could reduce risk of heart failure in patients regardless of their diabetes status.

The American College of Cardiology and the American Heart Association have already endorsed the class for prevention in patients with diabetes who have tried lifestyle changes and metformin.

But are there new populations who might benefit from the drugs?

 titled, “Have we lost SGLT2 inhibitors to the cardiologists?” Silvio Inzucchi, M.D., a Yale endocrinologist, shared data that show that patients in the Farxiga trial  who did not have diabetes were 32% less likely to progress to diabetes during the course of the study, which in this analysis had a follow-up period of  18 months. All the patients in DAPA-HF had chronic heart failure with reduced ejection fraction; of this group, 58% already had diabetes. Among the rest, nearly all who developed diabetes started the trial with prediabetes, meaning their A1C was between 5.7% and 6.4%.

“This is the first SGLT2 inhibitor trial to show a potential diabetes prevention effect-the effect was principally driven by our participants who have prediabetes,” Inzucchi said.

The challenge now, experts say, is getting cardiologists on board with the idea of prescribing SGLT2 inhibitors in their patients, even if they do not have diabetes. As Jeffrey M. Testani, M.D., MTR, of Yale School of Medicine, said during Saturday’s panel discussion, the roadblock has been that cardiologists don’t want to “own” responsibility for a patient’s A1C level-which may be tied to quality ratings and reimbursement. 

But Inzucchi said sheer numbers mean that for the right patients to get the care they need; cardiologists must be educated. He and Mikhail Kosiborod, M.D., a cardiologist at St. Luke’s Mid-America in Kansas City, Missouri, calculated that patients with diabetes and cardiovascular risk are four times more likely to see a cardiologist than an endocrinologist, and if the patient has heart failure, the likelihood of seeing the cardiologist first goes even  higher.
	
	“So, if we’re going to get patients with diabetes and cardiovascular disease on these [medications], in cases that have a significant clinical impact, in both morbidity and mortality, it's going to have to be through cardiology, not necessarily endocrinology,” Inzucchi said. “Certainly, in those patients that have cardiovascular disease or heart failure, and don't have diabetes, obviously, this becomes a cardiovascular therapy.”

Inzucchi added, “Any opportunity we have, whether it's an endocrinologist, cardiologist or a primary care physician, to assess the diabetes management in our patients, to see if we can transition them to more evidence-based therapies, I think will have an enormous impact on the lives of our patients.”

Author | Mary Caffrey

Articles

Word From FDA, NIH on COVID-19 Vaccine: No Cutting Corners

3 Ways to Promote Telehealth During COVID-19 for Patients With Drug, Alcohol Addiction

Keytruda Approved for Early Treatment of Colorectal Cancer in Patients With Genetic Mutations

SGLT2 Inhibitors In Heart Failure, Diabetes Prevention Take Center Stage at American Diabetes Association Annual Meeting