Gilead/Remdesivir Update: Politics & Methodology Issues Cloud Research

GileadRemdesivir Update Politics & Methodology Issues Cloud Research TrialsiteN

As reported by StatNews on May 5, Gilead announced April 29th that remdesivir was found to speed recovery from COVID-19, but effectively changing the study hypotheses midstream leads to doubt about the results. Why, it was asked, did the study’s main goal change only weeks prior? StatNews notes that defining the “primary endpoint” is key. According to some wise people out there, this is analogous to declining to call a shot in pool—you may get credit, but for an accidentally sunk ball. And, “Changing a primary endpoint when you already know the data is even worse. It can even amount to outright research fraud. To mix sports metaphors, researchers often liken it to drawing a target around an arrow after you shot it, and then claiming a bull’s-eye.” 

In defense of the research, the NIAID said “the change was made while still blinded to all outcome data because agency statisticians had performed modeling showing that the original endpoint—an eight-point scale of how subjects were doing that ranged from dead (the worst outcome) to out of the hospital with no restriction on activities and no need for oxygen (the best) on the 15th day of the study—might not detect a difference where one existed. Instead, they changed the goal to the time it took patients to no longer require supplemental oxygen in the hospital or to be out of the hospital entirely.” This “mean[s] the endpoint change is less of a concern than it might at first appear—although, again, many researchers will want to wait for a full data presentation.” 

Gilead Lobbying Efforts

An NPR article from May 2nd outlines Gilead’s recent lobbying efforts. They note that Gilead spent a record amount of money for lobbying Congress and the administration in 2020 Q1. The $2.45 million spent is a 32% increase over 2019 Q1. “The first quarter is also when Congress drafted and passed the Coronavirus Aid, Relief and Economic Security Act, which contained numerous provisions affecting the pharmaceutical industry, including funding for the development of vaccines and treatments in response to the pandemic.” Also, “Early drafts of the legislation included a provision stipulating that COVID-19 vaccines, drugs and tests be affordable if they were developed with taxpayer funds. But the final bill included additional language that undercut that requirement.”

The lobbying bump coincided with Gilead’s “ramping up clinical testing of remdesivir….” On May 1, the FDA approved emergency use of remdesivir for “severe cases of COVID-19.” According to NPR, “The data shows that remdisivir has a clear-cut, significant, positive effect in diminishing the time to recovery,” according to Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, regarding a study his institute supported. He said the drug would become “the standard of care.” But the same day, a Lancet article based on a Chinese study found little benefit over placebo when looking at survival rates and “time to clinical improvement.” 

TrialSite News did question that story as we have reported there are considerable sets of observational data pointing to some level of remdesivir efficacy. Gilead asserts, “its lobbying expenditures increased sharply last quarter because in 2019, the company joined the trade group PhRMA, or the Pharmaceutical Research and Manufacturers of America.” Ben Wakana of Patients for Affordable Drugs, “suspects Gilead is laying the groundwork to push back against congressional attempts to control the prices of COVID-19 drugs.” The article from National Public Radio also points to evidence of “price gouging”-type behavior. 

Pricing Issues Loom

Representative Jan Schakowsy, D-Ill. says, “We have seen one after another of these drugs come on the market, which are fantastic, and except that they end up being out of reach for most consumers,” When they launched their 2013 hepatitis C cure, Gilead charged $1,000 per pill. Also, they are in a “legal battle” with the federal government over patents for its HIV medicine Turvada, which “has a list price of more than $22,000 a year, according to GoodRx, a website that helps patients get discounts on drugs. The price has kept many patients from getting access to the drug, patient advocates say.” 

While Gilead is donating its first 1.5 million doses, they decline to say what the “price might be after that.” In an April 29th conference call with investors, analysts asked CEO Daniel O’Day whether remdesivir would be as profitable as prior products. O’Day said, “There is no rulebook out there, other than that we need to be very thoughtful about how we can make sure we provide access of our medicines to patients around the globe….And do that in a sustainable way for the company, for … shareholders, and we acknowledge that.” The public partially funded remedesivir, so the CARES Act  included anti-price gouging limits.

“The line in the bill essentially said that any drug that was made with any money from taxpayers would have to have reasonable pricing,” but “a problem arose when another line made its way into the final bill that undercut the pricing assurance. It reads: “The [Health and Human Services] Secretary shall not take actions that delay the development of such products.” 

Per a Gilead email, “We’ve publicly committed that, should remdesivir be proven safe and effective, we are committed to making the medicine both accessible and affordable to governments and patients around the world[.]” And PhRMA said, “Our industry is working around the clock to develop treatments and vaccines to address the COVID-19 public health crisis and save patients’ lives,”

Studies Split on Remdesivir 

 India Express (IE) gave their take on remdesivir on May 4, noting that the drug was manufactured in 2014 to treat Ebola and that it has been used to treat MERS and SERS (coronaviruses); however, none of these applications were particularly successful. IE notes the week-old emergency approval of remdesivir for critical Covid-19 patients and that the drug inhibits the RdRp enzyme, the same enzyme being used by Covid-19 to help replicate in patients. 

The publication quotes Dr. Fauci being something of a cheerleader for remdesivir: “The data shows that remdesivir has a clear cut, significant, positive effect in diminishing the time to recover. Although a 31 per cent improvement does not seem like a knockout 100 per cent, it is a very important proof of concept. What it is proving is that a drug can block this virus.” 

IE goes on to record some issues in remdesivir research: “Then there was the study in The Lancet on April 29 about a clinical trial of 237 COVID-19 patients in 10 hospitals in China. ‘In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits,’ it said.” Another “study found adverse drug reaction in 18 people and stopped remdesivir treatment prematurely in them. It said that there were adverse events in 66% of the remdesivir-treated patients.”

In comments on the Lancet article, a Gilead spokesperson stated: “The study did not identify any new safety concerns with remdesivir treatment. Cardiac events (cardiac arrest or acute coronary syndrome) and treatment discontinuation due to respiratory failure were events associated with both remdesivir and placebo. The number of patients who completed the study was too low to enable any statistically meaningful conclusions. Data from fully-powered trials are needed to determine the safety profile of remdesivir as treatment for COVID-19.”

Call to Action: Was it the right thing to do to change the Primary Endpoint just a couple weeks before the end of the remdesivir study?  Let us know your thoughts.