The ‘very, very bad look' of remdesivir, the first FDA-approved COVID-19 drug
The Food and Drug Administration held no advisory meeting on antiviral, and the European Union signed contract without knowing of failed trial
- 28 OCT 2020
- BYJON COHEN, KAI KUPFERSCHMIDT
President Donald Trump and Food and Drug Administration Commissioner Stephen Hahn (right) met with Daniel O'Day (left), CEO of Gilead Sciences, when remdesivir received an emergency use authorization in May.AP PHOTO/ALEX BRANDON
Science's COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.
October was a good month for Gilead Sciences, the giant manufacturer of antivirals headquartered in Foster City, California. On 8 October, the company inked an agreement to supply the European Union with its drug remdesivir as a treatment for COVID-19—a deal potentially worth more than $1 billion. Two weeks later, on 22 October, the U.S. Food and Drug Administration (FDA) approved remdesivir for use against the pandemic coronavirus SARS-CoV-2 in the United States—the first drug to receive that status. The EU and U.S. decisions pave the way for Gilead's drug into two major markets, both with soaring COVID-19 cases.
But both decisions baffled scientists who have closely watched the clinical trials of remdesivir unfold over the past 6 months—and who have many questions about remdesivir's worth. At best, one large, well-designed study found remdesivir modestly reduced the time to recover from COVID-19 in hospitalized patients with severe illness. A few smaller studies found no impact of treatment on the disease whatsoever. Then, on 15 October—in this month's decidedly unfavorable news for Gilead—the fourth and largest controlled study delivered what some believed was a coup de grâce: The World Health Organization's (WHO's) Solidarity trial showed that remdesivir does not reduce mortality or the time COVID-19 patients take to recover.
Science has learned that both FDA's decision and the EU deal came about under unusual circumstances that gave the company important advantages. FDA never consulted a group of outside experts that it has at the ready to weigh in on complicated antiviral drug issues. That group, the Antimicrobial Drugs Advisory Committee (AMDAC), mixes infectious disease clinicians with biostatisticians, pharmacists, and a consumer representative to review all available data on experimental treatments and make recommendations to FDA about drug approvals—yet it has not convened once during the pandemic.
The European Union, meanwhile, decided to settle on the remdesivir pricing exactly 1 week before the disappointing Solidarity trial results came out. It was unaware of those results, although Gilead, having donated remdesivir to the trial, was informed of the data on 23 September and knew the trial was a bust.
"This is a very, very bad look for the FDA, and the dealings between Gilead and EU make it another layer of badness," says Eric Topol, a cardiologist at the Scripps Research Translational Institute who objected to remdesivir's FDA approval.https://www.science.org/content/article/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug
Here we have the first paragraphs of a fine muck-raking article on Science. At science.org you can read the rest of the article as well as other articles on the remdesivir caper.
Remdesivir
The remdesivir page on Wikipedia is quite exhaustive. I wish that Wikipedia could be as detailed about the vitamin D, HCQ, and IVR trials.
Remdesivir/baricitinib
In May 2020, the National Institute of Allergy and Infectious Diseases (NIAID) started the Adaptive COVID-19 Treatment Trial 2 (ACTT-2) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus baricitinib for treating hospitalized adults who have a laboratory-confirmed SARS-CoV-2 infection with evidence of lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation.[61][62][63]
In November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the drug baricitinib, in combination with remdesivir, for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[23] The data supporting the EUA for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID).[23] The EUA was issued to Eli Lilly and Company.[23]
Remdesivir/interferon beta-1a
In August 2020, the NIAID started the Adaptive COVID-19 Treatment Trial 3 (ACTT 3) to evaluate the safety and efficacy of a treatment regimen consisting of remdesivir plus interferon beta-1a for hospitalized adults who have a laboratory-confirmed SARS-CoV-2 infection with evidence of lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation.[62][64]
Authorizations and deployment
Remdesivir is approved or authorized for emergency use to treat COVID‑19 in around 50 countries.[13] Remdesivir has been authorized for emergency use in India,[65] Singapore,[66] and approved for use in Japan, the European Union, the United States, and Australia for people with severe symptoms.[8][9][67][68][69][70][58][59][7] In February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started an evaluation to decide if the indication for remdesivir should be modified to include those not requiring supplemental oxygen.[71]
Remdesivir is the first treatment for COVID‑19 to be approved by the U.S. Food and Drug Administration (FDA).[7] The approval by the FDA does not include the entire population that had been authorized to use remdesivir under an Emergency Use Authorization (EUA) originally issued on 1 May 2020.[7] In order to ensure continued access to the pediatric population previously covered under the EUA, the FDA revised the EUA for remdesivir to authorize the drug's use for treatment of suspected or laboratory-confirmed COVID‑19 in hospitalized pediatric patients weighing 3.5 kilograms (7.7 lb) to less than 40 kilograms (88 lb) or hospitalized pediatric patients less than twelve years of age weighing at least 3.5 kilograms (7.7 lb).[7] Clinical trials assessing the safety and efficacy of remdesivir in this pediatric patient population are ongoing.[7]
Australia
In July 2020, remdesivir was provisionally approved for use in Australia for use in adults and adolescents with severe COVID‑19 symptoms who have been hospitalized.[70][72] Australia claims to have a sufficient supply of remdesivir in its national stockpile.[73]
Canada
As of 11 April 2020, access in Canada was available only through clinical trials.[74] Health Canada approved requests to treat twelve people with remdesivir under the department's special-access program (SAP).[75] Additional doses of remdesivir are not available through the SAP except for pregnant women or children with confirmed COVID‑19 and severe illness.[74]
On 19 June 2020, Health Canada received an application from Gilead for the use of remdesivir for treating COVID‑19.[74] On 27 July 2020, Health Canada conditionally approved the application.[76][3]
On 22 September 2020, Minister of Public Services and Procurement Anita Anand announced that Canada had entered into a deal to obtain up to 150,000 vials of remdesivir from Gilead starting in October.[77] As of 8 October, remdesivir was still not widely available in Alberta, because Alberta Health Services was undertaking a "formulary review" to be completed by mid-November.[78]
Czech Republic
On 17 March 2020, the drug was provisionally approved for use for COVID‑19 patients in a serious condition as a result of the outbreak in the Czech Republic.[79]
European Union
On 17 February 2016, orphan designation (EU/3/16/1615) was granted by the European Commission to Gilead Sciences International Ltd, United Kingdom, for remdesivir for the treatment of Ebola virus disease.[80]
In April 2020, the European Medicines Agency (EMA) provided recommendations on compassionate use of remdesivir for COVID‑19 in the EU.[81]
On 11 May 2020, the Committee for Medicinal Products for Human Use (CHMP) of the EMA recommended expanding the compassionate use of remdesivir to those not on mechanical ventilation.[82] In addition to those undergoing invasive mechanical ventilation, the compassionate use recommendations cover the treatment of hospitalized individuals requiring supplemental oxygen, non-invasive ventilation, high-flow oxygen devices or ECMO (extracorporeal membrane oxygenation).[82] The updated recommendations were based on preliminary results from the NIAID-ACTT study,[83] which suggested a beneficial effect of remdesivir in the treatment of hospitalized individuals with severe COVID‑19.[82][84] In addition, a treatment duration of five days was introduced alongside the longer ten-day course, based on preliminary results from another study (GS-US-540-5773) suggesting that for those not requiring mechanical ventilation or ECMO, the treatment course may be shortened from ten to five days without any loss of efficacy.[82] Individuals who receive a five-day treatment course but do not show clinical improvement will be eligible to continue receiving remdesivir for an additional five days.[82]
On 3 July 2020, the European Union granted a conditional marketing authorization for remdesivir with an indication for the treatment of coronavirus disease 2019 (COVID‑19) in adults and adolescents (aged twelve years and older with body weight at least 40 kilograms [88 lb]) with pneumonia requiring supplemental oxygen.[8][85] At the end of July, the European Union secured a €63 million (US$74 million) contract with Gilead, to make the drug available there in early August 2020.[86]
On 8 October 2020, Gilead Sciences and the European Commission announced they had signed a joint procurement framework contract in which Gilead agreed to provide up to 500,000 remdesivir treatment courses over the next six months to 37 European countries. Among the contracting countries were all 27 EU member states plus the United Kingdom, "Albania, Bosnia & Herzegovina, Iceland, Kosovo, Montenegro, North Macedonia, Norway, and Serbia".[87] At the time, the price per treatment course was not disclosed; on 13 October, Reuters reported the price was 2,070 euros, thereby implying the total value of the contract (if all 500,000 courses are ordered) is approximately €1.035 billion.[88] Under the new contract, each participating country will directly place orders with Gilead and pay Gilead directly for its own orders.[88]
Iran
Remdesivir has been also produced in Iran by Barakat; Iran is planning to increase the productions of Remdesivir ampoules from 20,000 to 150,000 ampoules per month. It has also the permission of the "Food and Drug Administration" of MOHME[89]
Japan
On 7 May 2020, Japan's Ministry of Health, Labour and Welfare approved the drug for use in Japan, in a fast-tracked process, based on the US emergency authorization.[9][69]
Mexico
On 23 October 2020, Deputy Secretary of Prevention and Health Promotion Hugo López-Gatell Ramírez stated at a news conference that Mexico would not necessarily follow the United States in approving the drug for use in Mexico. López-Gatell explained that Cofepris had already twice denied the approval of remdesivir because, in that agency's view, the evidence does not suggest "sufficient efficacy".[90] On 12 March 2020, Cofepris authorized the drug for emergency cases, advising to give continuous surveillance of the integral health of the patient.[91]
United States
On 20 March 2020, United States President Donald Trump announced that remdesivir was available for "compassionate use" for people with COVID‑19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference.[92] It was later revealed that Gilead had been providing remdesivir in response to compassionate use requests since 25 January.[15][93] On 23 March 2020, Gilead voluntarily suspended access for compassionate use (excepting cases of critically ill children and pregnant women), for reasons related to supply, citing the need to continue to provide the agent for testing in clinical trials.[94][95]
On 1 May 2020, the US Food and Drug Administration granted Gilead emergency use authorization (EUA) for remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID‐19.[68][27] Severe COVID‐19 is defined as patients with an oxygen saturation (SpO2) <= 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO), a heart–lung bypass machine.[38][27][96][97] Distribution of remdesivir under the EUA will be controlled by the US government for use consistent with the terms and conditions of the EUA.[27] Gilead will supply remdesivir to authorized distributors, or directly to a US government agency, who will distribute to hospitals and other healthcare facilities as directed by the US government, in collaboration with state and local government authorities, as needed.[27] Gilead stated they were donating 1.5 million vials for emergency use[96] and estimated, as of April 2020, they had enough remdesivir for 140,000 treatment courses and expect to have 500,000 courses by October 2020, and one million courses by the end of 2020.[98][99]
The initial distribution of the drug in the US was tripped up by seemingly capricious decision-making and finger-pointing, resulting in over a week of confusion and frustration among health care providers and patients alike.[100][101][102] On 9 May 2020, the United States Department of Health and Human Services (HHS) explained in a statement that it would be distributing remdesivir vials to state health departments, then would allow each department to redistribute vials to hospitals in their respective states based upon each department's insight into "community-level needs."[103] HHS also clarified that only 607,000 vials of Gilead's promised donation of 1.5 million vials would be going to American patients.[103] However, HHS did not explain why several states with some of the highest caseloads had been omitted from the first two distribution rounds, including California, Florida, and Pennsylvania.[103] In May 2020, Gilead indicated they would increase the number of doses donated to the US from 607,000 to around 940,000.[104][102] Some of the initial distribution was sent to the wrong hospitals, to hospitals with no intensive care units, and to facilities without the needed refrigeration to store it.[102]
On 29 June, HHS announced an unusual agreement with Gilead in which HHS agreed to Gilead's wholesale acquisition price, HHS would continue to work together with state governments and drug wholesaler AmerisourceBergen to allocate shipments of remdesivir vials to American hospitals through the end of September 2020, and in exchange, during that three-month timeframe (July, August, and September), American patients would be allocated over 90% of Gilead's projected remdesivir output of more than 500,000 treatment courses.[105][106] Absent from these announcements was any discussion of allocation of remdesivir production to the approximately 70 countries omitted from Gilead's generic drug licensing agreements—including much of Europe[107] and countries as populous as Brazil, China, and Mexico—or the 127 countries listed on those agreements (during the time it will take for Gilead's generic licensees to ramp up their own production).[108] As the implications of this began to sink in, several countries publicly confirmed the next day that they already had adequate supplies of remdesivir to cover current needs, including Australia,[109] Germany,[110] and the United Kingdom.[111]
On 28 August 2020, the FDA broadened the Emergency Use Authorization (EUA) for remdesivir to include all hospitalized patients with suspected or laboratory-confirmed COVID‑19, irrespective of the severity of their disease.[112][113] The Fact Sheet was updated to reflect the new guidance.[38]
On 1 October 2020, Gilead and HHS announced that HHS was relinquishing control over remdesivir allocation because production of the drug had finally caught up with US domestic demand.[114][115][116] AmerisourceBergen will remain the sole distributor of Veklury in the US through the end of 2020.[116]
On 22 October 2020, the FDA approved remdesivir and also revised the EUA to permit the use of remdesivir for treatment of suspected or laboratory confirmed COVID‑19 in hospitalized children weighing 3.5 kilograms (7.7 lb) to less than 40 kilograms (88 lb) or hospitalized children less than twelve years of age weighing at least 3.5 kilograms (7.7 lb).[7][38][117][60]
In November 2020, the FDA issued an EUA for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[23] The data supporting the EUA for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID).[23] The EUA was issued to Eli Lilly and Company.[23]
In the face of emerging sales of the drug's active ingredient to compounders, the FDA recommended in February 2021 that remdesivir "should not be compounded."[118]
Manufacturing
Remdesivir requires "70 raw materials, reagents, and catalysts" to make, and approximately "25 chemical steps."[119] Some of the ingredients are extremely dangerous to humans, especially trimethylsilyl cyanide.[119] The original end-to-end manufacturing process required 9 to 12 months to go from raw materials at contract manufacturers to finished product, but after restarting production in January 2020, Gilead Sciences was able to find ways to reduce the production time to six months.[119]
In January 2020, Gilead began working on restarting remdesivir production in glass-lined steel chemical reactors at its manufacturing plant in Edmonton, Alberta.[119] On 2 February 2020, the company flew its entire stock of remdesivir, 100 kilograms in powder form (leftover from Ebola research), to its filling plant in La Verne, California to start filling vials.[119] The Edmonton plant finished its first new batch of remdesivir in April 2020.[119] Around the same time, fresh raw materials began to arrive from contract manufacturers reactivated by Gilead in January.[119]
Another challenge is getting remdesivir into patients despite the drug's "poor predicted solubility and poor stability."[120] In June 2020, Ligand Pharmaceuticals revealed that Gilead has been managing those issues by mixing Ligand's proprietary excipient Captisol (based on University of Kansas research into cyclodextrin) with remdesivir at a 30:1 ratio.[120] Since that implies an enormous amount of Captisol is needed to stabilize and deliver remdesivir (on top of amounts needed for several other drugs for which the excipient is already in regular use), Ligand announced that it is trying to boost Captisol annual manufacturing capacity to as much as 500 metric tons.[120]
On 12 May 2020, Gilead announced that it had granted non-exclusive voluntary licenses to five generic drug companies in India and Pakistan to manufacture remdesivir for distribution to 127 countries.[121][122][123] The agreements were structured so that the licensees can set their own prices and will not have to pay royalties to Gilead until the WHO declares an end to the COVID‑19 emergency or another medicine or vaccine is approved for COVID‑19, whichever comes first.[121] On 23 June 2020, India granted emergency marketing approval of generic remdesivir manufactured by two Gilead licensees, Cipla and Hetero Drugs.[124]
Pricing
On 29 June 2020, Gilead announced that it had set the price of remdesivir at US$390 per vial for the governments of developed countries, including the United States, and US$520 for US private health insurance companies.[125] The expected course of treatment is six vials over five days for a total cost of US$2,340.[125] Being a repurposed drug, the minimum production cost for remdesivir is estimated at US$0.93 per day of treatment.[126]