Following reports of shortages of several drugs needed to treat patients with COVID-19 infections, the U.S. Drug Enforcement Administration (DEA) announced this week that it is increasing its aggregate production quotas for certain controlled substances identified by the Department of Health and Human Services as impacted by the pandemic. The agency issued a final order increasing the 2020 quotas by 15% for fentanyl, morphine, hydromorphone, codeine, ephedrine and pseudoephedrine, as well as controlled substance intermediates that are essential to the production of those schedule II drugs. The DEA also will increase the quota for methadone to ensure that opioid treatment programs have sufficient supplies to treat patients. In addition, the agency is increasing the authorized amounts of certain schedule III and IV controlled substances that may be imported into the U.S. to treat patients on ventilators. These drugs include ketamine, diazepam, midazolam, lorazepam and phenobarbital. Higher quotas will allow manufacturers to ramp up production of the controlled substances to meet the increased demand. The DEA said it will reevaluate the demand and adjust the quotas as needed once the pandemic recedes.
Given the increased demand for chloroquine phosphate and hydroxychloroquine sulfate, which are being used off-label and in clinical trials in the U.S. and many other countries to treat COVID-19, the FDA issued final product-specific guidances to support generic drug development for the antimalarial drugs. The guidance for hydroxychloroquine finalizes a draft issued nine years ago and adds advice about a Biopharmaceutics Classification System-based biowaiver option. The guidance for chloroquine is the first the agency has issued for the drug and is being implemented without prior public comment because the “FDA has determined that prior public participation for this guidance is not feasible or appropriate,” according to a notice slated for publication in the April 14, 2020, Federal Register. The guidance clarifies that chloroquine phosphate has an AA rating in the Orange Book, which means it has no known or suspected bioequivalence problems and no in vivo studies are necessary. Both guidances are being implemented immediately.
Success in a petri dish does not mean a drug will be safe and effective against COVID-19 in humans, the FDA is warning, as it cautions people not to take ivermectin approved for animals. The agency is concerned that a recent research article describing the effect of ivermectin, an antiparasitic, against the coronavirus in an early lab test could lead to people self-medicating by taking ivermectin products intended for animals. The concern comes after a man died when he ingested fish food that contained chloroquine phosphate. “People should not take any form of ivermectin unless it has been prescribed to them by a licensed health care provider and is obtained through a legitimate source,” the agency said. Ivermectin is approved in tablet form for use in people for the treatment of some parasitic worms and in topical formulations to treat external parasites such as headlice and skin conditions such as rosacea. Veterinarian formulations are approved for prevention of heartworm disease in some small animal species and for treatment of certain internal and external parasites in various animal species.
The European Commission, EMA and the European medicines regulatory network have developed a question-and-answer (Q&A) guidance on regulatory expectations for human drugs and flexibility during the COVID-19 pandemic. With a focus on crucial medicines used to treat patients infected with the virus, the guidance discusses marketing authorizations and regulatory procedures, quality variations, manufacturing and importation of active pharmaceutical ingredients and finished products, and labeling and packaging requirements with flexibility to facilitate the movement of drugs within the EU. The guidance will be continuously updated.
Real world data is coming into its own as drug regulators from more than two dozen countries recognized how data generated during clinical practice could complement evidence from clinical trials testing potential therapeutics or vaccines against COVID-19. During a workshop on the coronavirus, the International Coalition of Medicines Regulatory Authorities acknowledged “the importance of observational studies of real world data for increasing the effectiveness and efficiency of regulatory processes and decision-making in the development, authorization and monitoring of medicines and vaccines to prevent and treat COVID-19 and to address knowledge gaps that cannot be addressed by clinical trials,” according to the EMA, which organized the workshop.
The U.K.’s National Institute for Health and Care Excellence (NICE) Thursday published three new rapid COVID-19 guidelines on treating patients with cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and certain dermatological conditions. Patients with CF should be supported in continuing all their usual self-care arrangements, NICE said. Since CF patients are extremely vulnerable to COVID-19, the guideline recommends several ways to provide care while minimizing face-to-face contact and hospital visits. The COPD guideline recommends that patients continue taking their regular inhaled and oral drugs, including corticosteroids. However, COPD patients who develop COVID-19 symptoms should not start a short course of corticosteroids or antibiotics, and they should not routinely start prophylactic antibiotics to reduce their risk from the coronavirus. COPD patients using noninvasive ventilation at home should be advised of precautions to take to protect others from potentially infectious aerosols from the ventilators. The guideline on dermatological conditions treated with drugs that affect the immune response recommends that patients with COVID-19 should continue topical treatments. In treating new skin conditions, doctors should consider using topical treatments rather than systemic ones. These patients shouldn’t suddenly stop taking oral corticosteroids. While they may continue to take hydroxychloroquine, mepacrine, dapsone and sulfasalazine, NICE said they should consider temporarily stopping all other oral immunosuppressive therapies, novel small-molecule immunosuppressants, biologics and monoclonal antibodies. The agency plans on issuing more COVID-19 guidelines, including ones for acute cardiac injury and the use of immunosuppressant drugs for gastrointestinal conditions. NICE is making the guidelines available internationally.
The first patients have enrolled in the NIH’s ORCHID trial that’s testing hydroxychloroquine as an add-on to standard of care in treating COVID-19. The blinded, placebo-controlled, randomized trial is intended to enroll more than 500 adults who are hospitalized with the coronavirus or in an emergency department with anticipated hospitalization. Preliminary reports from small studies have suggested the drug may have potential efficacy against the virus, according to the NIH. That’s led to demand for the drug without a lot of safety and efficacy data to support its use in COVID-19. “Many U.S. hospitals are currently using hydroxychloroquine as first-line therapy for hospitalized patients with COVID-19 despite extremely limited clinical data supporting its effectiveness,” said Wesley Self, an emergency medicine physician at Vanderbilt University Medical Center and the PETAL Clinical Trials Network investigator leading the trial. “Thus, data on hydroxychloroquine for the treatment of COVID-19 are urgently needed to inform clinical practice.”
The FDA's Office for Human Research Protections has issued new guidance intended to address questions regarding how the Department of Health and Human Services human subjects protection regulations apply to actions taken by institutions and investigators in response to the COVID-19 outbreak. Among the guidance were assurances that actions taken for public health or clinical purposes, not for research, don't require institutional review board (IRB) approval before being implemented and that "investigators may implement changes to approved research prior to IRB review and approval, if the changes are necessary to eliminate apparent immediate hazards to the subject." An example of the latter would be "cancelling or postponing non-essential study visits or conducting phone visits instead of in-person visits to reduce COVID-19 transmission risks," the office said.
Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) updated its Q&A guidance on how to manage clinical trials during the COVID-19 pandemic. The guidance provides information on alternative measures that can be used when a process predetermined in the study protocol is not deemed feasible due to COVID-19, such as when participants can’t visit the site to receive study drugs, devices or other products used in the trial. “In any situation, protection for the safety of trial participants should be given first priority, and any changes/deviations from the study protocol should be well documented,” the PMDA said. The agency also is allowing institutional review boards (IRB) to meet via email or virtually when an immediate meeting is necessary to enable a quick start of clinical trials for COVID-19 products. The actual process and conduct of such meetings should be well noted, the agency said.
Responding to public demand for more information on prescription drugs under evaluation, Australia’s Therapeutic Goods Administration (TGA) will be implementing enhanced transparency measures. Beginning in June 2020, the TGA will provide earlier publication of information on the potential availability of new drugs, or new uses for medicines and new combinations that include at least one new drug as an active ingredient. As of early 2021, the TGA plans to give innovators earlier notification of generic applications. Meanwhile, the agency is seeking feedback from sponsors on ways to implement the two measures. Comments should be submitted by June 9, 2020.