Drug Development in Wake of COVID-19: Slowing or Not?By
Is drug development and the drug-review process slowing due to the novel coronavirus? What do new drug approvals and updates from the top pharmaceutical companies show?
Drug development and regulatory review
With the pharmaceutical industry, both pharmaceutical companies and regulatory agencies, engaged in research and other efforts relating to the novel coronavirus (COVID-19), what has been the impact on other drug-development activities?
Looking first from a regulatory-review perspective, the US Food and Drug Administration (FDA) issued a statement earlier this month (April 16, 2020) to say its drug-review process has continued according to established time frames established under user-fee programs, such as Prescription Drug User Fee Act (PDUFA) provisions, but that the COVID-19 situation may impact future resource allocation.
“Throughout this public health emergency, we’ve continued to execute our review activities while responding to the public health needs of the current COVID-19 pandemic,” said FDA Commissioner Stephen M. Hahn, in an April 16, 2020 statement. “We continue to perform our user-fee review activities and our application review teams across the agency remain focused on their work as we do everything possible to maintain continuity of operations in a very dynamic situation. Part of these actions include looking at ways to use technology and established agreements with our foreign counterparts to minimize impact to applications under review.”
Hahn, however, acknowledged that due to changing resolution-allocation needs due to COVID-19, the agency may have to make future adjustments. “With many staff working on COVID-19 activities, it is possible that we will not be able to sustain our current level of performance indefinitely,” said Hahn in the agency’s April 16, 2020 statement. “Our staffs are working at full capacity, and we are striving to ensure that the drug programs continue to see minimal interruptions during this time. However, if there is an increase in drugs shortages and supply disruptions, we will be ready to reprioritize more of this work, as necessary.”
New drug approvals thus far in 2020
One measure to see how the industry and regulators are faring in the wake of COVID-19 is to examine the drug-review process as it relates to the number of new drug approvals. Through April 24, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) had approved 16 new molecular entities (NMEs) thus far in 2020 (see Table I at the end of the article), which is actually above the number of NMEs approved at the same time in 2019. As of the end of April 2019, FDA’s CDER had approved nine NMEs. Although the FDA’s review process is based on the number and the nature of the new drug applications and original biologics license applications received and does not follow a chronological timetable per se, the fact that NME approvals thus far in 2020 are above last year’s level at this time is an indication that regulatory review, despite the COVID-19 outbreak, is proceeding at similar levels.
Clinical trials and COVID-19: where the impact resides
The impact of COVID-19, however, is more apparent not on the regulatory-review process as it relates to NME approvals but on drug-development activities, particularly the administration of clinical trials. Both the FDA and the European Medicines Agency (EMA) have issued guidance to pharmaceutical companies to advise them of adjustments and revised protocols that pharmaceutical companies can use to account for the impact of COVID-19.
This week (April 28, 2020), the EMA updated guidance for clinical-trial sponsors on how they should adjust the management of clinical trials and participants during the COVID-19 pandemic. The guidance covers concrete changes and protocol deviations for dealing with extraordinary situations, such as the need for isolating participants, limited access to public spaces, and the reallocation of healthcare professionals. The EMA’s guidance issued on April 28, 2020 provided additional flexibility and clarification on several measures: (1) the distribution of medicines to trial participants to take into account social-distancing measures and possible limitations in trial site and hospital resources; (2) the remote verification of source data in the context of social-distancing measures; and (3) notification requirements for actions needed to be taken to protect trial participants against an immediate hazard or of other changes taken to support patient safety or data robustness.
The EMA also issued guidance on the actions that sponsors of clinical trials should take to help ensure the integrity of their studies and the interpretation of the study results while safeguarding the safety of trial participants. In line with this guidance, the EMA says it will be “flexible and pragmatic” during the assessment of affected clinical trial data submitted to the agency as part of marketing-authorization applications.
The issuance of guidance for clinical trials by EU authorities closely follows the FDA issuing final guidance on March 18, 2020 to provide general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic. The FDA outlined that in the wake of COVID-19, certain challenges may arise in conducting clinical trials, for example, from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with SARS-CoV-2, the virus that causes COVID-19.
The FDA acknowledged that these challenges may lead to difficulties in conducting the clinical trials and that it is aware that protocol modifications may be required and that there may be unavoidable protocol deviations due to COVID-19. Considerations recommended by the FDA include that sponsors evaluate alternative methods for assessments, such as phone contacts or virtual visits, and that sponsors offer additional safety monitoring for those trial participants who may no longer have access to the investigational product or the investigational site.
Companies adjust clinical-trial research strategies
Companies have had to re-adjust their clinical-research activities in light of the COVID-19 pandemic with several of the large pharmaceutical companies providing updates this month (April 2020).
In its first-quarter 2020 earnings release issued April 28, 2020, Pfizer provided an update on the actions that the company has taken to date with respect to clinical trials. In late March 2020, Pfizer paused the recruitment portion of certain ongoing global interventional clinical studies and delayed most new study starts. “Pfizer took this action in the interests of public health, so that clinical site partners and Pfizer could concentrate on care for patients in ongoing clinical trials and to avoid adding to the demands on the healthcare system during the peak of the COVID-19 crisis,” said the company in its update provided on April 28, 2020.
In late April 2020, Pfizer began to restart recruitment across the development portfolio, including new study starts, at all clinical trial sites that are currently operational, and where Pfizer and investigators are able to monitor safety and where health authorities have allowed recruitment to resume. Pfizer said it will work with investigator sites to ensure their readiness before any new study participants are enrolled. Completion of certain studies currently in the recruitment stage or studies that have yet to begin could be delayed, said the company.
For all ongoing clinical trials, Pfizer said it is working closely with clinical trial sites to understand their needs and is performing remote monitoring to oversee study conduct. In addition, the company said that processes to enable tele-health and home healthcare are being utilized where appropriate to continue the data collection process and support patient safety.
Novartis reported in its first-quarter earnings release issued on April 28, 2020 that its clinical trials are continuing and that it is using digital tools to limit the disruption caused by the pandemic. “We are seeing slowdowns in new enrollments in ongoing clinical studies and start-up with new studies,” said the company in its earnings release. “We are utilizing the SENSE digital technology implemented in 2018 that allows us to track in real time all of our clinical trials (500+) in more than 70 countries at the level of individual patients and shift to contingency plans rapidly as the situation evolves. This includes, direct-to-patient medication delivery supported by home nursing services, virtual safety assessments. and remote medical monitoring.”
The company says at this time, it is “confident the impact on our ongoing clinical trials is manageable. Looking ahead for the remainder of the year, we do not expect delays in our planned 2020 regulatory submissions.”
In its first-quarter 2020 results released this week (April 29, 2020), AstraZeneca says it has focused on ensuring the continued safety of patients in all of its ongoing clinical trials while activating continuity plans in order to minimize clinical-trial disruption from the pandemic. Mitigation strategies included home-based treatment and monitoring options, moving patient recruitment to less-affected regions, and planning for accelerated recruitment once the pandemic has receded. “Having assessed the COVID-19 impact across the pipeline, the company does not expect material delays to anticipated dates of late-stage and lifecycle-management news flow in 2020 and 2021,” said the company.
In an update issued earlier this month (April 7, 2020), Bristol-Myers Squibb (BMS) reported that it has provided clinical-trial investigators with overarching principles and guidance regarding the conduct of BMS clinical trials worldwide in light of COVID-19 and are taking into account guidance from health authorities, where applicable. “In some instances, we are continuing clinical studies as planned while in others we are temporarily suspending or postponing trials as appropriate,” said BMS in its April 7, 2020 statement. “For trials which were suspended or postponed, plans are underway to get them back up and running when circumstances on the ground permit.”
Eli Lilly and Company provided an update of its clinical-trial activities in light of COVID-19 in its first-quarter earnings results provided on April 23, 2020. The company has delayed most new study starts and has paused enrollment in most ongoing studies, but will continue ongoing clinical trials for patients who are already enrolled in clinical studies. The company says that it expects clinical trial enrollment in existing studies, as well as initiation of new clinical trials, to resume in the second half of 2020.
In its first-quarter 2020 results issued on April 29, 2020, GlaxoSmithKline (GSK) also said that it has paused recruitment in some clinical trials and continues to evaluate the impact on the COVID-19 pandemic on its clinical-trial activities. “As we have seen elsewhere, recruitment for clinical trials has slowed due to disruption from the pandemic and diversion of resources to other clinical priorities, “said GSK in its April 29, 2020 earnings release. “We are continuing to support enrolment of new patients into ongoing clinical studies, provided that investigators are confident they will be able to conduct the protocol required. Where necessary and based on our own assessments, we have proactively paused recruitment. We have a number of products undergoing regulatory review and, at this time, we do not anticipate any significant delays to regulatory approvals due to the pandemic. However, this is clearly a very dynamic and uncertain situation and the ultimate severity, duration and impact of the pandemic remain unknown at this point.”
In its first-quarter results issued on April 28, 2020, Merck & Company reported that with respect to its clinical-trial activities: “Conditions are fluid and evolving, but as local conditions allow, we are enrolling patients in ongoing studies, and we are starting new studies.”
Roche reported in its first-quarter 2020 results issued on April 22, 2020 that its regulatory filings and product launches for 2020 are largely on track. and that pivotal trial read-outs and pivotal starts in 2020 are also largely on track. “While in general clinical studies in cancer seem to continue without major delays, there could potentially be some impact of COVID-19 on chronic diseases studies,” said the company in its April 22, 2020 release. “We are taking significant efforts to protect all studies with continued support by health authorities, but the ultimate outcome will depend on the length and severity of the pandemic.”
|Table I: Approvals of New Molecular Entities as New Drug Applications (NDAs) and Original Biologics License Applications (BLAs) by the US Food and Drug Administration’s Center of Drug Evaluation and Research as of April 24, 2020.|
|Company||Brand name (active ingredient); application type||Indication|
|Acacia Pharma||Barhemsys (amisulpride); NDA||Prevent nausea and vomiting after surgery|
|AstraZeneca||Koselugo (selumetinib); NDA||Neurofibromatosis type 1, a genetic disorder of the nervous system causing tumors to grow on nerves|
|Biohaven Pharmaceuticals||Nurtec ODT (rimegepant); NDA||Migraine|
|Blueprint Medicines||Ayvakit (avapritinib); NDA||Unresectable or metastatic gastrointestinal stromal tumor (GIST) in adults|
|Braintree Laboratories||Pizensy (lactitol); NDA||Chronic idiopathic constipation (CIC) in adults|
|Bristol-Myer Squibb||Zeposia (ozanimod); NDA||Relapsing forms of multiple sclerosis|
|Epizyme||Tazverik (tazemetostat hydrobromide); NDA||Epithelioid sarcoma|
|Esperion Therapeutics||Nexletol (bempedoic acid); NDA||Heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C|
|Horizon Therapeutics||Tepezza (teprotumumab-trbw); BLA||Thyroid eye disease|
|Immunomedics||Trodelvy (sacituzumab govitecan-hziy); BLA||Metastatic triple-negative breast cancer patients who received at least two prior therapies for metastatic disease|
|Incyte||Pemazyre (pemigatinib); NDA||Cholangiocarcinoma, a rare form of cancer that forms in bile ducts|
|Lundbeck||Vyepti (eptinezumab-jjmr); BLA||Preventive treatment of migraine in adults|
|Neurocrine Biosciences||Ongentys (opicapone); NDA||Postpartum depression in adult women|
|Recordati Rare Diseases||Isturisa (osilodrostat); NDA||Cushing’s disease patients who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease|
|Sanofi||Sarclisa (isatuximab-irfc); BLA||Multiple myeloma|
|Seattle Genetics||Tukysa (tucatinib); NDA||Advanced unresectable or metastatic HER2-positive breast cancer|
Bristol-Myers Squibb acquired Celgene in November 2019 and gained Zeposia (ozanimod).
Source: US Food and Drug Administration’s Center for Drug Evaluation and Research.