Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

	In addition to providing billions in support for industry and individuals in the United States suffering economic loss from the COVID-19 pandemic, the $2-trillion Coronavirus Aid, Relief, and Economic Security Act (CARES–HR 748) includes multiple less-noticed provisions to bolster healthcare programs and to advance the development of new treatments and preventives to combat the virus.

), which was approved March 27, 2020, provides some $30 billion to federal health agencies to develop countermeasures and vaccines, including platform technologies to advance US production of new therapeutics, diagnostics, vaccines, and medical supplies. FDA gains an extra $80 million to support medical product development and approval, on top of a similar provision in the first COVID-19 emergency bill that gave the agency an additional $61 million. Congress again specifies that a portion of the added funds should promote adoption of advanced manufacturing systems for medical products, an initiative long supported by FDA officials and now gaining added prominence as important for accelerating access to any promising therapies and vaccines emerging from new R&D programs.

	Much of the added funding to support health-related funds ($27 billion) goes to support the development of countermeasures and vaccines by the Public Health & Social Services Emergency Fund, which is managed by the secretary of Health and Human Services (HHS). That includes $3.5 billion for the Biomedical Advanced Research and Development Authority (BARDA) and another $1 billion for the National Institutes of Health (NIH).

	Important for pharmaceutical manufacturers, the legislators specify that some of the added FDA resources should support monitoring of medical product supply chains to ensure access to medicines and APIs imported from abroad. Companies should provide FDA with additional information on where interruptions in supply affect APIs as well as drugs, and medical device makers need to report such information to FDA for the duration of the public health emergency. Firms also should maintain contingency plans for back-up supplies of critical products, and the National Academics of Sciences, Medicine, and Engineering (NASEM) gains $1.5 million to prepare a study on ways to strengthen the manufacturing supply chain for drugs and devices to avoid shortages.

	One big surprise is a separate legislative provision granting long-sought authority for FDA to collect new user fees to support a streamlined oversight program for over-the-counter (OTC) drugs. Similar language was approved almost unanimously by the Senate last year, with strong support from FDA officials and industry. The measure also calls for FDA to provide Congress with updated information on evaluating pediatric cough and cold medicines for young children and offers extended market exclusivity to firms developing more innovative OTC therapies. The measure further updates rules governing standards for sunscreens to streamline the review of new applications for revised products, a provision long backed by sunscreen producers.

	Support for health programs and providers

	In addition to providing $100 billion to help hospitals and health centers contend with the COVID-19 pandemic, this broad legislation includes a number of important healthcare provisions. The bill cancels certain rules and language that complicate Medicare reimbursement processes and supports wider use of telehealth systems and virtual patient visits during the pandemic. To ensure timely access to medicines, Medicare and Medicaid should provide longer-term prescription refills and drop utilization management requirements for now.

	And wider testing of patients for the COVID-19 virus is promoted through provisions to reduce copayments and ensure reimbursement by insurers for such procedures. Health plans have to cover preventive services related to the virus, and insurers will waive co-pays for lab tests and cover tests developed by hospitals. The legislation also delays planned cuts to Medicare reimbursement to commercial diagnostic laboratories. However, Congress’ failure to authorize an added $5 billion sought by those firms prompted loud complaints from the clinical laboratory industry regarding its dire need for support to rapidly ramp up test capacity.

	Pharma companies quietly applauded the decision to drop drug pricing measures from the final legislation. There’s language calling for products developed with federal funds to be purchased based on “fair and reasonable pricing,” and to be “affordable in the commercial market,” which industry finds acceptable. But manufacturers lost out on adding a measure providing added incentives for developing antibiotics. These initiatives and a long list of additional health-related proposals could make it into an anticipated fourth COVID emergency bill, which many analysts believe will be needed to further address economic dislocations and healthcare needs created by the pandemic.   

Articles

The bill includes multiple less-noticed provisions to bolster healthcare programs and to advance the development of new treatments and preventives to combat the virus. 

COVID-19 Emergency Bill Bolsters FDA and Healthcare Coverage

	Still smarting from charges of inaction and confusion that delayed the availability of much-needed diagnostics to detect patients infected with the coronavirus (COVID-19), FDA officials are rolling out guidance and support for researchers striving to assess potential treatments for the deadly virus, both existing therapies and new drugs and vaccines that warrant clinical testing. 

	The agency’s leadership seeks to regain credibility by objecting to premature optimism about the effectiveness of unproven therapies and to offset calls from politicians and struggling clinicians seeking access to treatments offering any signs of effectiveness. 

	FDA commissioner Stephen Hahn only recently moved to moderate exaggerated claims from President Trump, along with strong hopes from some health care providers, that long-used malaria treatments chloroquine and hydroxychloroquine may be effective against the new virus. Some very preliminary data from France fanned optimistic predictions, and doctors who lacked alternative therapies for a rising volume of sick patients began a run on the drugs, despite warnings of potentially serious side effects for some individuals. This initiated shortages of the typically available medicines, which are critical for treating lupus and rheumatoid arthritis. 

	Hahn issued a statement last week noting that without evidence that chloroquine products are effective against COVID-19, “we risk treating patients with a product that might not work” instead of more appropriate treatments. He supported efforts by manufacturers to ramp up production to ensure ample supplies if clinical data is promising.  

	FDA is also working with biopharma companies to process the hundreds of requests being filed for individual emergency-use access to still unproven therapies, while also facilitating data collection through randomized controlled clinical trials. The challenges in supporting expanded access programs parallel to gold-standard clinical studies became clear. For instance, when Gilead announced this week that it would suspend providing its experimental drug remdesivir via compassionate use-which requires each patient request for treatment to be evaluated individually-that task became impossible, with hundreds of requests overwhelming its treatment access system for this potential Ebola treatment, which may be effective against COVID-19. 

	Meanwhile, FDA is rolling out a range of guidance documents and policies to provide flexibility for manufacturers facing added challenges in meeting various regulatory requirements. New guidance related to COVID-19 do not follow the usual comment-and-revision process, but instead go into effect immediately. One 

, for example, aims to ensure that patients will continue to access vital medicines provided through risk evaluation and mitigation strategies (REMS) by permitting pharma companies to waive lab tests and imaging studies normally required, but likely to increase the risk of COVID-19 infection and add to the burdens on health care systems during the pandemic.

 to support flexibility for all regulated firms to delay reporting certain adverse events because of personnel disruptions and other problems affecting food and drug companies during the pandemic. The agency 

 flexibility for biopharma companies looking to halt or modify ongoing clinical trials in response to difficulties in carrying out tests or enrolling. And the Center for Biologics Evaluation and Research (CBER) 

, informing manufacturers to stop providing samples or lot release protocols in physical form, but to instead submit such information to the agency electronically and to anticipate final release notifications from CBER via email. 

	Regulatory modifications, along with an emphasis on the importance of scientific evidence regarding drug and vaccine safety and efficacy, is critical for FDA to maintain public confidence in the agency’s ability to speed needed treatments to patients based on sound evidence that the product may benefit patients. Too often, FDA critics cite delays and missteps as evidence that government regulators merely hinder individuals from making personal decisions on treatment options. Yet, uninformed actions can lead to harmful effects that endanger public health and delay development of effective care strategies. Such actions also open the door for unscrupulous entities to promote unproven and often dangerous tests and treatments to the public. Strong leadership that can deflect and address erroneous and unscientific responses to the COVID-19 pandemic is needed now more than ever. 

FDA officials are rolling out guidance and support for researchers striving to assess potential treatments for COVID-19 while the agency tries to object to premature optimism and regain public credibility.

FDA Struggles to Balance Early Access Demands with Need for Valid Test Information

	As the process for conducting conventional clinical trials becomes more difficult and more risky at a time when the public is advised to shelter at home and healthcare facilities become overwhelmed with caring for seriously ill patients, FDA is offering advice and added flexibility to help sponsors adjust ongoing and planned clinical research programs. Strategies for ensuring the health of participants and site personnel are mapped out, along with processes for maintaining the integrity of the research program if it is altered or discontinued altogether. Several biotech firms recently announced the termination of clinical trials or decisions to delay launching planned studies, and more firms are expected to follow suite.

for drugs, biologics, and medical devices recognizes that the COVID-19 pandemic is disrupting research programs, as the risk of infection prevents site visits and testing of research participants. Research site closures, quarantines, travel limitations, and interruptions in clinical supplies may make it difficult for sponsors and investigators to enroll study participants, and patients may not be able to access study sites or to spend a day in a clinic for testing.

	Such difficulties may require a sponsor to revise or reduce testing procedures, shift to online or remote monitoring, revise protocols, alter informed consent procedures, adopt new data collection practices, and to decide whether to continue a research program altogether. While the agency aims to help industry and investigators “assess how to move forward with critical clinical trials,” patient safety is a prime concern, stated Anand Shah, FDA deputy commissioner for medical and scientific affairs, in announcing the guidance this week. The advisory goes into effect immediately, omitting the usual period for comment and revision.

	FDA hopes the guidance will help sponsors to address such developments quickly and efficiently, including strategies for modifying protocols, altering trial designs and regions of study, or delaying or cancelling ongoing studies. The National Institutes of Health (NIH) similarly 

 conducting NIH-funded human studies to address patient safety issues and unanticipated costs and delays in research programs during the medical emergency.

	The FDA guidance advises sponsors to fully document contingency measures implemented, all study participants affected by altered procedures, and the impact of participant discontinuation and alternative procedures for analyzing study results. Although sponsors can make necessary protocol changes immediately without approval of the agency or institutional review board (IRB), they should consult with appropriate FDA review divisions and IRBs as soon as possible regarding such actions, including the use of virtual assessments, delays in assessments, and alternative collection methods for specimens. And there should be clear documentation of how the pandemic has affected the use of the investigational product and the conduct of the trial.

FDA is offering advice and added flexibility to help sponsors adjust ongoing and planned clinical research programs during the COVID-19 outbreak.

FDA Updates Clinical Research Policy to Reflect COVID-19 Disruptions

	Building on the efforts of Civica Rx, a number of organizations and political leaders are mapping strategies for producing drugs and biologics that they believe will be faster, more reliable, and less costly. The stated aims are to prevent or remedy drug shortages quickly, while also expanding patient access to less expensive medicines, primarily sterile injectables. The many challenges in producing drugs to meet quality standards, however, could undermine these undertakings.

	The issue has surfaced among Democratic presidential contenders as part of the debate over strategies for cutting drug prices. Sen. Elizabeth Warren (D-Mass) has proposed that Congress empower the federal government to manufacture drugs, an approach she said would lower the price of insulin and HIV treatments, as well as EpiPens and top-selling biotech therapies. And if Congress fails to act, Warren said she would do this administratively as a first initiative after becoming president.

	Local governments are eyeing similar activities, as seen in the January announcement of California Governor Gavin Newson’s plan for the state to establish its own generic drug label to gain access to cheaper medicines (1). The state’s strategy is to use its buying power to contract with existing generic-drug manufacturers for low prices on certain products, with a state purchasing list and prices to come. And the state could extend the program to brand products by allowing all drug purchasers in California-public plans, private insurers, self-insured employers-to combine purchasing power to negotiate a lowest price for all.

	A move to ensure supplies and reduce costs of cutting-edge gene therapies is the goal of an initiative by a leading research hospital to expand an existing small-scale operation that provides clinical supplies for early-stage gene therapy trials into broader production to handle anticipated growth in studies of gene-based treatments. The Columbus, Ohio-based Nationwide Children’s Hospital’s Abigail Wexner Research Institute (AWRI) aims to establish Andelyn Biosciences as a for-profit operation to support the production and advancement of novel gene therapies for rare diseases. Initially, Nationwide will extend current production from early research to supplies for more advanced clinical studies, and eventually gear up for commercial production of gene therapies (2).

	California officials acknowledged in announcing their drug production plan that it was modeling its program on that established by the Civica Rx nonprofit formed in 2018 by a large group of hospitals and healthcare systems to create and produce more affordable generic drugs. The stated aim was to overcome chronic shortages in vital therapies for emergency care and hospital procedures (3). Led by Intermountain Healthcare, HCA Healthcare, Mayo Clinic, and several others, the group obtained funding from major philanthropies and engaged former Amgen Chief Quality Officer Martin VanTrieste as CEO.

	Civica began supplying drugs to its hospital members in 2019, based on an initial production contract with the Danish company, Xellia, to provide certain anti-infectives. In July 2019, Civica signed a five-year agreement with Hikma Pharmaceuticals to manufacture and supply 14 sterile injectable medications to the organization, with Civica serving as a private label distributor and using its own drug code. Then in January 2020, Civica announced an agreement with Thermo Fisher Scientific to develop its own medicines for member hospitals, starting with nine drugs used in critical or emergency care that have experienced supply problems (4). By providing a guaranteed market for these contract manufacturers, Civica aims to obtain the agreed-on medicines at lower, set prices. Ultimately Civica hopes to establish its own manufacturing facilities to produce more of its own generic drugs.

	Similarly, the hospital service firm Premier Inc.’s Provide Gx program negotiated a contract with Exela Pharma Sciences to produce certain sterile injectables experiencing long-term shortages for hundreds of hospitals in its network. The initiative started in October 2019 by resolving shortages of several drugs, including cysteine hydrochloride injection for parenteral nutrition (5). 

	Meanwhile, Civica took an important step to expand its customer base by forming a partnership with the Blue Cross Blue Shield Association (BCBS) to create a subsidiary to manufacture generic drugs for health plans serving some 40 million patients. BCBS invested $55 million in the new venture, which aims to start with production by 2022 of 7–10 products lacking competition (6). Analysts expect that insulin will be a main target.

	In addition to addressing shortages and affordability of vital medicines, VanTrieste emphasized the larger goal of providing high-quality medicines that are always available at a public meeting on drug quality sponsored by FDA and the Duke Margolis Center for Health Policy in Washington, DC in February 2020. Convened to address stakeholder concerns about drug access and threats to quality from an expanding global supply chain, officials from the Center for Drug Evaluation and Research described efforts to encourage manufacturers to invest in advanced manufacturing and innovative technology to support drug quality systems able to avoid shortages. In lamenting the uncertain quality of drugs made in China and India, VanTrieste said his program would disclose where the drug is made and the origin of active ingredients. Manufacturing costs may be higher for Civica products made in the United States, he acknowledged, but this non-profit organization will maintain low prices. VanTrieste further supported FDA proposals for some kind of quality system score card, which would help companies that excel to expand, and those that fall short to see where to fix problems. 

	Civica’s strategy of working with established contract manufacturers appears appropriate, given the difficulties hospitals and health agencies often have with in-house production of drugs that meet FDA standards for quality and safety. Several years ago, the National Institutes of Health (NIH) had to shut down a clinical supplies production unit at its main Clinical Center due to contamination and sterility issues identified in FDA inspections. A report on the program issued in 2016 documented the challenges in producing sterile injectables at even such a prominent health center and advised NIH not to rebuild the pharmaceutical production unit, but to tap commercial sources for sterile products (7). The report concluded by noting that manufacturing novel drugs for clinical trial use is “a high-risk process” that requires attention to quality, extensive staff training, and clearly defined standards.

	1. M. Gutierrez, “California Eyes Selling its Own Brand of Generic Prescription Drugs to Battle High Costs,” 

, Jan. 9, 2020.
	2. Nationwide Children’s Hospital, “Nationwide Children’s Hospital Announces Plans for Andelyn Biosciences,” Press Release, Jan. 13, 2020.
	3. Civic Rx, “Not-for-profit Generic Drug Company Officially Established, Attracts Interest of More Than 120 Health Organizations,” Press Release, Sept. 6, 2018.
	4. Civica Rx, “Civica Rx Partners with Thermo Fisher Scientific to Develop and Manufacture Drugs with a History of Drug Shortages,” Press Release, Jan. 16, 2020.
	5. Premiere, “Partnership Between Premier’s ProvideGx Program and Exela Pharma Sciences, LLC, Successfully Resolves National Shortage of Cysteine Hydrochloride,” Press Release, Oct. 8, 2019.
	6. BCBS, “Blue Cross and Blue Shield Companies Join Forces with Civica Rx to Lower Costs of Select High-Cost Generic Medications,” Press Release, Jan. 23, 2020.
	7. NIH, 

Reducing Risk and Promoting Patient Safety for NIH Intramural Clinical Research


	Vol. 44, No. 3
	March 2020
	Pages: 14-15

	When referring to this article, please cite it as J. Wechsler, "Drug Production Draws Multiple Contenders," 

States, hospitals, and insurers support manufacturing arrangements to ensure access to affordable medicines. 

Drug Production Draws Multiple Contenders

	The continued novel coronavirus (COVID-19) outbreak has fueled fears of drug shortages, primarily for APIs produced in China, including key ingredients in antibiotics, painkillers, and diabetes drugs. Although several Chinese manufacturers recently reported they were back in business after the holiday closures, US and European regulatory officials continue to anticipate supply shortages in multiple areas, as are generic-drug producers in India, which also obtain APIs from China.

	Biopharma companies also face disruptions from delays in conducting clinical trials in China. Many US and global drug companies have launched studies in China as part of multi-regional development programs, as well as local trials to support the marketing of a drug in China that is already approved in other regions, as documented in 

. Sponsors looking to test potential antivirals and vaccines for effectiveness against COVID-19, moreover, are experiencing difficulties in identifying and enrolling suitable study participants who have been exposed to the virus but have not had previous treatment.

	FDA is paying attention to these issues, as seen in 

a statement by FDA Commissioner Stephen Hahn

 last week acknowledging that the continued spread of the coronavirus could lead to disruptions and shortages of critical medical products in the United States. So far, the main supply problems have involved respirators, surgical masks, and other protective gear, which FDA is monitoring to identify excessive orders to distributors. The agency also wants drug manufacturers to report on emerging supply issues and is beefing up resources to review and coordinate such data.

	At the same time, FDA has postponed planned inspections of medical product manufacturers in China due to a State Department travel warning. The agency usually conducts some 500 inspections a year in China, but now has put on hold routine surveillance site visits scheduled for February and March. In the meantime, Hahn said the agency will increase import sampling and seek to review records of uninspected facilities to determine the need for any import alerts. And as with all APIs, FDA will continue to hold manufacturers of finished dosage forms “responsible for ensuring the quality of their products.”

	The delay in inspections is sure to raise concerns on Capitol Hill, where leading legislators have been voicing concerns about the nation’s growing reliance on drugs and APIs from China and limited FDA inspections and oversight of these products. The chair of the House Energy & Commerce health subcommittee, Rep. Anna Eshoo (D-Ca), has listed US reliance on foreign manufacturing of generic drugs as a “top-line issue” for 2020, a move fueled by ongoing recalls and warnings about several widely used drugs contaminated with nitrosamines. Military and national security experts also have warned about a possible trade war with China aggravating the nation’s overreliance on imports of such critical products. Various commissions and think tanks have proposed stronger federal efforts to ensure the safety of medical product imports, expand drug production in US facilities, and more FDA oversight of foreign producers.

	Similar fears about drug shortages have raised alarms in Europe, where manufacturers also are dependent on APIs from Asia, as reported at a meeting of European Union health ministers last week. Although the European Medicines Agency (EMA) has not received reports of supply disruptions, a sustained virus outbreak and production shutdowns could undermine the pharmaceutical supply chain, particularly for generic drugs, the officials agreed. The EU may launch a joint procurement plan to purchase protective medical equipment.  

	FDA also is concerned about manufacturers making false claims or marketing fraudulent products related to preventing or treating the virus. An FDA task force is closely monitoring for such activities related to COVID-19 and is working with retailers to help monitor online promotions making illegal claims.

	The potential for increased import and sales of illicit medical products continues to be a main regulatory challenge, as seen in the recent FDA 

of a broad enforcement action to halt massive imports of dangerous, unapproved drugs and medical devices from India. A joint operation in January 2020 involving FDA and India’s customs and border protection agency stopped some 500 shipments of unapproved or illegal products, including opioids. Many of the illicit products were transshipped through other countries and ordered through illegal online pharmacies.

US and European regulatory officials continue to anticipate supply shortages in multiple areas.

Virus Spread Threatens Pharmaceutical Supplies and Clinical Research

	The alarming spread of the dangerous virus that emerged several weeks ago in Wuhan, China is prompting small biotech researchers and leading pharma companies to launch a range of initiatives for developing new treatments, preventives, and diagnostics. The research community is moving quickly to launch clinical trials of potential countermeasures, while regulatory authorities aim to support product development through regulatory flexibility.

	After appearing to be confined to China, the virus began to emerge in other countries in February 2020, as it showed signs of human-to-human transmission. The World Health Organization (WHO) declared an international health emergency, prompting public health agencies and industry to ramp up efforts to better diagnose infections and provide treatment. As of February 5, the virus (2019-nCoV) had infected more than 24,000 people and caused more than 500 deaths, but these numbers increase daily. Several cases have been identified in the United States, where hundreds of recent arrivals from China have been quarantined in hopes of limiting the epidemic.

 (EUA) for the Centers for Disease Control and Prevention (CDC) to distribute a new coronavirus diagnostic, permitting qualified laboratories around the country to use the test, as opposed to just the federal agency. While 

in monitoring and limiting the outbreak, the Trump Administration appointed a broad committee headed by Health and Human Services (HHS) Secretary Alex Azar to map out a strategy and response to the epidemic. The panel includes top officials from FDA, CDC, the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), as well as delegates from the State Department, Homeland Security, Department of Transportation, and Office of Management & Budget.

	Meanwhile, a number of companies announced plans to test promising and related compounds for effectiveness against the new virus. An early comer is

, which looks to parlay its research on an antibody against Ebola into a treatment for the new virus. Similarly, 

 plans to test its experimental antiviral drug, remdesivir, which has been in Ebola clinical trials and was administered to a US patient infected with the new virus, with positive, but inconclusive, results. Gilead has provided the drug to Chinese officials who have set up a process for conducting randomized clinical trials on multiple infected patients and with multiple compounds. Several clinical trials sponsored by academic research institutions are testing therapies approved to treat AIDS and hepatitis for effectiveness against the new coronavirus.

	Leading biopharma companies also moved to develop vaccines, with Johnson & Johnson announcing a vaccine R&D effort in the Netherlands. The Coalition for Epidemic Preparedness Innovations (CEPI), a global partnership based in Oslo, has 

four projects with biotech firms to develop a vaccine. GlaxoSmithKline also agreed to provide CEPI with access to its pandemic vaccine adjuvant platform to support these efforts. Any successful vaccine development, however, will require leading pharma manufacturers to step in with the capacity to scale up vaccine production quickly.

	While research expands, health authorities are looking to contain the virus through quarantines and travel bans; Chinese industry and business came to a halt in many areas, as authorities examine the extent to which nCoV can be spread by individuals without symptoms. So far, the outbreak appears to be traveling faster than the SARS pandemic in 2003 and may be more deadly. While several endemic coronaviruses circulate continuously around the globe, they largely affect animals and cause colds and sometimes pneumonia in children and the elderly but are seldom fatal.

	While researchers seek new therapies to stem the pandemic, fears have grown that the shutdown in China of much manufacturing and production will dry up vital supplies of APIs and some finished medical products. Many Chinese producers extended Chinese New Year breaks for added weeks. In addition, FDA halted staff travel to China, postponing inspections of manufacturing sites and other business. Chinese producers are particularly important for antibiotic production, which could be affected by prolonged closures.

	Another concern is that the pandemic could disrupt numerous commercial clinical trials being conducted in China, and notably in Wuhan, for a range of therapies under development by leading biopharma companies. Delays in enrolling and treating research subjects could postpone product development.

	These initiatives to stem the outbreak require additional funding and resources. 

 on the international community to provide $675 million to bolster preparedness and response over the next three months, including support for research and innovation. The Bill & Melinda Gates Foundation is 

 up to $100 million to improve detection, isolation, and treatment efforts; $60 million is earmarked for accelerated development of vaccines, drugs, and diagnostics. HHS has requested leeway to shift funds from other programs to bolster CDC efforts, but added resources will be needed to support more extensive research and response initiative.

The research community is moving quickly to launch clinical trials of potential countermeasures, while regulatory authorities aim to support product development through regulatory flexibility. 