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

Jill Wechsler

	Despite continuing clamor against high prices on critical treatments and vaccines to combat COVID-19, the leading authority on developing effective countermeasures against the pandemic believes that price control strategies will backfire. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), says that efforts to limit all returns on investment will drive biopharma companies away from developing much-needed interventions.

	Even after several decades of addressing major lethal diseases such as HIV and Ebola, dealing with the COVID-19 outbreak is “my worst nightmare,” he conceded. Such a highly transmissible virus that has devasted the world in just four months is unprecedented, Fauci lamented. And “it isn’t over yet,” he warned in an online presentation to the 2020 annual conference of the Biotechnology Innovation Organization (BIO), held digitally this year.

	The main strategy for containing the current pandemic involves developing effective therapies and vaccines, and industry collaboration with government and academia is vital for advancing the science. But if you try to enforce price controls on companies that have multiple different opportunities to do different things, Fauci warned, “they will walk away.” In a profit-driven industry, Fauci acknowledged that companies expect some degree of economic return. At the same time, he advised, that pricing calculations have to ensure that regions of the world that cannot afford very expensive interventions will be able to access needed therapies. As long as a price is “not so outrageous” that it becomes “completely outside the realm” of the people who really need the medicines, some degree of profit may be appropriate.

	Fauci would like to see “fair pricing” for new therapies but aims to achieve that by working with companies to gain an understanding of what that means, especially in situations where government funding helps the company in developing a product. He acknowledged that there is a good deal of discussion about utilizing the “reasonable pricing clause” in government contracts to obtain low prices, but he has found that the big question always is “what’s a reasonable price?” When you’re dealing with firms that expect some kind of economic return, you cannot realistically expect companies to “just give it away,” he said.

	Fauci praised industry for aggressively stepping up to the plate in developing many different types of therapeutics and a number of vaccine candidates. The expanded collaboration between industry and government is “something we should be proud of,” he commented. He expects current research will lead to “more than one winner” in each area, as multiple candidates get approved and widely used. Fauci considers this a plus, as vaccine experts believe that different individuals and patient groups may respond better to one vaccine, as compared to another.

	With the spotlight on industry’s involvement in developing pandemic treatments, financial analysts expect pharma companies to refrain from high pricing moves and to shift away from a what-the-market-will-bear pricing strategy. Although economists calculate that new drugs and vaccines able to contain the COVID outbreak could prevent trillions of dollars in economic losses, basing prices on such potential gains would cost industry a great deal in public good will and policy decisions.

	All eyes are on Gilead Sciences, as speculation continues about how the company will price its experimental treatment remdesivir. Gilead has avoided controversy so far by providing the medicine at no cost under its emergency use status. But once it gains FDA approval, the company is expected to set a price around $4000 per course of treatment in the United States and $2000 in less developed countries, despite considerable federal government assistance over the past decade in developing the drug. Gilead is familiar with these issues, as it was blasted several years ago for setting a high price initially for its hepatitis C treatment Solvaldi and continues to be embroiled in lawsuits over prices and patents for its HIV-prevention treatment.

	Biopharma companies have won plaudits for sharing strategies and joining collaborative research programs with competitors, non-profits, and public agencies to advance knowledge and evidence for effective anti-COVID treatments. Broad drug pricing legislation appears to be a low priority for now on Capitol Hill and in the White House, and industry would like to maintain that situation through this election year. At the same time, leading Democrats continue to back a measure limiting new drug prices during a public health emergency to no more than 10% of cost, and public pricing controversies would only generate support for such requirements.

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Will efforts to limit all returns on investment drive biopharma companies away from developing much-needed interventions for COVID-19.

Fauci States that Industry Will “Walk Away” from Price Controls

	The recent surge in demand for certain common medicines hyped as potential COVID-19 therapies led to serious drug shortages at hospitals and pharmacies, notably for the common malaria treatment hydroxychloroquine and antibiotics such as azithromycin. Widespread use of ventilators to relieve respiratory distress in very ill patients, moreover, depleted supplies of sedatives and painkillers administered with such equipment.

	These supply problems highlight the reliance of the US healthcare system on generic drugs, many produced overseas or made with imported APIs. Manufacturers have rushed to fill the gaps, particularly to aid patients already relying on these medicines to treat serious medical conditions. FDA issued guidances on developing generic versions of chloroquine phosphate and hydroxychloroquine sulfate to help address the shortages (1). Even so, policymakers continue to lament the nation’s unreliable supply chain for vital medicines, many made in India, China, and other regions.

	These developments reflect the importance of regulatory and legislative policies in facilitating generic-drug development and market approval. FDA has expanded and reorganized its Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER) to streamline and accelerate the approval process for follow-on medicines, supported by generic-drug user fee revenues. A sign of success is FDA’s record-breaking approval of more than 1000 abbreviated new drug applications (ANDAs) in 2019 (2). An important gain is OGD’s ability to process and approve more ANDAs in one review cycle by encouraging manufacturers to file more complete applications that avoid time-consuming discussions on application shortcomings.

	FDA also seeks to advance the development and approval of more complex generics, such as topicals and inhaled products, as outlined in the agency’s Drug Competition Action Plan of 2017 for facilitating access to less expensive alternatives to a broader range of innovator therapies (3). FDA has published lists of more than 500 drugs that lack competition and warrant extra agency assistance in determining what tests and data are needed to gain market approval. Multiple guidances on developing specific complex therapies support the program, including an advisory issued in March 2020 outlining the process for a manufacturer to seek designation for a product as a Competitive Generic Therapy that warrants expedited development and review (4). 

	The development of complex generics also has support from FDA research that addresses technical and scientific issues related to testing innovative generic products. At an FDA public workshop in May 2020, agency scientists sought further industry input on research priorities and challenges related to developing complex generics, drug-device combination products, new bioequivalence testing methods, and new data analysis and modeling strategies to support these initiatives (5).

	Congress also has furthered generic-drug development in approving the long-debated CREATES Act in December 2019 as part of a must-pass budget bill. The measure helps generic-drug makers access innovator supplies needed for bioequivalence testing and product approval, even when the brand is subject to a risk evaluation and mitigation strategy (REMS). The legislation also provides flexibility in establishing shared REMS programs for innovators and generics, another effort to avoid roadblocks to accessing less costly prescription drugs (6).

	To further identify and prevent looming drug shortages, moreover, the legislators also included a provision in the CARES Act, the $2-trillion COVID emergency bill enacted in March that supports FDA efforts to monitor medical product supply chains and ensure access to both drugs and APIs imported from abroad. The bill expands FDA authority to require information on where problems might interrupt access to APIs, as well as drugs, and calls on firms to establish back-up plans for ensuring supplies of critical products (7).

	Generic-drug development also may advance from global agreement on standards for testing and regulating these medicines. A new project of the International Council for Harmonization (ICH) aims to establish bioequivalence standards for immediate-release solid oral dosage forms to support generic product development and approval in multiple regions (8). Additional ICH guidelines for generics are expected, as the group explores opportunities for standards related to a number of complex generic medicines.

	These and other initiatives were discussed at an FDA Generic Drugs Forum, which attracted more than 4000 registrants from 73 countries to the online program held April 15–16, 2020. FDA staff provided practical advice to manufacturers on minimizing deficiencies in applications and described opportunities for OGD assistance in developing complex generic products and on navigating the regulatory process (9).

	1.  FDA, “Product-Specific Guidances for Chloroquine Phosphate and Hydroxychloroquine Sulfate,” 

2019 Office of Generic Drugs Annual Report, www.fda.gov

Competitive Generic Therapies, Guidance for Industry

 (CDER, March 2020).
	5.  FDA, FY 2020 Generic Drug Regulatory Scien

ce Initiatives Public Workshop, online, May 4, 2020.

 (Jan. 31, 2020).
	9.  FDA/SBIA, Generic Drugs Forum, online (April 15–16, 2020).


	Vol. 44, No. 6
	June 2020
	Pages: 14–15

	When referring to this article, please cite it as J. Wechsler, "Generic Drugs in Spotlight as Pandemic Creates Shortages,"

FDA and the US Congress support innovation and access to cheaper medicines. 

Generic Drugs in Spotlight as Pandemic Creates Shortages

	While scientists around the world are striving to discover, produce, and distribute safe and effective vaccines to halt the coronovirus outbreak, cadres of anti-vacciners are revving up misinformation campaigns to undermine public confidence in such preventives. Despite the clear danger of COVID-19 to global health, vaccine opponents have gained ground, as fearful populations lose faith in the capabilities of industry and government to protect public health.

	The latest tactic of anti-vaccine forces is to align with protests against government lock-down policies and restrictions on business and daily life. The “Reopen America” campaign has attracted groups fighting state vaccine requirements for school-age children. Despite strong childhood vaccination rates (over 90%) in the United States, notable pockets of resistance dot the nation, as anti-vacciners show considerable savvy in communicating their message through social media to fuel more widespread “vaccine hesitancy.” A recent poll by the Associated Press and NORC at the University of Chicago found that while 49% of respondents plan to get vaccinated against COVID-19, 20% say they will not and 31% are not sure. 

 cite fear of side effects, of getting infected from the vaccine, belief that the new vaccines don’t work well, and reduced concern about getting sick-issues that need to be addressed clearly by manufacturers and health authorities.

	Ironically, the high-profile US campaign to develop and produce vaccines against COVID-19 quickly, as promoted by the Trump Administration’s Operation Warp Speed initiative, may fuel such objections. Instead of undergoing five or 10 years of pre-clinical and clinical testing involving tens of thousands of individuals, current experimental COVID-19 vaccines are moving quickly through the development and approval process. Although such accelerated discovery is widely applauded, it also opens the door to fears that resulting preventives may be inadequately tested and less safe.

	Related to this is the rise in novel technologies being explored to expedite vaccine development and production. Among some 150 COVID-19 vaccines in development, early front-runners utilize mRNA, DNA, new gene therapies, and additional adenovirus vectors to trigger an immune response. Anti-vacciners describe these approaches as “synthetic” and “unnatural” and likely to generate adverse events more lethal than the virus itself.

	Suspicions in vaccines also stem from charges that biopharma companies and international organizations are foisting risky treatments on the world just to make huge profits. Anti-vaccine crusaders have levelled conspiracy charges for years, particularly at the Bill and Melinda Gates Foundation and the World Health Organization for seeking to control the global health system in ways to track individuals’ activities. Such accusations have undermined international efforts to expand vaccine access to developing nations and to vulnerable populations.

	Pharma critics also oppose industry patents on pandemic treatments, particularly those discovered and tested with significant financial support from government and public agencies. Although manufacturers of early experimental therapies have provided some treatments at no cost, and analysts have calculated fairly high values for vaccines that save lives and help restore the world economy, the debate over cost and access will continue.

	Policy makers face further disagreement over the extent that anti-COVID-19 vaccination will be required for individuals to engage in activities involving greater personal interaction. With clear evidence that COVID-19 is highly contagious and dangerous, local and state governments may move beyond requiring certain vaccinations for children to attend school to mandating or recommending vaccination for those in certain jobs, to attend public events, and to utilize public facilities. Employers and service firms may impose similar requirements on staff, while the federal government could require vaccination for travel in and out of the country. Medical authorities estimate that 60–70% of the population would need to be vaccinated or found immune to achieve “herd immunity,” a high number that will require millions of vaccine doses fairly quickly.

	The Centers for Disease Control and Prevention (CDC) has launched a “vaccinate with confidence” campaign to address concerns of those hesitant about vaccination, as opposed to the relatively few vocal vaccine opponents, explained Nancy Messionnier, director of CDC’s National Center for Immunization & Respiratory Diseases, in a recent virtual meeting on tackling vaccine access and hesitancy issues organized by the Forum on Microbial Threats at the National Academies of Sciences, Engineering and Medicine (NASEM). The group will further examine the impact of declining vaccine confidence at a 

	CDC also is concerned that scheduled vaccinations for young children have declined in recent months, largely because parents have delayed routine doctors’ appointments for fear of infection at medical facilities. While vaccination rates are expected to return to normal, the current drop raises fears of measles and meningitis and other outbreaks in coming months. Health authorities already are pressing for widespread seasonal influenza vaccination in the fall to reduce health risks from a second COVID-19 outbreak when cold weather returns.

	Transparency and full disclosure of vaccine benefits and risks are important for overcoming public fears of new preventives. Manufacturers and regulators need to clearly communicate potential adverse events, while moving away from the long lists of possible side effects that confuse and scare the public. Clear assurance of product quality and safety also will be critical, especially for any vaccine produced overseas.

Despite the clear danger of COVID-19 to global health, vaccine opponents have gained ground, as fearful populations lose faith in the capabilities of industry and government to protect public health.



Vaccine “Hesitancy” Threatens COVID Immunization Efforts

	There’s been considerable hat-changing in FDA leadership during the past week, as the White House looks to bring in credible experts for its Operation Warp Speed initiative to advance therapies and vaccines to combat the coronavirus pandemic. This prompted major leadership changes at FDA, with Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), stepping down temporarily from that role in order to head up the administration’s efforts to identify and accelerate development of promising treatments and preventives pending development of a new vaccine against COVID-19. Woodcock is being detailed to the office of FDA Commissioner Stephen Hahn during this assignment.

	At the same time, Peter Marks will remain as head of the Center for Biologics Evaluation and Research (CBER), instead of shifting over to direct vaccine development under Warp Speed. FDA initially said that both of these top officials would be involved in leading the administration’s public-private partnership to speed new therapies, vaccines, and diagnostics to the public and would recuse themselves from evaluating regulatory applications to avoid potential conflicts of interest. However, concerns about maintaining clear distinctions between funding research on promising treatments and serving as the final FDA arbiter of new product approvals prompted the revised assignments.

	While Woodcock leaves CDER for Warp Speed, the center will be led by deputy director Patrizia Cavazzoni, with support from Doug Throckmorton, deputy director for regulatory programs, Grail Sipes, deputy director for regulatory policy, and Bob Temple, deputy director for clinical science. Woodcock’s work will support FDA’s Coronavirus Treatment Acceleration Program, which aims to bring new therapies to patients as quickly as possible while also supporting research to further evaluate these medical countermeasures,

	Hahn further explained that Marks will remain at CBER to accelerate vaccine testing and development and support collaborative regulatory work with industry, federal, domestic, and international partners. This change to have Marks step away from the Warp Speed role is supported by strong vaccine expertise leading the administration’s partnership. Moncef Slaoui, former vaccine chief at GlaxoSmithKline and board member of vaccine developer Moderna, heads up the initiative. The vaccine team also is supported by Matt Hepburn, who has more than 20 years experience in vaccines and public health at the Department of Defense, along with several other experts from the Defense Health Agency.

	By remaining at CBER, Marks will be positioned to lead FDA efforts to review vaccine and therapeutic candidates and applications supported by the national partnership, while also avoiding policy conflicts that could arise from being in a position to select certain drug and vaccine candidates for government funding and support, while also evaluating research studies and applications for market approval.

after the initial announcement of the dual roles for Woodcock and Marks. Critics noted that being involved with efforts to produce a viable COVID-19 vaccine by the end of the year would make it difficult to also evaluate what kind of data are needed to support approval of products to treat this relatively unknown disease. The Public Citizen health research group pointed out that having FDA executives on the White House task force could undermine the agency’s strong reputation for setting the “gold standard” for credible biomedical research and could raise questions about the integrity of the agency’s review of medical products funded by the administration’s initiative.

	Meanwhile, Operation Warp Speed in moving forward. The program made headlines last week with its decision to award $300 million to AstraZeneca to provide at least 300 million doses of its experimental coronavirus vaccines now being tested in collaboration with the University of Oxford in the United Kingdom.

The White House looks to bring in credible experts for its Operation Warp Speed initiative to advance therapies and vaccines to combat the coronavirus pandemic. 

FDA Leadership Shifts to Advance COVID-19 Treatments

	The Trump Administration has awarded a hefty contract to a new pharmaceutical manufacturing consortium to produce in the United States all components of certain critical medicines needed to combat COVID-19. The 

 of an initial $354-million, four-year award to Phlow Corp. by the Biomedical Advanced Research and Development Authority (BARDA) is to reduce the nation’s reliance on foreign producers for both the ingredients and finished dosage forms of certain drugs experiencing supply shortages, in some cases due to international supply chain issues [see ].

	In announcing the surprising BARDA award, which can rise to $801 million over 10 years, Peter Navarro, director of the White House Office of Trade and Manufacturing Policy, made clear that a prime objective is to reduce the nation’s reliance on foreign suppliers for vital medicines as envisioned by the administration’s “Buy American” campaign. Navarro lamented the US reliance on foreign manufacturing and supply chains for “our most important medicines and active pharmaceutical ingredients,” which places “Americans’ health, safety, and national security at grave risk.”

	A main question about the initiative, though, is whether it can provide high-quality, made-in-the-USA generic drugs at affordable prices without the large subsidy from BARDA. Many industry analysts have documented how production of APIs and generic drugs moved offshore in the 1980s to reduce costs and avoid more stringent environmental regulations. Ongoing shortages of generic drugs, particularly sterile injectables, relate to quality manufacturing issues in all regions, according to reports from FDA and other authorities. Yet US policy makers and drug purchasers show little interest in supporting higher prices to address these issues, even to achieve higher quality production.

	Richmond, VA-based Phlow will operate through an alliance with the US chemical company Ampac Fine Chemicals (AFC) to provide chemical precursor and APIs and with Civica Rx, the non-profit generic drug producer for a network of leading hospitals, which will produce finished medicines. The company is led by Phlow president Eric Edwards and co-founder Frank Gupton, head of the Medicines for All Institute at Virginia Commonwealth University College of Engineering. Edwards was a founder of Kaleo Pharmaceuticals, which gained some infamy several years ago for astronomical price hikes of the drug-overdose rescue treatment naloxone, plus earlier difficulties with an alternative to Epi-Pen. 

	The partnership began operations this week with Civica Rx delivering 1.6 million doses of five critical generic medicines, including antibiotics, pain management drugs, and medicines used for sedation to help patients requiring ventilator support. Phlow provided those therapies to the US National Strategic Stockpile (SNS) and also plans to build a Strategic Active Pharmaceutical Ingredients Reserve (SAPIR) to secure domestic supplies of key ingredients for essential medicines.

	Edwards and his partners emphasize that advanced manufacturing technologies will be key to producing more reliable, high-quality and affordable medicines. Gupton will provide strategies for commercializing innovative process technologies, such as “flow” chemistry and continuous advanced manufacturing processes to produce APIs. He predicted that the program will “revolutionize America’s generic drug manufacturing model” by producing affordable ingredients for high-quality, US-made products.

	AFC brings to the partnership experience in producing precursor chemical ingredients and APIs for the pharmaceutical industry through current good manufacturing practice (cGMP)-compliant operations in California, Texas, and Virginia. Phlow plans to work with AFC to build an advanced manufacturing capability in Virginia and facilities for producing sterile injectables. California-based AFC is part of SK pharmteco, a unit of Korea-based SK Holdings.

	Civica Rx was formed in 2018 as a non-profit corporation to provide high-quality, low-cost generic drugs to a network that now numbers more than 1200 hospitals in 50 health systems. It has supplied 20 sterile injectables in its first year with the aim of producing 100 medications by 2023. Through the partnership, Civica plans to build its own finished dosage form manufacturing facility near AFC’s Virginia operation to gain end-to-end production on the same site.

The Trump Administration has awarded a hefty contract to a new pharmaceutical manufacturing consortium to produce in the United States all components of certain critical medicines needed to combat COVID-19. 

Partnership Gets Millions to Supply US-Made Generics for Pandemic

	As the Trump Administration revs up its Operation Warp Speed initiative to provide new COVID-19 vaccines and therapeutics for patients, biopharmaceutical companies and federal agencies have been working overtime and assuming considerable risk to be able to supply billions of doses of any safe and effective preventive. With research underway for more than 175 vaccine candidates across a wide range of technologies, experts expect to identify several promising vaccines in the coming months. The aim is to have “multiple shots on goal,” along with multiple goals to shoot at, the experts quip. But the tight timeframe means that companies cannot wait for final clinical test results to begin preparing large-scale manufacturing operations and to address supply chain issues critical for delivering preventives globally.

	Consequently, manufacturers and funding agencies will “have to proceed at risk,” acknowledges Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). Instead of spending several years testing vaccine candidates and then ramping up production based on successful findings, industry and government agencies have to invest in things and build things “that we may never use,” 

sponsored by the Duke Margolis Center for Health Policy May 13, 2020. It means launching production as sponsors transition from Phase I studies, even though such investment may well exceed $1 billion or more, he noted.

	To move to full-scale production, manufacturers have to assess which vaccine manufacturing sites can switch to a new product and where a company can reduce current production of a vaccine with less demand, explained former FDA and National Security Council official Luciana Borio, now at In-Q-Tel. The development of a range of vaccine platforms-inactivated, non-replicating, live attenuated, protein, RNA-will require a similar variety in manufacturing capacity and create added challenges for scale-up. And if a COVID-19 vaccine emerges this fall, that would coincide with the annual seasonal flu vaccination campaign, making it difficult for companies to pull away from production in that area, noted former FDA Commissioner Scott Gottlieb.

	A related problem is shortages in glass vials and needles needed for expanded fill/finish operations, said Adrian Hill of the Jenner Institute and Oxford Martin Programme on Vaccines in the United Kingdom, and that companies often “can’t just stop manufacturing other vaccines.” Paul Stoffels of Johnson & Johnson’s Janssen Pharmaceuticals similarly considers “fill and finish critical,” noting that it’s impossible to plan to produce 300,000 vaccines without vials and finishing operations.

	While manufacturers and funding agencies aim to support “equitable distribution” of any successful vaccines to all regions, Gottlieb believes it is “inevitable” that countries developing and producing a successful preventive will first provide it to its own population. That speaks to importance of multiple vaccine platforms and large-scale manufacturing in many regions. The UK vaccine program is working with manufacturers in India and China with extensive vaccine production capacity, while the Coalition for Epidemic Preparedness Innovation (CEPI) is supporting several programs to develop vaccines for global distribution.

	Given the many challenges in manufacturing any one vaccine, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), agreed that multiple vaccines will need to be approved to meet global demand. As more vaccines move into clinical testing, FDA is working overtime to provide the best regulatory advice it can, and very quickly, he commented. Marks said that FDA is “willing to take certain calculated risks to get into Phase I,” and will accept novel trial designs, particularly with vaccine platforms that have been used before. But preclinical testing still will have to be done, as FDA has to convince people that we’re “not taking shortcuts here.”

	Fauci emphasized the importance of coordinating clinical trials for the many different vaccine candidates and the need for consistent protocols to gain definitive answers about whether a candidate works or not. Without complete clinical trials, he worries that researchers may get a signal that “strongly indicates” a response, but “doesn’t nail it down.” He recommends that sponsors utilize clinical research networks in locations with high incidences of COVID cases to facilitate obtaining clear results. Marks similarly advised sponsors to “go where the cases are-not the traditional sites,” acknowledging that widespread infection rates, ironically, should facilitate getting needed answers. And while sponsors should “space out” trials to different locations to avoid bias, study endpoints should be similar enough to be able to compare results from different trials.

	While the medical community reports that many patients are recovering from COVID by mounting a strong immune response to the virus, Marks acknowledges that scientists still have only a limited understanding of what will constitute long-term, definitive protection. This vaccine expert admits to having “great concerns” about a second pandemic wave this fall and winter and hopes to have some viable treatment by then. He’d be very pleased with a vaccine with strong efficacy data, and one that could get to herd immunity “would be really nice,” he commented. But regulators and researchers will take any preventive that indicates it can help get the pandemic under control, even, at this point, with only limited assurances for long-term success.  

Biopharmaceutical companies and federal agencies have been working overtime and assuming considerable risk to be able to supply billions of doses of any safe and effective preventive. 