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

Jill Wechsler

	FDA announced in July that it plans to resume inspections of some US-regulated facilities this week, but it’s not clear how it will decide which sites to visit and what alternative oversight strategies will apply where on-site inspections are difficult. Yet, the resurgence in COVID-19 cases in the United States looks to limit actual inspections and require FDA to rely more on “virtual” inspections or “paper reviews.” The prospect of further delays in initiating foreign inspections, moreover, raises a host of questions about assuring access to the growing volume of drugs and active ingredients produced overseas and may boost collaboration with foreign inspectorates to vet their local facilities. Overriding all these planning efforts, however, is the expectation that multiple new COVID-19 vaccines and therapeutics will seek regulatory approval in the coming months and will require full FDA vetting of production facilities, operations, and records to allay consumer fears about product safety and quality.

field inspections, citing the need to protect staff overseas and the agency’s ability to block the import of any unsafe products at the borders. FDA officials emphasized that inspections are just one part of FDA’s program for assuring product quality and safety, and that manufacturers ultimately are responsible for ensuring compliance with standards. Although FDA initially indicated that inspections would halt for only a month or so, in May Commissioner Stephen Hahn 

 the need to further delay “routine surveillance inspections” as the pandemic continued.

	During this inspection hiatus, FDA has conducted some “mission critical” site visits but has not provided details as to where such oversight has been warranted and how it was carried out. FDA inspections are particularly important for companies looking to resolve earlier Official Action Indicated (OAI) citations that prevent the filing of new applications and limit business opportunities. And manufacturers looking to bring new drugs to market usually require a pre-approval inspection (PAI) for final approval. But as the recent surge in COVID-19 cases in the US further delays state and local reopening, FDA is under pressure to devise new strategies for meeting application review deadlines set by user fees that increasingly involve drugs and medical products from facilities that were not inspected prior to the pandemic.

	FDA now says it will resume “prioritized” domestic inspections in local areas able to reduce new COVID-19 cases and hospitalizations. Based on a state’s phase of reopening and local trend and intensity of infection, the 

 where the agency can resume mission-critical inspections only, all inspections with measures to protect staff, or all regulatory activities. This approach has raised questions about which localities will qualify for site visits and what fits “mission critical” or “priority” categories:  A new drug nearing its approval deadline? A site able to produce medicines in shortage? Or a firm looking to demonstrate that it has fixed earlier quality problems and wants to resume all operations?

	One surprise is that FDA stated it will pre-announce all prioritized inspections, an approach that is routine overseas, but not at home. The agency explains that providing time to plan for site visits in advance will enhance the safety of both the inspectors and of company staff and also ensure that appropriate personnel are on-site when needed.

	All these challenges raise the prospect that FDA may be conducting fewer on-site inspections in the coming months and will look to tap policies and programs that provide alternative oversight approaches. FDA gained more explicit authority under the FDA Safety and Innovation Act (FDASIA) of 2012 to use new methods to track manufacturing operations in the US and abroad, initially to reduce drug shortages linked to an increasingly global pharmaceutical supply chain. The 

a risk-based approach for determining inspection frequency, strengthened FDA’s authority to take action against manufacturers that refuse or delay an inspection, and authorized the agency to request and access manufacturer records “in lieu of or in advance” of an inspection.

	This “in lieu of” provision for obtaining manufacturing records is considered key to providing a framework for more virtual or “records-only” inspections, according to experts participating in a recent webinar hosted by the Food and Drug Law Institute (FDLI). So far, FDA has been reluctant to conduct full remote inspections, but has accessed records for less formal “assessments” to help determine the need for and timing of a site visit. FDA 

 issued in October 2014 outlines procedures for the agency to request and obtain plant operating records for such purposes. With these provisions in mind, manufacturers should be establishing policies and systems able to evaluate and comply with FDA requests for production records, e-data bases, and relevant documents. At the same time, industry should be seeking more information from FDA on how it will restart its current inspection program, including the time frame for advance notices of planned inspections, how the agency is prioritizing inspections, and how a remote inspection would be conducted.

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Industry should be seeking more information from FDA on how it will restart its current inspection program.

Will FDA Inspections Ever Be the Same?

	With more than 100 vaccine research programs looking to address the pandemic, FDA officials are moving to clarify standards and requirements for vetting and approving viable preventives. The agency recently

 outlining recommendations for documenting vaccine quality, safety, and efficacy in order for a product to move forward.

	A main point of discussion is the provision that a vaccine should be at least be 50% more effective than placebo in preventing the disease, a standard that some criticized as much too low to tackle COVID-19 effectively. However, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), which oversees vaccine production and approval, considers the 50% benchmark as hitting the “perfect spot,” he said in a webinar sponsored by the Alliance for a Stronger FDA on July 8, 2020. Efficacy lower than the 50% level yields a vaccine that may have very little effect, he explained, but if manufacturers had to achieve an 80% effect, there might not be a vaccine for months. “So,” he said, “50% seems the right place.”

	Marks expects that clinical trials for the first COVID vaccines will need to pursue a fairly traditional approval process, with Phase III studies enrolling 10,000–50,000 patients in each arm. Clinical trials for COVID vaccines need to be done efficiently and quickly, but still must be randomized, blinded. and placebo controlled. And adaptive trials need to describe the study plan up front. Studies should aim to enroll a broad spectrum of the population, as it will be important to see the effect of a vaccine on both older individuals and pediatric populations, as well as those with immune compromised systems and specific health conditions.

	FDA also seeks consistent, high-quality manufacture of vaccine candidates to ensure product safety. Safety concerns often link back to manufacturing quality issues, Marks explained, noting that CBER scientists will assess product sterility and potency through lot release requirements and look for consistency in manufacturing processes and controls for scale-up. Early safety studies need to enroll at least several thousand patients, because even a rare adverse event could affect thousands with a vaccine administered to many millions. And post-market surveillance will be important to track vaccine effectiveness in the real world, with manufacturers following up for a year or longer through well-planned pharmacovigilance programs. “We don’t want to skimp here,” stated Marks.

	A main objective for the agency is to instill widespread confidence in any FDA-approved vaccine, a critical factor at a time of considerable vaccine “hesitancy” in the United States. Marks admits to being very scared by polls showing that up to one-third of Americans are hesitant about taking the vaccine. “People need to have confidence that what’s out there will be of high quality and safe and effective, and that we’ll be monitoring for any problem.” And he emphasizes that full transparency on the part of manufacturers is very important to support clear messages about likely vaccine side effects and acceptable risks.

	The vaccine development approach mapped out by FDA is unlikely to produce an approved preventive this fall, Marks acknowledged. It will take weeks or months to enroll the thousands needed in clinical trials. And most of the current candidates will require two doses, which adds to testing timeframes. FDA will support efforts by manufacturers to look for ways to speed production. But “at the end of the day,” Marks stated, “we have to be able to tell the public that these are high quality products, and that corners were not cut.”

FDA officials are moving to clarify standards and requirements for vetting and approving viable preventives. 

FDA Maps Expectations for COVID Vaccine Proposals

	Ongoing shortages of critical medicines, many linked to supply chain disruptions due to the COVID-19 pandemic, continue to generate calls to shift production of drugs and pharmaceutical ingredients from foreign nations to the United States. The globalization of the biopharmaceutical industry during the past 30 years has encouraged production of drugs, particularly generic medicines and APIs, in regions offering cheap labor and less restrictive environmental and other regulations. Now the White House and some members of Congress look to “on shore” drug production to better ensure reliable access to vital medicines now produced overseas.

	An example of how the Trump Administration’s “Buy American” campaign could apply to pharmaceuticals is the announcement on May 19, 2020 of an initial $354 million, four-year award to Phlow Corp. by the Biomedical Advanced Research and Development Authority (BARDA) to boost US production for both the ingredients and finished dosage forms of certain drugs experiencing supply shortages (1). Peter Navarro, director of the White House Office of Trade and Manufacturing Policy, made clear that a prime objective is to reduce US reliance on foreign manufacturing and supply chains for “our most important medicines and active pharmaceutical ingredients,” to avoid placing “Americans’ health, safety, and national security at grave risk” (2).

	A main question about the BARDA award, which can rise to $801 million over 10 years, is whether the investment can ensure access to high-quality, made-in-the-USA drugs at affordable prices without the large government subsidy. It’s well documented how production of APIs and generic drugs moved to India and China and other regions in the 1980s to reduce costs. One result has been ongoing product shortages, many related to quality manufacturing issues, as firms at home and abroad delayed improvements and modernization of facilities and accepted ingredients with limited quality assurance.

	Members of Congress have proposed multiple measures to address US reliance on foreign drug production, some specifically targeting products made in China to protect access to vital medicines in case of a trade war. Other bills seek to encourage more US manufacturing through tax credits and other economic incentives, and to require firms producing finished drugs to disclose more information to FDA on sources for APIs and starting materials. There is little talk, though, about accepting higher prices for generic sterile injectables to ensure product quality.

	One rationale for boosting pharma production in the US is to facilitate FDA oversight of product quality and compliance with good manufacturing practices (GMPs). The rise in foreign drug production has strained FDA efforts to monitor and inspect manufacturers that export to the US, a situation aggravated by the halt to all drug facility inspections since March 2020 due to the pandemic (3).

	FDA oversight of foreign drug manufacturing was revisited at a hearing before the Senate Finance Committee in early June, following up on earlier Congressional reviews of the need for FDA to increase its oversight of overseas firms, particularly those in China and India (3).  FDA reported to the Senate panel that it was conducting more inspections of foreign plants in recent years, a development supported by the Government Accountability Office (GAO), which has conducted regular assessments of FDA’s foreign pharmaceutical inspection program since 2008 due to concerns about inadequate oversight of foreign producers (4). Yet, GAO continues to criticize FDA for routinely providing advance notice to foreign manufacturers of planned site visits, as opposed to unannounced inspections in the US. FDA foreign inspectors also have to rely on local company translators and limited time frames for examining extensive foreign facilities.

	Pharma companies, not surprisingly, oppose requirements to shift manufacturing to the US or to disclose proprietary information on ingredient sources. The Pharmaceutical Research and Manufacturers of America (PhRMA) emphasizes that US firms support more than four million jobs in the US, including 120,000 high-wage manufacturing positions at more than 1300 facilities. PhRMA maintains that “geographic diversity” in drug production can best ensure supply stability and warns that efforts to shift all global manufacturing to the US would upset the entire supply chain (5).

	Generic-drug makers also are not enthusiastic about made-in-America requirements, but are more receptive to economic incentives for boosting US operations. The Association of Affordable Medicines (AAM) issued a supply chain security “blueprint” in April that calls for the federal government to identify certain “priority medicines” to set the stage for negotiating long-term price and volume guaranteed contracts with manufacturers and for funding construction of US-based facilities to produce needed drugs in short supply. Additional tax incentives would encourage relocation of foreign operations to the US, and FDA would streamline regulatory processes to expeditiously approve new facilities and tech transfer processes (6).

	Advocates for boosting pharmaceutical production in the US emphasize that FDA can better ensure the quality of these products through more regular and comprehensive inspections and oversight, while also addressing concerns about security and product availability. At the same time, FDA officials would like to see manufacturers, particularly those gaining public support for constructing new facilities, adopt advanced manufacturing systems better able to ensure more efficient and reliable production of quality medicines, and to bolster supply chain redundancy and reliance. One hope is that policy makers assess issues raised by the current pandemic in considering approaches to better handle future emergencies, which may include strategies to support more drug manufacturing in the US.

	1. HHS, “HHS, Industry Partners Expand U.S.-Based Pharmaceutical Manufacturing for COVID-19 Response,” Press Release, May 19, 2020.
	2. Phlow Corporation, “Phlow Corporation Awarded $354 Million HHS/ASPR/BARDA Contract to Manufacture Essential Medicines in Shortage,” prnewswire.com, Press Release, May 19, 2020.
	3. US Senate Committee on Finance, 

COVID-19 and Beyond: Oversight of the FDA’s Foreign Drug Manufacturing Inspection Process

, June 2, 2020.
	4. M. Denigan-Macauley, 

“Drug Safety, COVID-19 Complicates Already Challenged FDA Foreign Inspection Program,” 

GAO Testimony Before the Committee on Finance, US Congress, June 2, 2020. 
	5. N. Longo, “America’s Global Leadership in Biopharmaceutical Manufacturing,” 

, June 4, 2020.
	6. AAM, “A Blueprint for Enhancing the Security of the U.S. Pharmaceutical Supply Chain,” 


	Vol. 44, No. 7
	July 2020
	Pages: 14–15

	When referring to this article, please cite it as J. Wechsler, “Pandemic Spurs Efforts to Boost Pharma Manufacturing in US,” 

FDA can better monitor quality production of domestic versus foreign firms. 

Pandemic Spurs Efforts to Boost Pharma Manufacturing in US

	The imperative to accelerate the development and production of new therapies and vaccines to treat patients infected by the COVID-19 virus has prompted a steady wave of new advisories from FDA on strategies for assessing new therapies and for ensuring quality products. The pandemic has required revisions in how companies maintain safe operating practices and how research sponsors assess and implement changes necessary to fit this new reality.

	One result of the coronovirus pandemic is an emphasis at FDA on developing guidance documents more quickly and efficiently, and agency officials expect that such approaches may continue in the future. In recent months, the agency has devised a more streamlined process for guidance development due to pressures to address R&D issues quickly, observed Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), at the June 2020 virtual annual meeting of the Drug Information Association (DIA). In considering likely changes in operations from the pandemic, Marks noted that FDA is moving away from what in the past has been a “challenging and somewhat tortured” process, where it often took two or three years of deliberations to devise a guidance document-with the result that the resulting advisory was “often outdated by the time it is published,” he commented. Now FDA staffers resolve their differences quickly, he said, resulting in a shorter process that often produces fresher and more useful documents.

outlines how manufacturers should ensure that workers who become infected by COVID-19

 do not compromise drug products or quality standards. FDA advises manufacturers to evaluate how the coronovirus increases risk of contamination under existing manufacturing controls and what kind of restrictions should be placed on sick workers.

 for developing drugs to treat bacterial pneumonia, in both community and hospital settings, and for ventilator-associated conditions. These final guidances offer new approaches for study randomization, patient enrollment, primary endpoints, and intravenous drug formulations to treat these conditions.

	Also important to manufacturers was a final guidance published in March 2020 in response to concerns about increased drug shortages due to the pandemic. FDA updated policies for manufacturers to notify the agency of any 

anticipated discontinuance or interruption 

2020 provide more flexibility for pharmaceutical compounders to respond more readily to shortages in needed drugs. And a draft guidance issued in May 2020 contains recommendations for permitted daily exposures to three residual solvents, developed by experts collaborating under the International Council for Harmonisation (ICH). The 

solicits comments from manufacturers and other experts as part of the process for updating the ICH Q3C guideline on permitted daily exposures to such substances. 

	FDA continues to update an overarching guidance published in March 2020 on how sponsors and researchers can modify clinical trials to adjust effectively to health care realities related to the pandemic. Recent additional guidance address the 

use of alternative laboratory or imaging centers

 and implementing video conferencing in ongoing studies. FDA also has advised on how and when sponsors should report serious adverse events related to a trial and on accepted changes to informed consent practices to facilitate the use of e-signatures and remote assessments during the pandemic.

FDA is placing emphasis on developing guidance documents more quickly and efficiently, and agency officials expect that such approaches may continue in the future. 

FDA Speeds New Guidance Development to Inform Manufacturing and Research During Pandemic

	The biomedical health community blasted FDA’s decision in March to authorize emergency use of malaria drug hydroxychloroquine (HCQ) and its earlier version, chloroquine (CQ), to treat patients seriously ill from COVID-19. Medical authorities cited a lack of evidence of effectiveness for these products and ongoing concerns about adverse effects on patients with cardiac problems. The situation exposed FDA to charges of responding to White House pressure to make the drugs more widely available, as advocated by President Trump, difficulties aggravated by missteps by the agency’s new commissioner Stephen Hahn, who was criticized for failing to address shortages and failures in authorizing effective diagnostics able to track the spread of the COVID-19. HCQ use emerged as a political issue between conservatives seeking open access to any promising medicine and Democrats charging the Trump Administration with ignoring science and medical authorities to promote favored remedies.

	Now FDA has revoked its Emergency Use Authorization (EUA) for these medicines, citing new evidence and reanalysis of earlier data confirming that the drugs show no evidence of effectiveness against the coronavirus and raise continued concerns about cardiovascular safety risks. Furthermore, FDA 

 not to administer HCQ with remdesivir, as the combination may reduce antiviral activity of that drug, which appears to provide some benefits for COVID patients.

	The reversal of this closely watched drug access policy appears to reflect efforts by Commissioner Hahn to assert FDA’s independence in basing decisions on objective scientific measures. In a 

to the Alliance for a Stronger FDA on June 1, Hahn emphasized his reliance on “rigorous data in support of advancing innovation and discovery” and that agency approval decisions must be based on good science for the American public to “have confidence in the products regulated by the FDA.” Hahn also acknowledged that when he came to FDA at the beginning of the year he was unprepared to handle a health emergency “of this magnitude” but has learned much over recent months.

	However, Hahn left it to his staff to announce the EUA revocation, staying out of the limelight-or avoiding the line of fire. FDA Deputy Commissioner for Medical and Scientific Affairs, Anand Shah, said the policy change was based on “the most trustworthy, high-quality, up-to-date evidence available.” And FDA 

 following “a rigorous assessment by scientists,” added Patrizia Cavazzoni, acting director of the Center for Drug Evaluation and Research (CDER) following Janet Woodcock’s move to Operation Warp Speed.

	The EUA repeal was applauded by public health officials, even though FDA had limited use of HCQ to health professionals treating hospitalized patients with confirmed COVID-19 in an effort to minimize broader adverse events. FDA officials 

that permitting access to some 3 million pills donated to the strategic national stockpile managed by the Biomedical Advanced Research and Development Authority (BARDA) would help address mounting shortages of the drug, which was needed for its approved use in treating patients suffering from lupus and rheumatoid arthritis, and that such emergency use did not represent approval of the drug for a new use.

	At the same time, former BARDA director Rick Bright lost his job, allegedly due to his refusal to implement administration demands to authorize a much broader expanded access policy for HCQ, as outlined in Bright’s 

.  Bright praised FDA officials for supporting the EUA that limited use to hospital care and now gains credibility from the agency conclusion that HCQ is “unlikely to produce an antiviral effect,” as stated in the 

 from FDA Chief Scientist Denise Hinton to BARDA.

	FDA’s policy change may not halt use of HCQ to treat COVID patients, as it remains available in large quantities in many hospitals and may be prescribed by physicians for off-label uses. More than 100 clinical trials have been launched to test HCQ with other therapies, although the World Health Organization and European regulators have halted many studies. At the same time, HHS secretary Alex Azar interpreted the EUA revocation as opening the door to broader use of HCQ, while White House trade policy advisor Peter Navarro scolded FDA bureaucrats for blindsiding the administration, according to press reports. The situation has reignited calls to make FDA an independent agency, similar to the Social Security Administration, to protect its decision-making processes from political interference. Such a move has been proposed in the past amidst policy controversies and remains one way to separate regulatory decisions from changing political preferences.

FDA has revoked its Emergency Use Authorization hydroxychloroquine and chloroquine, citing new evidence and reanalysis of earlier data confirming that the drugs show no evidence of effectiveness against the coronavirus and raise continued concerns about cardiovascular safety risks. 