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

Jill Wechsler

	FDA officials are proposing new rules, beefing up regulatory resources, and promoting digital technologies to support the development and marketing of safe and innovative over-the-counter (OTC) therapies. The agency and manufacturers continue to hope that Congress will approve legislation authorizing new user fees to modernize the OTC monograph review program, a plan that has been high on the legislative agenda for several years. But even without final agreement on that reform initiative, officials at the Center for Drug Evaluation and Research (CDER) expect to establish an expanded review office for nonprescription drugs as part of a broader reorganization of the Office of New Drugs (OND). In addition, the revamped office will better manage new drug applications (NDAs) for non-prescription medicines, including the new Nonprescription Safe Use Regulatory Expansion (NSURE) initiative to facilitate switches of prescription therapies to nonprescription status.

	“OTC monograph reform remains a top priority for the agency,” stated FDA Chief of Staff Lauren Silvis at the recent meeting of the Consumer Health Products Association (CHPA). She described agency plans to facilitate prescription-to-OTC switches to increase consumer access to medicines that can be used safely without a prescription. Draft guidance issued in 2018 should encourage manufacturers to provide additional information on proper product use than what is found in the approved drug facts label (DFL).

	CDER also is working to finalize a proposed rule for developing and marketing OTC sunscreens, an issue that has raised a host of issues relevant to ensuring safe and proper use of these widely available products. FDA seeks additional data to document the safety of ingredients commonly used in sunscreens that can be absorbed in ways to possibly have systemic effects on the body.

	FDA also is concerned about dietary supplements made with unlawful ingredients or promoting violative claims. An agency initiative aims to communicate information on new ingredients in supplements that FDA has not yet determined to be safe and legal, while also seeking further input on efforts to encourage “responsible innovation” in supplement marketing.

	In all these initiatives, FDA looks to utilize new technology that enables manufacturers to ensure the safe use of products beyond approved labeling. Silvis noted that new digital health technologies such as mobile applications and in-store digital kiosks can help consumers understand where additional conditions can be treated with an OTC product and facilitate consumer self-selection of treatment.

	Of great public interest is FDA’s recently launched review of appropriate regulatory approaches for assessing the safety, risks, and benefits of foods, dietary supplements, and therapies with cannabidiol (CBD) ingredients. The agency seeks to gain scientific information that can help it evaluate how to oversee cannabis and cannabis-derived compounds at a public hearing held May 31, 2019, which has attracted hundreds of speakers and comments.

	This initiative arose from Congressional approval of legislation in late 2018 that removed hemp from the federal controlled substances list, launching a stampede to market products made or infused with CBD. The measure also authorized FDA to examine how its authorities apply to CBD products, Silvis explained, and what “scientific uncertainties” should be addressed for legal marketing. FDA aims to protect the public from unsafe or ineffective products, including those that make unproven disease claims.

	One issue is whether it is appropriate to use CBD in cosmetics or dietary supplements.  FDA is looking for “reliable scientific research” on health and safety risks, on how standards or processes can help ensure product quality, and what kind of policies may address marketing, labeling, and sales issues. By seeking input from a range of stakeholders, Silvis added, FDA aims to “clarify our regulatory authority over these products” and to make “sound, science-based decisions to protect the public’s health.”

	After hearing from nearly 150 interested parties at the public hearing, an FDA cross-agency working group of senior staff will review both oral and further written comments on these issues. Meanwhile, Silvis advises manufacturers to hold off on submitting applications that look to claim a CBD product as a new dietary ingredient.

Articles

FDA is supporting the development and marketing of OTC therapies, including CBD products, by proposing new rules and an expanded review office and promoting digital technologies.

Opportunities and Challenges for Advancing Non-Prescription Medicines

	Concerns about the quality and safety of the growing volume of medicines imported to the United States, pressure to set international policies for genome editing of other scientific developments and escalating international trade disputes have prompted FDA to examine and update its programs for overseeing global operations and international affairs. The Office of Global Policy and Strategy in the newly named Office of Policy, Legislation & International Affairs (OPLIA) aims to better link consideration of international policy and trade issues with the challenges in ensuring the quality of ever-more imported medical and food products. The change reflects the global importance of FDA’s public health mission and its engagement in multiple initiatives to streamline and harmonize international standards and policies for regulated products.

	A “clear global policy strategy” has never been more important, says FDA Deputy Commissioner and OPLIA Director Anna Abram, noting the need for FDA to respond quickly and effectively to international disease outbreaks such as Ebola and to deal with a soaring amount of food and drug imports. More than three-fourths of APIs are produced by firms located outside the US, Abram noted at the recent annual meeting of the Food and Drug Law Institute (FDLI) in Washington, D.C., adding that the agency’s network of foreign offices provides a valuable overseas “presence” for FDA and are important in supporting foreign inspections, obtaining feedback on international developments, and for explaining FDA actions and policies to foreign constituencies.

	FDA is involved with a number of partnerships and collaborations with regulatory counterparts designed to streamline procedures for bringing new products to market in multiple regions, Abram noted. An important challenge is to inspect the thousands of foreign facilities that export to the US to ensure the quality of imported pharmaceuticals and other regulated products. As this task has expanded exponentially, FDA seeks to rely more on inspection reports produced by competent regulatory authorities in the European Union and other advanced nations. FDA and EU authorities have negotiated a mutual recognition agreement (MRA) that enables sharing of inspection reports for domestic drug manufacturers as a way to avoid duplicate inspections and to focus resources on more high-risk situations. The MRA is on track to be finalized this year following FDA’s recent announcement that it now has assessed and recognizes inspectorates in 24 of 28 EU member states.

	Despite this and other collaborations, FDA still needs to monitor a vast number of drug manufacturers in China and India and other third-world nations that produce APIs and generic drugs for the US. Deborah Autor, senior vice-president at Mylan Pharmaceuticals, expects that more drugs and medical products will be coming in from overseas, as manufacturers move to more corners of the world where it is less expensive to operate. Regulatory partnerships for conducting inspections and for establishing product standards are “crucial” to advancing drug development and for expanding patient access to needed therapies, Autor observed at the FDLI meeting, so that manufacturers may satisfy registration requirements in multiple markets based on an approval one regulatory authority.

	International standards for drug testing and manufacturing can further this goal by reducing a proliferation in divergent regulatory approaches around the world, as seen in new initiatives at the International Council for Harmonization (ICH), which has expanded to include representatives of nations from all regions of the world. ICH is shifting from establishing specific technical standards to developing more conceptual guidelines for modernizing good clinical practices, drug safety assessment, and quality production. A new draft guideline (E8) on the design and conduct of clinical trials, for example, identifies principles and practices in clinical studies that are crucial to ensuring data quality and for results to be accepted by regulators. Harmonization may extend to approaches for conducting drug-drug interaction studies, adaptive clinical trials, and for incorporating pediatric information extrapolation into drug development plans.

	In the drug quality area, ICH participants are scheduled to finalize a new framework for managing post-approval manufacturing changes as a way to facilitate improvements in drug products and production methods during the product lifecycle. Additional projects aim to harmonize policies for overseeing continuous manufacturing and for bioequivalence testing of generic drugs. Also, in the works are initiatives to streamline the collection of safety data in late-stage trials and post-marketing studies, to improve validation of bioanalytical assays for non-clinical and clinical studies, and to agree on electronic standards for submitting individual case safety reports to regulatory authorities.

	To further ensure that FDA policies are effective in enhancing public health at home and abroad, the agency has 

 that the National Academies of Science, Engineering and Medicine review its foreign operations and how well they enhance public health. In particular, the project is assessing FDA’s ongoing efforts to build the capacity of food and drug regulatory agencies in low- and middle-income countries to help ensure the safety and quality of regulated products.

FDA is examining and updating its programs for overseeing global operations and international affairs. 

International Harmonization Gains Importance for Global Pharmaceutical Industry

	During the nearly two years that Scott Gottlieb headed FDA, the agency achieved record approvals of new drugs and generics, and advanced important innovations in clinical research methods and in quality drug manufacturing to enhance competition and innovation in the bio/pharmaceutical industry. At the same time, the commissioner navigated the political pitfalls of Washington to gain increased funding for the agency and support for more aggressive policies to promote public health. FDA issued multiple new rules and guidance documents and utilized important new authorities to expand staff expertise and agency capabilities.

	Two critical public health issues drew considerable attention from Gottlieb. He championed steps to curb inappropriate prescribing of opioids while also encouraging the development of safer and more effective painkillers. Most recently, he promoted a comparative standard for approving new opioid painkillers to permit only treatments with clear additional benefits to come to market. And data showing sharp increases in teen use of nicotine products prompted a high-profile campaign to curb “vaping” and flavored cigarettes for the young, while maintaining access for adults looking to stop smoking.

	Gottlieb expects FDA to continue these initiatives under Acting Commissioner Ned Sharpless and a strong leadership team at the agency. But it will be a challenge for any newcomer, even an experienced scientist and administrator such as Sharpless, to maintain support and implement the broad spectrum of critical agency programs outlined in FDA’s 2020 budget request to Congress. In addition to promoting medical product safety and innovation, top priorities include advancing medical countermeasures, ensuring a safe national blood supply, implementing drug compounding rules, and preventing and detecting contamination of the nation’s food supply.

	As the Trump Administration and congressional leaders press for action to reduce drug prices, the FDA commissioner will have the task of explaining how expanded drug importing could open the door to unsafe products, particularly with the rise of lethal forms of fentanyl coming from overseas. Gottlieb was particularly adept at articulating how FDA can help bring down drug prices through more efficient approval of generic therapies and biosimilars that enhance competition. He railed at a farewell discussion sponsored by the Alliance for a Stronger FDA that innovators blocking access to supplies needed to test new generics for equivalence was “particularly pernicious.”

	Gottlieb expects continued efforts at FDA to implement innovative methods for conducting clinical trials and documenting new drug efficacy and safety. One promising development, he predicted, is that increased agency access to electronic health records will bring about a “profound change” in using real-world data for determining new drug effectiveness and safety. 

	Another challenge for FDA leaders is to continue efforts to modernize good manufacturing practices (GMPs), particularly for APIs coming from overseas. The continuing wave of recalls and shortages of blood pressure medicines due to contamination with cancer-causing impurities illustrates ongoing difficulties in this area. Gottlieb provided strong support for industry investment in continuous manufacturing systems and modern drug production methods to better ensure product quality and to reduce recalls and shortages in the process, issues that have challenged the Center for Drug Evaluation and Research (CDER) for the past decade. 

	During his tenure at FDA, Gottlieb sought to increase direct contact between the commissioner and center directors so that agency leadership could better understand staff challenges and priorities. That reform was formally implemented as part of an agency reorganization plan finalized just before Gottlieb’s departure in early April 2019. In addition, FDA centers implemented a range of internal organizational changes during the past two years, particularly for the approval and oversight of medical devices and for cell and gene therapies regulated by the Center for Biologics Evaluation and Research (CBER). CDER continues to revise its Office of New Drugs, which recently formed a new Office of Therapeutic Biologics and Biosimilars and shifted the division of hematology out of Oncology Products. Still to come are broader changes in oversight of over-the-counter medicines and updates in FDA regulation of diagnostics.

	Gottlieb was successful in expanding FDA resources and authority by building strong relationships with legislators, constituencies, and industry. He generated enthusiasm for many proposals through a barrage of official 

and social media commentary (1). Many observers expected him to come to FDA as a deregulator, canceling regulations and requirements, he acknowledged in his parting comments. Instead he expanded FDA authority, particularly in the critical areas of opioid prescribing and tobacco regulation. He left FDA in good hands but facing further upheavals in federal healthcare policy and partisan infighting likely to stymie regulatory innovation and squeeze agency funding.

	1.  FDA, “Remarks by Dr. Scott Gottlieb to Final All Hands Meeting,” 


	Volume 43, Number 5
	May 2019
	Pages: 14–15

	When referring to this article, please cite it as J. Wechsler, "FDA Faces Challenges After Gottlieb," 

New agency leadership is pressed to promote innovation while addressing safety and quality issues.

FDA Faces Challenges After Gottlieb

	Under a new “knowledge management” approach for the Center for Drug Evaluation and Research (CDER), manufacturers will submit applications that present data on drug safety and efficacy in a structured format. The data then can be transmitted to teams of FDA experts from multiple disciplines for timely and efficient assessment. The aim is to shift away from long, narrative documents filed in PDF format that are repetitive and obscure important issues and toward assessment teams that will examine data to answer key questions relevant to the product under review.

	This effort to modernize the review of clinical data for new drug applications (NDAs) and biologics license applications (BLAs) parallels changes in the format and review of manufacturing and quality data submitted to CDER’s Office of Pharmaceutical Quality (OPQ). Similar approaches also are being implemented for assessing pharmacologic studies for generic drugs to avoid multiple review cycles.

	CDER Director Janet Woodcock is finalizing this more streamlined approach process for evaluating new drugs in order to be able to handle the surge in submissions that reflects important advances in biopharmaceutical science, as well as the digital revolution that has expanded exponentially the data and information supporting biomedical research. Our understanding of clinical pharmacology, she commented at the recent Biostatistics Industry & Regulator Forum sponsored by the Drug Information Association (DIA) and FDA, and the vast amount of data from gene sequencing, requires “a new approach” for providing an assessment-not a review-of drug applications.

	FDA hopes that this process, moreover, will make new treatments more affordable. The aim is to find out early if patients will be better off or not from access to a new therapy, Woodcock observed, acknowledging that greater scrutiny of drug value currently is a major topic of debate.

	To be able to assess more applications for increasingly complex medicines, review teams will identify key issues during the investigational new drug (IND) stage to focus on them efficiently and with appropriate expertise. New drug review teams will consult with experts from CDER statistical groups, clinical pharmacology, and OPQ as needed. OPQ has been implementing a team approach to assessing the manufacturing; chemistry, manufacturing, and controls (CMC); and microbiology aspects of new drugs and generics to reach early agreement on key risks and issues in need of further scrutiny. The resulting assessment document will present a benefit/risk evaluation, the drug development program, key issues, and recommendations, aiming to create a more transparent process that is more useful for advisory committees.

	This approach aims to finish the initial assessment midway through the review period to leave ample time for FDA and the manufacturer to discuss post-market research commitments, including the need for a Risk Evaluation and Mitigation Strategy (REMS), well before approval deadlines. This will lead to “high quality, more uniform work products,” Woodcock said, “with fewer surprises and last-minute changes.”

	At the same time, Woodcock is reorganizing CDER’s Office of New Drugs (OND) to increase the number of review offices and establish a centralized project management group and a new policy office. These changes will support a more automated CDER work flow management system based on standard processes and protocol assessment templates. OND is trying out the new team approach on a few applications and hopes to have it in place by the end of this year.

	Looking to the long-term, Woodcock envisions the data-based assessment process will provide a model to reform how CDER manages post-market safety information. Eventually data submitted by sponsors may move to the “cloud” in standardized formats to facilitate data exchange and analysis.  These innovations reflect a “big cultural change” that will take some time to accomplish, Woodcock acknowledged. But with the rise of patient-focused drug development, genetic targeting to treat rare conditions, demand for greater transparency in the regulatory process, and more startup biotech companies focused on innovation, she believes that FDA needs new approaches for dealing with these and future challenges.

CDER Director Janet Woodcock is finalizing this more streamlined approach process for evaluating new drugs to handle the surge in drug application submissions.

FDA Moves to Modernize Drug Review Process

	FDA’s new leader, Ned Sharpless, M.D., praised the talent and diversity of the agency’s staff in expressing amazement over FDA’s “huge portfolio” of programs and responsibilities and emphasized that he is not planning “any radical changes” from what FDA has been trying to accomplish. This means continued efforts to support the development of new treatments and cures and to increase competition to reign in prescription drug costs by approving more generic drugs and biosimilars. His actions will be “guided by science” and the need to protect and promote public health, he emphasized in an 

	Sharpless will seek further solutions to the opioid crisis and work to reduce cigarette use in adults and kids. And he pledged support for stronger communication around the safety and effectiveness of vaccines, citing his horror as a physician to see outbreaks of measles “making a tragic comeback because of vaccine avoidance.”

	His work in cancer research and treatment, he noted, has made him a “champion” of the use of real-world evidence to speed clinical trials and to support regulatory decision-making around novel products. And he cited the importance of FDA’s field force in using enforcement actions to protect public health by halting drug counterfeiting, adulteration, untruthful advertising, and marketing dangerous products to children. A main initiative is to modernize and reform FDA oversight of the burgeoning dietary supplement industry, which recently has drawn agency warnings for marketing supplements with unlawful ingredients.

	In the next week, FDA will launch a newly updated FDA.gov website, Sharpless announced, anticipating improvements in providing “more accessible, user-friendly” information important to consumers. Although he serves as FDA’s acting commissioner, he emphasized that he did not see his role as temporary or part-time, and that he planned to “proceed at full speed ahead.”

Sharpless will seek further solutions to the opioid crisis and work to reduce cigarette use in adults and kids. 

Sharpless Outlines Priorities for Overseeing FDA’s “Huge Portfolio”

	Regulatory authorities in the United States and other regions are encouraging investment in continuous manufacturing (CM) processes to better ensure quality drug production, avoid shortages, and ultimately lower the cost of medications for patients. The aim is to support an industry shift away from step-wise batch production, which is vulnerable to contamination, errors, and stoppages, to the use of automated modular systems better able to reduce human error, waste, and delays.

	As of January 2019, FDA has approved five products from four manufacturers that use CM systems. These involve small molecules, but more comprehensive CM processes are in development for proteins and biologics. FDA reports that approximately 20 companies-both brand and generic-are talking to agency staff about developing and implementing CM processes.

	To spur more manufacturers to join the trend, FDA published new draft guidance in February 2019 that clarifies its policy regarding CM approaches (1). The aim is to address manufacturer concerns that adoption of CM technology could delay approval of new drug applications or complicate switching from a batch to a CM process for marketed products, explained then FDA commissioner Scott Gottlieb and Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), in a statement highlighting agency efforts to expand industry investment in modern manufacturing systems (2).

	The new guidance provides advice on what process and control strategy designs, including equipment, are needed to meet regulatory considerations. The guidance applies to CM for drug substances of all finished dosage forms, including drugs, generic drugs, and over-the-counter products, but not to biologics. It aims to clarify definitions of batches, process validation, and quality systems considerations for CM and to provide recommendations for scaling up production and demonstrating stability for finished drugs produced with CM systems.

	To overcome company concerns about the cost of investing in new production technologies, FDA emphasizes that CM platform technology can be used to manufacture multiple products, which can help reduce the risk of drug shortages and facilitate scale-up of production when needed. An added benefit is the smaller footprint for CM systems, along with greater efficiency and consistency in these operations.

	Gottlieb and Woodcock also cite increased FDA funding for private organizations assessing CM technology in laboratories, as well as support for internal agency investigation of CM and other technologies. CDER’s Emerging Technology Team (ETT) also is providing additional help for early adopters of CM in implementing new technology and navigating the application review process for products made with these modern methods. Additional funds in FDA’s 2019 budget will support further development of a standard operating approach for CM and advanced manufacturing, with the overall aim of reducing dependence on the import of pharmaceutical ingredients and products to better assure quality and supply.

	At the same time, the International Council for Harmonization (ICH) is moving forward to establish standards for continuous manufacturing of drug substances and drug products, with the aim of developing a common framework for regulating and approving products that utilize CM methods. ICH approved a concept paper on the topic at its November 2018 meeting, and a panel of experts is mapping plans for developing a new quality guideline (Q13) on this topic.  The aim is to establish common definitions for CM, articulate key scientific issues, and harmonize regulatory concepts and expectations across the regions. Participants hope to complete the project by the end of 2021, after conducting a series of site visits to CM facilities for both small and large molecules and learning more about state-of-the-art technologies. The expert working group includes representatives of industry and regulatory authorities in the United States, Europe, Japan, Canada, China, Korea, Singapore, and other nations.

	While most CM operations so far have involved small molecules, manufacturers of biologics also are assessing how CM may apply to both upstream and downstream biotech production. This topic was examined in depth at the January 2019 CMC Strategy Forum on Continuous Manufacturing for Biologics organized by CASSS (3). Industry experts discussed advances in implementing CM for small molecules, noting that adoption of this approach in biomanufacturing has been limited largely to upstream “hybrid” approaches. BioMarin Pharmaceutical vice-president, Novato Operations, Erik Fouts noted that equipment manufacturers are offering small and pilot-scale CM systems for integrated continuous upstream and downstream processes and that these approaches are drawing interest as ways to boost productivity, lower the manufacturing footprint, and avoid waste in raw materials.

	Participants at the Forum supported the ICH effort to develop the Q-13 guideline on CM as important in encouraging flexible approaches for implementing CM in manufacture of small molecules and therapeutic proteins. The aim is to clarify regulatory concepts, such as batch, process validation, and continuous process verification. While CM has the potential to increase flexibility and robustness in biomanufacturing, and to reduce costs and product heterogeneity, challenges remain in assuring sterility and advancing process controls.

	These issues were addressed more broadly at the CASSS WCBP 2019 Scientific Program (4). The three-day program concluded with a review of initiatives to achieve flexible and modular facilities and the use of process analytical technology (PAT) in continuous manufacturing. PAT for an integrated continuous biomanufacturing platform is “becoming a reality today,” the experts concluded, noting that there remain many questions to consider in the journey to flexible and modular facilities.

Quality Considerations for Continuous Manufacturing Guidance for Industry, Draft Guidance

	2. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., and Director of FDA’s Center for Drug Evaluation and Research Janet Woodcock, M.D., on the FDA’s Continuing Efforts to Maintain Its Strong Oversight of Generic Drug Quality Issues Domestically and Abroad,” 

Welcome to the CMC Strategy Forum Continuous Manufacturing for Biologics


	Volume 43, No. 4
	April 2019
	Pages: 14-15

	When referreing to this article, please cite it as J. Wechsler, "Continuous Manufacturing Gains Major Push from FDA," 

FDA is moving to shift industry away from step-wise batch production.