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

Jill Wechsler

	FDA’s new commissioner, Stephen Hahn, emerged in public last week by announcing his priorities at an FDA “all hands” staff meeting and further discussing challenges and issues with the press. Of prime interest were his comments on how the agency might continue to address high drug prices, whether FDA is approving new therapies too fast based on too little evidence, and new concerns arising from the fast-spreading coronavirus.

	A prominent oncologist and top official at the MD Anderson Cancer Center in Houston, Hahn won support from several former commissioners and was quickly confirmed by the Senate in December 2019, despite his limited familiarity with FDA operations or policies. Since then, he has been appointing new staffers to the commissioner’s office and reviewing prime topics on FDA’s agenda. In January, he announced the appointment of Anand Shah as deputy commissioner for medical and scientific affairs. Shah briefly was a medical officer at FDA’s Oncology Center of Excellence before moving to the Center for Medicare and Medicaid Services (CMS) where he was involved in big data initiatives. Other new senior advisors include Colin Rom and attorney Lowell Zeta.

	Hahn’s more formal presentation to FDA staffers on Jan. 30, 2020 avoided most controversial topics, such as opioids, cannabis-based medicines, vaping, and wider drug importing. A main goal of his tenure, he said, is to continue modernizing FDA information systems, an undertaking that aims to provide reviewers and analysts with better data to speed up product assessments, while ensuring that information is accurate and of high quality. He also promoted several popular initiatives, including wider use of patient input to improve information on new drugs and medical devices, and better communications with consumers.

	Another Hahn goal is to capitalize on today’s “unsurpassed scientific and technological innovation,” while also maintaining a balance between the speedy approval of new products and the integrity of the data and the process itself. He aims to support the development of newer, more effective products “while maintaining FDA’s gold standard for safety and effectiveness.” To accomplish these goals, Hahn pledged to work to ensure sufficient resources for the agency, with an emphasis on supporting efforts to retain and attract scientists and experts to the agency. 

	In subsequent comments, Hahn addressed issues related to rising drug costs. While emphasizing that FDA does not traditionally deal with drug pricing, he suggested that the agency can work with Medicare and Medicaid to extend coverage and reimbursement of new therapies. And he indicated support for implementing the Trump Administration’s plan to let states import drugs.

	The emergence of the coronavirus pandemic clearly will be a main concern for the new commissioner, who acknowledged that the outbreak is affecting FDA by halting staff travel to China to conduct plant inspections and deal with other issues. At the same time, FDA is poised to play an important role in efforts to develop new vaccines, treatments, and diagnostic tests for the new virus.

	Hahn said that FDA is closely monitoring for supply chain disruptions involving the many medical products and active ingredients imported from Asia. The growing reliance of US biopharma companies on Chinese supplies and products threatens to aggravate drug shortages and increase access challenges. Members of Congress and consumer groups have been voicing concerns about the unreliable quality of drugs from China and added FDA difficulties in overseeing the expanding global drug supply chain will further the debate.

Articles

The FDA Commissioner plans to address drug prices, the drug approval process, and supply chain issues during his time as commissioner of FDA.

Hahn Era Begins at FDA

	Rising imports of drugs and APIs, at a time when FDA is struggling to inspect and oversee foreign manufacturers, has focused attention on difficulties in ensuring the quality and safety of drugs made overseas. A main FDA strategy is to align with other capable regulatory agencies through agreements to share inspection reports and resources. Ironically, the difficulties in monitoring foreign producers raise questions about efforts by the White House and Congress to boost importation of drugs from Canada to reduce outlays for medicines at home.

	FDA’s challenges in overseeing foreign producers were outlined starkly at a hearing before the House Energy & Commerce subcommittee on Oversight & Investigations in early December 2019. This followed a similar session by the panel’s Health subcommittee in October 2019 on the rising volume of APIs entering the United States through a vulnerable supply chain. A main fear is that unreliable and contaminated imports could aggravate shortages of critical drugs and create security risks for the US. The legislators questioned the adequacy of FDA’s foreign drug inspection program, noting ongoing recalls of blood pressure medications manufactured in China and India that were contaminated by trace amounts of carcinogens.

	Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, had the unenviable task of explaining how the agency was addressing these issues. She acknowledged in December that FDA was conducting fewer inspections of foreign drug producers, largely due to difficulties in hiring and training sufficient numbers of investigators to conduct site visits overseas. But she also reported a decline in never-inspected foreign sites and a rise in the number of facilities rated acceptable by the agency (1).

	In response to concerns raised in a report from on ongoing investigation by the Government Accountability Office (2), Woodcock noted FDA efforts to engage more translators so that FDA inspectors do not have to rely on regulated companies for translation services. A continuing difficulty, she acknowledged, is FDA’s need to announce planned visits to foreign sites to ensure that the facility is operational, while domestic inspections are unannounced. Woodcock noted that limited FDA resources hinder fast resolution of these problems but hoped that a modernized FDA current good manufacturing practice inspection process being implemented would improve the effectiveness of its oversight of all manufacturing facilities.

	FDA also looks to reduce the need to inspect certain manufacturing facilities in Europe and other nations through increased participation in Mutual Recognition Agreements (MRAs) with other capable inspectorates. FDA and the European Union finalized an MRA in July 2019 that allows FDA to rely on inspections in EU member states, while European inspectors similarly can request FDA inspection reports on US facilities (3).

	More recently, FDA announced a new pilot program with the European Medicines Agency and regulators in the United Kingdom, Australia, Canada, and Japan to share information from GMP inspections of sterile human drug manufacturing sites in these and other regions. FDA also is considering additional MRAs for overseeing clinical research sites, test laboratories, and additional products, such as veterinary medicines (4).

	In addition, regulatory authorities in all regions are working to improve the effectiveness and quality of GMP inspections through the Pharmaceutical Inspection Co-operation Scheme (PIC/S). Regulators from the US, Europe, Australia, Canada, and other nations have developed recommendations for how inspectors may evaluate a company’s pharmaceutical quality system to encourage more effective manufacturing systems around the world. PIC/S also has published documents to support effective oversight of biological medicines and advanced medical products.

	Regulatory programs that encourage manufacturers in all regions to invest in advanced manufacturing technology able to ensure product quality represents the best long-term solution to many of these issues, explained Woodcock at Congressional hearings and in multiple presentations to industry. At December 2019 meetings on global pharmaceutical regulation and risk management sponsored by the International Society of Pharmaceutical Engineers and by the Parenteral Drug Association, Woodcock made the case for establishing a system able to rate production sites on “quality maturity,” a desirable status that a firm could promote to customers and investors. And high-quality continuous manufacturing systems, she predicted, would reduce waste from failed batches and thus lower costs significantly.

	Meanwhile, concerns over high drug prices at home have prompted the Trump Administration to authorize new pathways for states and other entities to import drugs from Canada, and for manufacturers to import their own products made and sold overseas. The rules are complicated and will be subject to extensive comments and revisions; it’s not clear that any potential importer will meet all the requirements for ensuring that such imports will not risk public health and safety in the US-and provide savings for consumers.

	It’s also not clear that any manufacturer will seek to sell its own foreign-made drugs in the US at lower prices. And Canadian officials indicate no ability to expand drug supplies to meet US needs. But Florida and several other states have authorized drug importing and are looking for new strategies to do so, despite the potential for further complicating the drug importing picture.

Securing The US Drug Supply Chain: Oversight of FDA’s Foreign Inspection Program,”

  Testimony of Janet Woodcock, MD, Director, Center for Drug Evaluation and Research Food and Drug Administration Department of Health and Human Services Before the Subcommittee On Oversight and Investigations Committee on Energy and Commerce US House of Representatives, Dec. 10, 2019.
	2. GAO, 

“Drug Safety: Preliminary Findings Indicate Persistent Challenges with FDA Foreign Inspections,”

 Statement of Mary Denigan-Macauley, Director, Health Care, Dec. 10, 2019.
	3. Mark Abdoo, “Measuring the Impact of the Pharmaceutical Annex to the U.S./EU Mutual Recognition Agreement,” 

, Dec. 6, 2019.
	4. National Academies of Sciences, Engineering, and Medicine, “To Improve Public Health, Medicine Regulators Worldwide Should Collaborate, Remove Barriers to Sharing Information, Says New Report,” 


	Vol. 44, No. 2
	February 2020
	Pages: 14-15

	When referring to this article, please cite it as J. Wechsler, "Global Supply Issues Create Challenges," 

Increased reliance on foreign producers raises concerns and spurs collaborations.

Global Supply Issues Create Challenges

	In a recent staff memo, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), outlined several key initiatives and goals for the coming months, many affecting multiple CDER offices and addressing key challenges for the agency. At the top of the list is the need to track adverse events more effectively, especially those that did not appear during product development, as may be the case with new therapies that are tested and approved under accelerated programs. Postmarket assessment is important for identifying drug safety issues, such as the presence of genotoxic impurities, or nitrosamines, that have been identified in several types of drugs. Advances in tracking drug safety issues can help address continued drug shortages that too often limit patient access to medications and arise from manufacturing and supply failures involving multiple stakeholders.

	CDER also will continue to address the opioid crisis through multiple strategies. These include decreasing exposure to opioids and preventing new addiction; supporting the treatment of those with opioid use disorder and expanding access to naloxone; fostering the development of novel pain treatment therapies; improving enforcement of diverted opioids and illegal drugs; and accessing the benefit/risk framework that evaluates not only the outcomes of opioids when used a prescribed, but also the public health effects of inappropriate use of these drugs.

	A more internal goal is to fully implement CDER’s more streamlined, interdisciplinary new drug review process. This goal will further establish a more integrated review of new drug applications (NDAs) and biologics license applications (BLAs), as well as modernize approaches for managing investigational new drug (IND) applications and post-market drug safety. Despite some minor delays in standing up revised Offices of Nonprescription Drugs and of Specialty Medicine, Woodcock expects to have in place shortly a new organizational structure for CDER’s Office of New Drugs, along with changes in the Office of Translational Sciences, the Office of Surveillance and Epidemiology, and the Office of Pharmaceutical Quality. 

	More specific initiatives on the list involve finalizing a new regulatory approach to non-prescription sunscreen use and to further engage drug compounders to protect the public from contaminated products. A new Compounding Quality Center of Excellence aims to enhance collaboration among and provide educational programs for outsourcing facilities to improve the overall quality of compounded medicines.

	Looking to the future, CDER officials will begin the next round of user fee negotiations to set the stage for reauthorization of CDER’s three user fee programs in 2022. These involve drugs, generic drugs and biosimilars, and are critical to CDER being able to “fulfill our mission of protecting the public health and accelerating innovation in industry,” Woodcock stated. In conclusion, she noted the importance of working to further improve internal processes for CDER’s governance structure, information technology, and hiring-a process that involves a more streamlined interview and selection process.

Top of CDER’s to-do list for 2020 is tracking adverse events more effectively and combating the opioid crisis.

Woodcock Sets Priorities for Year Ahead

	Can a commitment to limit prices to ensure patient access to important new medicines regain public trust and confidence in the biopharmaceutical industry? That’s the hope of a large cadre of biotech company executives who recognize that recent scientific advances that promise to cure critical diseases must be linked to high integrity and corporate responsibility or face price controls and other policies that undermine support for continued discovery of new medicines.

New Biotechnology & Pharmaceutical Industry Commitment to Patients and the Public

” penned by six CEOs, more than 200 leaders from some 150 small and mid-size firms and research organizations acknowledge that out-of-pocket costs for individuals must be limited to sustain support for fiscal and patent policies key to advancing innovation. The group led by executives from Amicus, Nkarta, Ovid, Global Blood, GlycoMimetics, and Alnylam Pharmaceuticals back collaboration with healthcare entities, including payers, hospitals, and distributors, in efforts to eliminate co-pays and deductibles for all patients.

	Those signing the commitment letter also pledged to support ethical business practices and to invest “only in novel therapies that address unmet patient needs.” And they oppose companies and stakeholders who “abuse this commitment to patients and who abuse policies aimed at fairly rewarding innovation.” At the same time, the group supports the marketing of biosimilars and generic drugs after “legitimate patents and regulatory protections expire.”

	By itself, the public letter offers few specifics for effective change in current industry practice. Even so, the list of supporters is notable for the absence of big pharma and biotech firms who did not sign on, ostensibly due to legal concerns about joining any industry initiative that could be construed as involving multi-company price-setting agreements. The Biotechnology Innovation Organization (BIO) voiced support for the principles expressed here by many of its members, but did not officially endorse the statement. And while manufacturers can face stiff penalties for actions even hinting at price-setting agreements, these commitments to ethical practices should avoid such consequences by emphasizing responsible actions by individual companies.

Can a commitment to limit prices to ensure patient access to important new medicines regain public trust and confidence in the biopharmaceutical industry? 

Biotech Execs Pledge “Reasonable” Price Increases

	FDA did not set any records last year in approving new drugs and biologics for market, but it did speed a number of important new therapies to patients, continuing to demonstrate its flexibility and support for biomedical innovation. Based on its criteria, the Center for Drug Evaluation and Research (CDER) 

(NMEs) in 2019, a count that may vary according to different definitions. In addition, the Center for Biologics Evaluation and Research (CBER) approved the first gene therapy for spinal muscular atrophy, Novartis’ Zolgensma, as well as new vaccines for Ebola (from Merck) and Dengue (Sanofi). While the totals fall short of the record-setting 59 NMEs approved in 2018, the numbers are close to or exceed the agency’s performance in most previous years.

	Probably more important than the number is the wide range of breakthrough therapies moving through the agency’s review process, including nearly a dozen cancer treatments, some with innovative modalities. Speedy approvals at the end of the year included the first PARP inhibitor to treat advanced pancreatic cancer, Lynparza, from AstraZeneca and Merck. FDA also approved two antibody-drug conjugates (ADCs), one for urothelial cancer from Seattle Genetics and Astellas Pharma, and another for advanced breast cancer from Daiichi Sankyo and AstraZeneca.

	Earlier, Vertex Pharmaceuticals gained a fast approval for a new triple-combo treatment for cystic fibrosis, Trikafta, while new therapies for complicated urinary tract infections came from Shionogi and Merck. Particularly noteworthy is the success of two new drugs for sickle cell disease, which largely affects African Americans. These include Novartis’ Adakveo and Oxbryta from Global Blood Therapeutics. The list also includes important new drugs for postpartum depression from Sage Therapeutics, Intra-Cellular’s Caplyta for schizophrenia in adults, new migraine therapies from Eli Lilly and from Allergan, plus a new Novartis drug for a relapsing form of multiple sclerosis.

	Most surprising was FDA’s decision in December to approve Sarepta Therapeutics’ second drug for Duchenne muscular dystrophy, Vyondys 53. The agency had rejected the application only four months earlier.

	Speedy review from FDA, as well as high launch prices for many critical new drugs, will continue to raise controversy. Some critics claim the agency is moving too quickly in bringing new therapies to market based on limited testing, while others argue that FDA remains too slow in addressing the critical needs of many patients. And high price tags, particularly for some treatments for larger patient populations such as sickle cell disease, are sure to accelerate calls for pharmaceutical price controls. So far, Congress has stepped back from legislation to limit outlays for prescription drugs, but the debate will be aggravated by a number of new medicines with six-figure annual costs, as well as a large number of annual January increases in list praises for hundreds of brand medicines. 

The numbers of new molecular entities approved in 2019 are close to or exceed FDA’s performance in most previous years. 

New Drug Approvals Stay Strong in 2019

	While biopharma companies can anticipate continued success in discovering new gene and cellular therapies and in devising innovative treatments for multiple serious conditions, a range of issues are poised to shape R&D and regulatory policies in early 2020. Politicians on all sides will continue to hammer drug prices, prompting industry to emphasize the importance of maintaining strong investment in R&D. FDA will remain embroiled in addressing a number of high-profile public health issues, as well as drug shortages and complex drug development initiatives.

	With national elections looming in November 2020, and a host of Democrats seeking to regain the White House, health policy and pharmaceutical costs will remain leading issues for all candidates. The future of the Obama Administration’s Affordable Care Act hangs in the balance, with the debate poised to shape federal and state drug coverage and reimbursement as part of initiatives to lower outlays for medicines. Industry will challenge legislation authorizing drug importing or international reference pricing as a threat to continued innovation, but the full ramifications of election-year politicking remain to be seen.

	Important challenges await FDA’s new commissioner, Stephen Hahn, most notably ongoing efforts to address the nation’s devastating opioid epidemic and to halt teen vaping of e-cigarettes, which has been linked to dozens of deaths. There’s pressure on the agency to clarify its rules for cannabidiol products, particularly dietary supplements promoting health benefits, and to address concerns about the rise in antibiotic resistance and lack of research on new treatments to combat infectious diseases. Delays in Congress approving the federal budget for the 2019 fiscal year will continue to create difficulties for the agency in assuring support for its many crucial food and drug programs.

	In response to the public outcry over drug prices, FDA will continue to streamline and accelerate the approval of more generic drugs and biosimilars as alternatives to expensive brand therapies. However, most of the biosimilars approved so far have yet to reach the market due to complex patent issues as well as efforts by innovators to discourage acceptance of follow-on therapies by physicians and health plans. FDA will continue to oppose tactics to delay access to comparators needed to test generics and biosimilars, and some policy makers look to prevent brands from offering financial incentives to health plans and pharmacy benefit managers (PBMs) to favor their products. But the issues are complex and will present challenges in bringing biosimilars and generics to patients.

	FDA has worked to establish standards to support the development of innovative, life-saving cellular and gene therapies, as seen in the approval of several breakthrough products and industry programs to develop dozens more. Patient advocates will continue to provide important voices for shaping risk-benefit equations for promising therapies, while manufacturers will invest more in modern operations able to produce quality cutting-edge products more reliably and efficiently. All parties will be watching closely to detect any safety problems or signs of limited effectiveness that could raise concerns about the long-term value of a new treatment. The importance of reliable systems for producing safe and high-quality pharmaceuticals will remain in the spotlight as part of efforts to ensure access to needed medicines. Congressional leaders are concerned about continued shortages in a number of critical treatments, as well as increased reliance on drug ingredients imported from China, India, and other countries. FDA’s Office of Regulatory Affairs (ORA) is looking to implement more fully its pharmaceutical inspectorate process, which features highly trained professionals using templates to evaluate how well production systems and practices can ensure the regular production of quality products, and to support industry efforts to modernize operations and address problems expeditiously.

	More guidance from FDA should help improve testing and production of needed treatments, particularly new cellular and gene therapies that raise tricky quality control challenges. FDA will continue to support global harmonization of standards for drug production and for preclinical and clinical testing, as seen in a range of agreements with other regulatory authorities. These involve sharing and accepting reports on plant inspections, on certain testing programs, and more recently on information in market applications to achieve simultaneous drug approval decisions by multiple authorities. A main theme for the coming year will be to reduce extraneous requirements and promote more streamlined, risk-based approaches to drug development and production around the world.

	Congress may do more to support these and other R&D programs by advancing legislation to further initiatives authorized by the 21st Century Cures Act five years ago. This time, the legislators indicate an interest in promoting wider utilization of digital health technologies to improve access to new products and health services; in modernizing coverage policies for innovative, life-saving drugs; and in utilizing real-world evidence more broadly in drug development.

	When referring to this article, please cite it as J. Wechsler, "Pharma Regulation to be Shaped by Pricing and Production Issues,"

Pressures on FDA will affect industry’s success in bringing new therapies to market.