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

Jill Wechsler

	In an effort to ensure access to certain widely used drugs at affordable prices, a group of leading hospitals and health systems have established a 

 to produce therapies in short supply or subject to unusual price increases. Industry veteran Martin van Trieste, former chief quality officer for Amgen, was named CEO of Civica Rx, lending credibility to this much-anticipated plan. 

	An initial proposal for a provider-based system to counter rocketing drug prices and serious shortages was announced in 

. Since then it has attracted more than 120 health organizations, including Catholic Health Initiatives, HCA Healthcare, Intermountain Healthcare, Mayo Clinic, and Providence St. Joseph Health; these and others together represent more than one-third of the nation’s hospitals. The venture has received $30 million in funding from a number of foundations and investors and aims to raise $200 million to support the operation. 

	The plan is to initially produce 14 hospital-administered generic drugs through contract manufacturers or generic drug makers with FDA-approved facilities, with the aim of bringing an initial product to market by early 2019. Van Trieste, who had recently retired and is heading the venture with no salary, expects the venture to bring “much needed competition to the generic drug market.” 

	An unknown is how current manufacturers will respond to this operation, perhaps by reducing prices or boosting production. Many short-supply therapies are sterile injectables, which raise production challenges. But hospitals anticipate that access to more reliable supplies will be important in reducing the time and effort now needed to track supplies, seek out alternatives, and advise health workers on the need to vary prescribing and drug administration practices. 

Articles

More than 120 healthcare organizations plan to bring competition to generic drug market.

Hospitals Back Generic Drug Production Venture

	FDA has been issuing warning letters and managing new import bans and product recalls related to a wave of potentially impure drugs and APIs from China, India, and other foreign firms. The increase in GMP-related violations, which has raised alarms about distribution of possibly harmful medicines, heightens concern about the ability of US and other established regulators to detect and address such failures, especially as drug makers increasingly rely on foreign operators for APIs and other drug components.

	Most visible is a steady stream of recalls by manufacturers of valsartan, a widely used blood pressure medicine made largely with bulk ingredients from China. In June 2018, a leading Chinese manufacturer of the product, Zhejiang Huahai Pharmaceutical, informed customers that its valsartan contained traces of an impurity, N-nitrosodimethylamine (NDMA), which could cause cancer in certain amounts. Two other producers of bulk valsartan, in China and India, also disclosed a similar finding. The problem appears related to the use of a certain solvent in an updated manufacturing process, which may have been going on for several years. The lag in uncovering the situation raises questions about the conduct of pharmaceutical manufacturing operations in China, and the effectiveness of plant inspections by all parties.

 by some 50 firms that produce some 10 billion pills containing valsartan. In Europe, Novartis recalled Sandoz’ products containing valsartan, as did Teva, Stada, Dexcel Pharma, and others. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), 

that valsartan-containing medicines from Teva, Major Pharmaceuticals, and Solco Healthcare “did not meet our safety standards” and should be withdrawn.  In August, Torrent Pharmaceuticals recalled multiple lots of drugs containing the tainted API, as have additional pharma companies and repackagers.

	The valsartan debacle comes on the heels of another major scandal in China over the production and distribution of substandard vaccines for children. Regulatory officials discovered falsified production data for DPT vaccines at Changsheng Biotechnology Co. in November 2017 but permitted the distribution of the preventive to continue for several months, until similar problems with a rabies vaccine appeared in July 2018. Additional Chinese vaccine makers have admitted to distributing faulty vaccines, igniting a call for reform. China’s National Drug Administration said it would conduct unannounced inspections of all vaccine manufacturers, in an effort to regain credibility for the regulatory regime. The vaccine problems largely affect domestic Chinese supplies but do little to raise confidence in manufacturing quality in that region.

	Perhaps due to greater attention to the quality of drugs and ingredients coming from foreign producers, FDA appears to be ramping up scrutiny of drug manufacturing operations in China and other Asian countries. FDA 

six firms from China, India, and South Korea to its import alert roster following their refusal to admit FDA inspectors; products on the “red “list cannot be shipped to the United States.  

	Recent FDA warning letters have cited drug makers in Japan and China for failure to resolve data integrity and validation issues uncovered in recent inspections. Another Chinese firm received a 

following its failure to address a range of manufacturing and testing issues detected in several previous inspections. FDA also released 

 (form 483) citing continued issues raised by recent inspections of Celltrion’s South Korean biotech manufacturing site.

	Meanwhile, regulators seek to avoid enforcement actions that could lead to shortages of widely used medicines. FDA officials say they are monitoring supply situations closely in the wake of these widespread recalls and production disruptions. 

A wave of potentially impure drugs and APIs from China, India, and other foreign firms has prompted recalls and FDA warning letters. 

Quality Failures at Foreign Manufacturers Prompt Warnings and Recalls

	Instead of taking the usual August recess, the Senate stayed in Washington to approve several multi-agency budget bills for the government fiscal year that begins Oct. 1, 2018. The measures boost funding for FDA and the National Institutes of Health (NIH) and include a contentious provision that requires biopharma companies to disclose product prices in direct-to-consumer (DTC) advertising.

	The DTC ad measure was added to a major Senate appropriations bill for the Departments of Labor, Education, and Health and Human Services (HHS). That legislation provides a $2.3-billion increase in NIH funding, to $39 billion, with some of that money directed to combat the opioid epidemic by supporting NIH research to develop non-addictive pain therapies.

	Most notable is an amendment that aims to provide consumers with more information on drug costs by instructing HHS to develop and implement rules requiring manufacturers to list drug prices in ads. This provision most likely will involve a formal rulemaking process to clarify what information (e.g., list or discounted prices) should be disclosed and how the policy would be implemented.

	In another major funding bill for the Department of Agriculture and other agencies, the Senate approved a $159-million budget increase for FDA, to bring its resources up to $5.4 billion for 2019, including more than $2 billion in user fees. The Senate plan, though, provides much less than the $400-million hike for FDA requested by the administration, and is well below the $308-million boost approved by House committees. The Senate provides FDA an additional $88.5 million to enhance medical product development and oversight, compared to $260 million proposed in the House, with the added funds directed to advance drug and medical device manufacturing, modernize general drug development, and support new science to evaluate drugs.

	Senate leaders hope that their House colleagues will agree to negotiate final funding packages through conference committees, instead of waiting for formal House approval of separate budget bills. All parties want to finalize these spending bills before October 1, 2018 when the government could shut down without approved funding for the 2019 fiscal year. Pharma companies seek to remove the price disclosure provision, while advocates for sufficient FDA resources, such as the Alliance for a Stronger FDA, are working to gain final funding closer to the higher House proposals.

The Senate approved a $159-million budget increase for FDA, to bring its resources up to $5.4 billion for 2019, including more than $2 billion in user fees.

Senate Spending Bills Give Minor Boost to FDA, Seek Price Disclosures in Ads

Editor's Note: This article was first published online on Aug. 2, 2018.

	While cell- and gene-therapy products hold the promise of transforming the treatment of many diseases, difficulties in achieving consistent process control could stymie advancement in this field, cautions Peter Marks, director of FDA’s Center for Biologics Evaluation and Research (CBER). It’s “not simple” to bring a clinical production process to commercial scale, he says, voicing fears that important manufacturing issues could hinder efforts to advance new discoveries able to transform medical care.

	With more than 100 investigational new drug applications (INDs) filed last year for gene-therapy products and multiple R&D programs underway, FDA seeks to emphasize the challenges of developing and validating relevant manufacturing processes. CBER is receiving dozens of applications to test new gene therapies, Marks reported at the Cell and Gene Therapy symposium in July 2018, sponsored by CASSS. He acknowledged that the logistics of manufacturing autologous cells can be particularly challenging, and that limited capacity in cell lines stymie efforts to meet the demand for product development. While there is great excitement over the potential of CAR-T (chimeric antigen receptor) cell therapy to target and activate T cells to eliminate a cancerous or other undesirable cell type, Marks cautioned that the use of genetically modified cellular therapies to achieve a durable therapeutic effect requires a consistent process for producing and characterizing cells.

	Marks suggested that new manufacturing technology, such as partially automated closed systems and modular manufacturing facilities, could help address some of these difficulties. He cited a lack of capacity for manufacture of lentiviral and adeno-associated virus (AAV) vectors for limiting clinical development and noted that the process of production in current cell lines is not able to meet demand despite some improvement over the past few years. Clinical development is crucial, but industry needs to have “manufacturing under control,” Marks observed.

	FDA’s Regenerative Medicine Advanced Therapy (RMAT) program can help expedite oversight of certain tissue and cell products and gene therapies by providing support and assistance in developing products that treat serious or life-threatening conditions and address unmet medical needs. CBER had granted the RMAT designation to 24 products as of June 30, 2018, and more new products seek to qualify for that treatment.

	CBER also is working with the National Institute of Standards and Technology (NIST) and other public and private organizations to develop standards for advancing research and development of cutting-edge therapies. CBER scientists also are collaborating with public and private partners in initiatives to advance the development of improved cell lines for vector production. At the CASSS symposium, Samantha Maragh of NIST provided an update on collaborative efforts to develop measurement standards for genome editing, including an assay qualification process that would expand the capability to make targeted DNA changes. The NIST genome editing consortium includes a range of industry members and seeks experts who can help design reference materials and refine assay protocols.

	In addition, manufacturers pursuing initial development of novel gene and cellular therapies now may gain early advice from less formal meetings with FDA experts. A new INTERACT program (Initial Targeted Engagement for Regulatory Advice on CBER producTs) replaces current pre-pre-IND meetings for all CBER products. The aim is to help less experienced sponsors and investigators better understand FDA expectations for preclinical testing, aspects of manufacturing for first-in-human trials, and initial clinical development strategies, with the aim of avoiding unnecessary or inadequate studies. At the same time, CBER staff hopes to gain early insight into new products and technologies entering the R&D pipeline. These very early meetings still will be followed by more formal meetings between sponsors and FDA staff at pre-IND and pre-biologic license application (BLA) meetings, as 

 issued in July 2018 what manufacturing information is needed to support clinical development on chemistry, manufacturing, and control (CMC) information for investigational human gene therapies [see ]. This update of a 2008 advisory describes how manufacturers should provide sufficient CMC information to assure the safety, identity, quality, purity, and strength/potency of investigational gene therapies. A 

 addresses the proper testing of retroviral-based gene therapy products to ensure proper testing for replication competent retrovirus (RCR) during production.

 address how sponsors should assess when and how to monitor the long-term follow-up of gene therapies and provide recommendations for developing novel treatments for hemophilia, retinal disorders, and rare diseases. These guidances are “building blocks of a modern, comprehensive framework” for advancing the field of gene therapy, said FDA commissioner Scott Gottlieb, in 

 these advisories for advancing innovative R&D. Some of these products “are almost certainly going to change the contours of medical practice,” he commented, and FDA seeks to ensure the safety and effectiveness of resulting treatments to “build peoples’ confidence in this novel area of medicine.”


	Vol. 42, No. 9
	September 2018
	Pages: 16, 66

	When referring to this article, please cite it as J. Wechsler, "FDA Seeks to Enhance Manufacturing of Cell and Gene Therapies," 

More consistent and reliable production processes are critical for advancing innovative treatments.

FDA Seeks to Enhance Manufacturing of Cell and Gene Therapies

	Most FDA commissioners look to leave their imprint on the agency by making structural changes that update the roles and functions of lead operations. After more than a year at the agency’s helm, Scott Gottlieb now proposes to flatten out FDA’s structure by having the Center directors report directly to him, instead of through a level of “directorates” between the commissioner and Center staff. This change aims to give more authority to the agency’s six product regulatory Centers and to the Office of Regulatory Affairs (ORA) and will ensure that the commissioner remains “in close contact with the Center leadership,” Gottlieb said in an email to FDA staff announcing the reorganization plan.

	Certain cross-cutting activities now handled by the directorates will shift to new and existing offices. Of particular importance for the development of new drugs and medical products, a new Office of Clinical Policy and Programs (OCPP) will oversee programs that affect multiple Centers, including orphan products, pediatric therapeutics, combination products, and good clinical practice. OCPP also will manage new agency-wide initiatives for patient affairs and for healthcare provider affairs to strengthen FDA interactions with key stakeholder groups. Nina Hunter, currently deputy director for medical programs in the Office of Medical Products and Tobacco, will head this operation with the aim of better coordinating functions that affect the development of complex medical products and treatments for specialized patient populations.

	FDA’s Office of the Chief Scientist (OCS) under Denise Hinton will supervise the Office of Minority Health, Office of Women’s Health and Office of Laboratory Safety, as well as ongoing programs for counterterrorism, toxicological research, scientific integrity, and agency research. Deputy commissioner Rachel Sherman will manage agency operations and coordinate activities related to medical product development.

	Policy and legislative issues affecting FDA will be monitored and managed by a new Office of Policy, Legislation and International Affairs, headed by Anne Abram. The office will advise Gottlieb and Centers on topics affecting agency relations with Congress, state and foreign governments, and represent FDA’s perspective on trade and international issues to all entities.

	Separately, organizational changes are underway at the Center for Drug Evaluation and Research (CDER) and other Centers. CDER director Janet Woodcock recently announced plans to form an Office of Therapeutic Biologics and Biosimilars (OTBB) as part of a broader reorganization of the Office of New Drugs (OND). Woodcock also plans changes in the Office of Compliance to strengthen oversight of drug compounding and drug imports.

	All these changes will be disclosed more formally in the coming days and will require higher level review and approval by the administration and Congress, with the aim of implementation later this year.

Commissioner Gottlieb is reorganizing FDA in the hopes of streamlining policymaking.

Gottlieb Reshapes FDA to Elevate Centers

	For years, consumer advocates and state officials have pushed for access to less expensive prescription medicines available overseas, only to meet stiff resistance from FDA and government health authorities claiming that such action could bring unsafe and harmful products into the United States. This opposition has come from both Democratic and Republican administrations, bolstered by evidence that drugs supposedly from Canada or Europe are often of unknown origin and are shipped by unscrupulous website operators.

	Now rising pressure to do more to control drug prices is prompting Trump administration officials to explore where more flexible import policies may help ensure access to safe, effective, and more affordable medicines. With support from Health and Human Services (HHS) secretary Alex Azar, FDA commissioner Scott Gottlieb is forming a work group to consider strategies for importing prescription drugs from other countries. Such action would be in response to a “dramatic price increase” on a product that has no competition and thus threatens patient access. Importing would be limited to off-patent, off-exclusivity sole-source products where quality, approved alternatives may be available overseas.

	The work group will explore how enforcement discretion could lead to importation of drugs that would be suitable substitutes for an FDA-approved version of a medically-necessary medicine. Key topics to consider are the relevant statutory and regulatory requirements for advancing an import policy; how to define an “access dislocation” that could lead to serious shortages; and how FDA will assess the safety, effectiveness and labeling of a foreign-approved drug to ensure patient safety. Any authorized import under this framework would be temporary, 

, and policies would aim to prevent the import of counterfeit or unsafe drugs.

	Even with these caveats, manufacturers strongly oppose the plan, as seen in the alarm sounded by the industry-backed Partnership for Safe Medicines over widespread illegal importing of counterfeit fentanyl products and criminal organizations operating illegal pharmacy websites offering lethal therapies to American consumers. The Association for Accessible Medicines (AAM), which represents generic-drug companies, advises FDA and HHS to examine the factors leading to sole-source, off-patent drugs in the first place, which it blames on too-low generic drug prices that limit competition in certain markets.

	State and local governments have long sought to establish drug importing programs to obtain discounts for state health programs and public employee health plans, and Congress passed a law in 2003 that allows drug importing from Canada if HHS certifies that such action doesn’t increase safety risks for consumers. The feds have never provided that support, although FDA usually permits individuals to purchase foreign prescription drugs for personal use. Vermont is taking a new tack, with a new law that establishes a state wholesale bulk purchasing program to bring in less costly medicines from Canada, as part of broader legislation requiring drug manufacturers and insurers to disclose high prices of new drugs. It will be ironic if the current Republican administration authorizes similar action, altering long-held regulatory opposition to importing unapproved drugs.

Rising pressure to do more to control drug prices is prompting Trump administration officials to explore where more flexible import policies may help ensure access to safe, effective, and more affordable medicines. 