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

Jill Wechsler

	FDA has struggled for several years to establish a program for collecting data from biopharmaceutical manufacturers that can measure how well a firm produces high-quality products on a consistent basis. Now after months of inaction on advancing a proposed quality metrics initiative, the agency appears to be starting over by asking firms to discuss internal quality metrics efforts as part of the approval process for new medical products. FDA also is proposing that manufacturers invite agency staffers to visit sites to examine more closely a firm’s quality measurement program.

	FDA’s quality metrics initiative emerged several years ago as part of agency efforts to encourage industry investment in quality manufacturing systems able to reduce product defects that could lead to drug shortages and recalls. A 2015 draft guidance from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) proposed to collect data on manufacturing operations and product attributes that could help measure how well a firm was able to meet quality standards. In response to multiple comments from industry, FDA issued a 

 in 2016, which also drew a harsh response from stakeholders.

	The negative comments to these proposals reflect wide disparities in how pharma companies individually measure and track manufacturing operations and product quality. Firms raised concerns that FDA would make the reporting program mandatory, instead of voluntary, and that it was particularly difficult to assess a firm’s “quality culture,” involving how management encouraged and supported methods to quality production. Trade organizations asserted that the proposed metrics program would require substantial industry resources and significant operational changes that could undermine other quality improvement efforts. And there was strong opposition to indications that FDA might publicly disclose metrics data-whether to reward high performers or to encourage others to invest more in quality improvement.

	Since then, FDA has been quiet on the metrics issue, even as agency leaders have highlighted the importance of improving drug quality and adopting continuous manufacturing systems. At the ISPE Quality Manufacturing conference in June 2018, industry representatives discussed efforts to advance metrics measurement methods, and experts from the University of St. Gallen provided an update on their model for using metrics to drive continuous improvement and greater efficiencies in pharmaceutical production.

	Yet, FDA had little new to report. Tara Gooen-Bizjak, senior science policy advisor in CDER’s Office of Pharmaceutical Quality, had the unhappy task of reporting that “active discussions” about quality metrics were continuing at the agency, and that metrics data were regarded as important for improving quality. She acknowledged that most manufacturers use quality metrics as part of process validation, lifecycle management, and pharmaceutical quality assessment. But she could not say when FDA might issue revised guidance or further proposals on the metrics initiative.

	FDA’s recent announcement indicates that the agency is taking a fresh look at how manufacturers use metrics in their internal operations to inform its plan for collecting quality measures. A new Quality Metrics Feedback Program seeks to learn more about quality metrics activities across the industry. Manufacturers of new drugs are encouraged 

 Type C meeting to discuss these issues, and generic-drug makers may do so at pre-ANDA (abbreviated new drug application) meetings. Contract manufacturers and companies that produce active pharmaceutical ingredients and over-the-counter drugs may participate in a pilot program to provide feedback on their quality measurement activities.

 aims to send FDA teams to visit manufacturer facilities that have implemented quality metrics programs, particularly those designed to address significant manufacturing problems. The goal is for CDER and CBER staff to observe how firms gather, collect, and report quality data to management, and for participating establishments to explain the advantages and challenges associated with devising quality metrics programs and to showcase technologies that support such initiatives.

	FDA seeks several firms to apply by June 2019 to participate in these voluntary programs. In announcing the new initiatives, the agency says it seeks to “continue learning about the advantages and challenges” companies have experienced with metrics programs in order to inform policy development. One possibility is that metrics data will help devise a more risk-based inspection program that offers decreased establishment inspections for high-quality facilities. FDA also hopes to better identify situations likely to experience supply disruptions. More information on FDA manufacturing quality initiatives can be found at 

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/default.htm

	Orignially posted online at www.PharmTech.com on July 2, 2018.


	Vol. 42, No. 8
	August 2018
	Pages: 14Â­–15

	When referring to this article, please cite it as J. Wechsler, "FDA Seeks to Revive Quality Metrics Initiative," 

Articles

The agency is asking firms to discuss internal quality metrics efforts as part of the approval process for new medical products. 

FDA Seeks to Revive Quality Metrics Initiative

	The House recently enacted multiple legislative proposals to support treatment of opioid abusers and deter inappropriate drug prescribing and illegal distribution. This bipartisan action sets the stage for similar action by the Senate, as the legislators 

the deadly drug epidemic before the November midterm elections. A main objective of these policies is to widen access to medications for addiction treatment and overdose emergencies, a strategy backed by pharma manufacturers of buprenorphine and newer rescue drugs and opioid disorder therapies. The legislation also encourages prescribing of non-opioid pain therapies but stops short of mandating prescriber education on pain management-or of regulating drug prices.

	At the same time, the Justice Department 

 against dozens of individuals involved in prescribing and distributing opioids and illegal narcotics as part of a massive healthcare fraud enforcement action across the country. Although most of the 600 defendants face charges related to schemes to bilk Medicare, Medicaid, and other government health programs of some $2 billion in fraudulent claims, the campaign also targeted opioid-related activities, with more than 70 doctors and other health professionals facing charges related to “fanning the flames of the opioid crisis.”

	As part of ongoing FDA efforts to reduce illegal opioid prescribing and distribution, the agency seeks to curb the rise in opioid sales through online pharmacies. In June 2018, FDA sent 

 to operators of 53 websites to halt illegal sales of unapproved, misbranded, and dangerous medicines such as Tramadol and oxycodone, or face product seizures or injunctions.

 to discuss with leading Internet operators and other stakeholders ways to reduce the availability of opioids through misleading websites and search engines [see  ]. The agency cited a 

 from the Senate Permanent Subcommittee on Investigation indicating that online illicit drug sales reached more than $150 million in 2015, as use of the Internet to purchase opioids from online pharmacies has soared. 

	FDA invited leading tech companies to the summit, such as Facebook, Google, Microsoft, and Yahoo, as well as online shopping sites, shipping firms, payment processors, and trade associations representing online pharmacies and Internet operators. While the tech community maintains that online sales account for only a small portion of illegal drug transactions, FDA commissioner Scott Gottlieb called for concerted action: “We can’t just play whack-a-mole with illegal sites, shutting down URLs only to watch new ones pop up.” Cutting off the flow of illicit Internet traffic in opioids “is critical,” he said, urging attendees to work together to stop the “digital drug dealers.”

	FDA has increased resources to target and take action against illicit Internet drug marketers, despite multiple challenges in doing so. For example, progress in educating health professionals on the importance of reducing prescribing of opioids in favor of less addictive pain medicines now is predicted to send even more individuals suffering from opioid addiction to websites and other sources of illegal and potentially unsafe pills.

	Gottlieb acknowledged that the tech firms at the summit have “the expertise to transform this space.” He cited efforts by Google to de-index web pages linked to FDA warning letters, by Microsoft’s Bing to attach pop-up warnings to such illicit websites, and by Facebook to steer parties seeking opioids online to sites with information on addiction treatment. While there are difficulties associated with implementing these and other strategies, he urged further collaboration with Internet experts to devise technological solutions and collective approaches for decreasing opioid availability.      

Legislators look to widen access to medications for addiction treatment and overdose emergencies.

Congress and FDA Take Action to Combat Opioid Crisis

	A central strategy for enhancing access to more affordable medicines for the Trump administration, Congress, and FDA involves smoothing the pathway for the development and approval of high-quality biosimilars and interchangeable biotech therapies. Yet, only three biosimilars are on the market-of 11 approved products-eight years after enactment of legislation authorizing follow-ons. Recent entries include Pfizer’s Retracrit, the first approved alternative to Amgen’s widely used anemia treatment Epogen (epoetin alfa), and Fulphilia (Pegfilgrastim) from Mylan and Biocon, a competitor to Amgen’s Neulasta. But if current trends continue, it may be months or years before Americans gain access to these less costly therapies.

	 In the United States, biosimilars must overcome lengthy patent challenges and difficult reimbursement policies that block product marketing. Testing and production of biosimilars costs from $100 million to $250 million per program, much more than the $10 million involved in developing a conventional generic drug. Consequently, biosimilars come to market at prices only 15–20% below the innovator, which often is not enough difference to drive prescribing and industry investment in the field.

	Manufacturing problems also continue to cause delays, as experienced by both 

 last year (1,2). Celltrion also received FDA 

 for biosimilar applications for rituximab (Rituxan) and for trastuzumab (Herceptin) due to violations at its South Korea facility involving aseptic practices, which it says are now corrected (3). Other firms have run into delays in FDA approval related to technical and quality production issues.

	At FDA, Commissioner Scott Gottlieb, MD, is encouraging biosimilar development with initiatives to provide greater scientific and regulatory clarity for sponsors, a more efficient review process, and tools for using modern analytical techniques to make biosimilar development more predictable and less costly. With more than 60 biosimilar development programs to 31 different reference products in the pipeline, the Center for Drug Evaluation and Research (CDER) is 

and review functions to smooth the pathway to approval (4). FDA has finalized seven guidance documents since 2015 that spell out a range of procedures and policies for demonstrating biosimilarity to reference product, reports CDER Associate Director for Therapeutic Biologics Leah Christl. Now the agency is moving to prepare and revise advisories on several contentious issues, including biosimilar labeling, managing post-approval manufacturing changes, and demonstrating interchangeability with a reference product. Although FDA cannot change the legal standard for interchangeable biosimilars, Christl 

 at the April 2018 Medicines for Europe Biosimilar Medicines Conference in London, the agency is examining possible revisions in data elements necessary to support an interchangeability designation (5).

it would start over with guidance on statistical approaches for evaluating analytical similarity to better accommodate new scientific tools to streamline the studies required for comparisons between biosimilars and reference products (6). The aim is to clarify where natural variance in production lots for biologics occurs over time and how to incorporate this process into procedures for copying such variable products. FDA is examining innovative methods that may help manufacturers measure and control for routine lot differences, with an eye to addressing where it may not be necessary for a biosimilar to show comparability to a full range of variance in reference products.

	Another concern for FDA is evidence that innovators may delay biosimilar testing by blocking access to supplies of reference products needed for comparability testing and clinical trials. FDA has published lists of brand drugs subject to such complaints from generic-drug makers and has its eye on restrictive contracting and distribution strategies that similarly may affect biosimilar sponsors and create barriers to the submission of biosimilar applications.

	To encourage greater uptake of biosimilars, FDA also is doing more to educate clinicians and patients on product safety and efficacy and to address misconceptions that foster reluctance to prescribe and use these therapies. Biosimilar advocates are urging the agency to further explain its standards and policies to build public confidence that biosimilars are equally safe and effective as brand biologics. FDA recently 

 its educational materials on the development and approval of biosimilars and interchangeable products for healthcare professionals and patients (7). Biosimilar makers also anticipate that an efficient path for demonstrating product interchangeability with brands will help build prescriber and patient confidence in switching to the new products.

	Added efficiencies may arise from establishing a global market for biosimilars, and FDA is collaborating with regulatory authorities in Europe, Japan, and Canada to harmonize R&D requirements and share experiences in overseeing biosimilars. Such partnerships can support global economies of scale in biosimilar development programs across national boundaries, Christl noted at the London conference. Regulatory authorities from the United Kingdom and other European countries reported millions in savings from the growing uptake of biosimilars to rituximab, infliximab, and etanercept, as prescribers gain more confidence in switching patients to the lower-cost therapies.

	In the US, though, payment and rebate practices create additional barriers to biosimilar marketing and utilization. In a

 to health insurance firms in March 2018, Gottlieb pointed to rebating and contracting schemes and “Kabuki drug-pricing constructs” that expose consumers to high out-of-pocket costs for biosimilars and discourage manufacturers from investing in producing more affordable alternatives (8). The problem is that high rebates paid by brand manufacturers encourage health plans and pharmacy benefit managers (PBMs) to favor brand therapies on formularies. In April 2018, the 

PBMs directly about how “restrictive contracting, rebating, and distribution agreements deter coverage and reimbursement” for biosimilars (9). 

	The crux of the problem, Gottlieb explained, is the “rebate trap” that permits PBMs and insurers to profit from the spread between list price and the actual rebated price for an innovator therapy. Rebates can amount to hundreds of million of dollars in annual revenues for plans and typically are tied by manufacturers to volume or preferred formulary status. This system means that PBMs and plans lose substantial rebate revenues by shifting patients from an established drug to a biosimilar.

	As biologics account for an increasingly large portion of drug outlays, Gottlieb urged payers and insurers to reject such rebate arrangements and to encourage biosimilar use by lifting prior authorization requirements for biosimilars, designing formularies with biosimilars as the default option for newly diagnosed patients, and waiving co-insurance on these products. Payers must decide if they want to continue to benefit from profitable rebates, Gottlieb told the insurers, or “help generate a vibrant biosimilar market that can help reset biologic pricing.”

	These rebate and contracting issues that stymie biosimilar competition, along with a range of patent, regulatory, and reimbursement challenges, are discussed in a 

from the Biosimilars Council of the Association for Accessible Medicines (10). The group is pressing for legislation to facilitate access to test samples for generic-drug and biosimilar manufacturers, as well as policies to promote biosimilar competition at FDA and other government agencies.

	1. Pfizer, “Pfizer Provides Update on Proposed Epoetin Alfa Biosimilar,” 

, June 22, 2017.
	2. Mylan, “US FDA Approves Mylan and Biocon’s Fulphila™ (pegfilgrastim-jmdb), the First Biosimilar to Neulasta®,” 

, June 4, 2018.
	3. Celltrion, “Celltrion Completes Resubmission for Biosimilar Candidate to FDA for Review,” 

,” Medicines for Europe Biosimilar Medicines Conference, April 27, 2018.
	6. FDA, 

FDA Withdraws Draft Guidance for Industry: Statistical Approaches to Evaluate Analytical Similarity,

 June 21, 2018.
	7. FDA, FDA Video Series about Biosimilar and Interchangeable Products, 

.
	8. FDA, Capturing the Benefits for Competition for Patients, 

.
	9. FDA, Advancing Patient Crae Through Competition, 


	Vol. 42, No. 7
	July 2018
	Pages: 14-15

	When referring to this article, please cite it as J. Wechsler, "Biosimilars Raise Manufacturing and Regulatory Challenges," 

FDA seeks more efficient testing to spur development of less costly biotech therapies.

Biosimilars Raise Manufacturing and Regulatory Challenges

	FDA needs a more concerted effort to address nationwide shortages of intravenous drugs that put patients at risk and threaten public health, according to a group of leading Senators ranging from Republican Orrin Hatch to leading liberal Bernie Sanders. They and their colleagues have expressed dismay about limited supplies of critical, widely used injectable opioids, anesthetics, and sterile IV fluids that continue for months and years. Legislators 

 FDA Commissioner Scott Gottlieb, MD, convene an authorized Drug Shortage Task Force and develop recommendations by the end of 2019 to ensure that “appropriate supplies of essential medications are always available."

	Evidently, these policy makers believe that FDA can do more to prevent shortages than is indicated in the agency’s 

 on drug shortages for 2017, or that Gottlieb spelled out in a 

issued May 31, 2018. The annual report indicates that ongoing drug shortages continued to decline from a high in 2012, but that new shortages rose last year, largely due to a devastating hurricane season that ravaged drug production in Puerto Rico, plus the shutdown of a major manufacturer experiencing production difficulties.

	Douglas Throckmorton, deputy director of the Center for  Drug Evaluation and Research (CDER), 

with specifics on what FDA was doing to address shortages in IV fluids, pain medications, and EpiPen self-injectibles that raise particular concerns from health professionals. Throckmorton provided specifics on how hurricane damage in Puerto Rico shut down Baxter Healthcare production of saline and dextrose-based fluids widely used to deliver medications intravenously. The storm destruction aggravated already short supplies in IV fluids, and a severe flu season last winter raised demand for these products even more. FDA sought to address the crisis by approving production by other manufacturers, permitting temporary import of saline, and instructing health professionals in the use of alternative products.

	Similar action aims to address shortages in opioid analgesics used to treat pain in cancer patients and to manage surgical procedures. Here Throckmorton cites production delays due to changes and upgrades designed to address manufacturing quality issues at Pfizer’s Kansas drug production facility. Other manufacturers, including Akorn Pharmaceuticals, Fresenius Kabi, and West-Ward Pharmaceuticals, have increased their production at FDA’s urging, although Throckmorton noted that expansion of sterile injectible production takes time.

	The CDER official also reported that Mylan expects limited availability of EpiPens in certain areas to be a short-term supply issue. FDA is working to address regional supply disruptions and manufacturing issues that have contributed to this situation and encouraging other manufacturers of epinephrine auto-injectors to expand production.

	The FDA annual drug shortage report notes that the agency helped to prevent 145 shortages in 2017, a rise from the previous year, by being able to exercise regulatory “flexibility” in authorizing the release of alternative products and importing to alleviate short supply situations. Early notifications from manufacturers of anticipated supply disruptions also is important: FDA reports that it was notified of 520 potential drug and biological product shortage situations by 86 different manufacturers in 2017 and was able to resolve most of these before they created problems, often through expedited review of applications or supplements and early inspections of facilities.

	Gottlieb cites manufacturing and product quality issues as the leading cause of drug shortages, along with limited availability in active ingredients, which can affect several drug manufacturers. Only 2% of drug shortages result from a company’s decision to discontinue production of a medicine, he noted, situations that can be related to manufacturing costs, changes in patent life, and product profitability. At the same time, evidence supporting additional uses of a drug can increase demand for a product and put more pressure on supplies. Gottlieb is hopeful that new continuous manufacturing systems and other innovative production technologies will increase manufacturing reliability and prevent quality-related shortages over the long run but acknowledges that the initial cost of investing in such new equipment “presents challenges.”

	It may be helpful, the commissioner said, for Congress to expand FDA’s existing authority to require new drug manufacturers to conduct a risk assessment to identify vulnerabilities in their drug supply chains, particularly problems that could lead to a shortage. FDA cannot require a company to produce any drug or to increase production or control distribution, Gottlieb acknowledged, but advance notification and contingency plans can help mitigate the impact of shortages.

Legislators have requested that FDA do more to prevent drug shortages.

Congress Presses FDA to Do More to Combat Drug Shortages

	After years of consultations and deliberations, regulatory authorities have published draft guidance negotiated by the International Council on Harmonization (ICH) on strategies to facilitate pharmaceutical lifecycle management. The 34-page

 aims to establish common policies and practices for data and testing required by regulators in all regions to authorize 

	A main feature of the guidance is to establish a process for manufacturers to identify established conditions that warrant notification or prior approval by regulatory authorities, as opposed to less critical product features that need less regulatory oversight. The policy aims to reduce regulatory burdens and promote manufacturing innovation and improvements by offering a process for industry to demonstrate to regulators how increased product and process knowledge can support changes with reduced regulatory submissions. This approach aims to encourage continual improvement in products and manufacturing methods, reducing costs, and ensuring reliable supplies.

	This effort to harmonize regulatory requirements for post-approval changes builds on previous ICH quality standards developed over the past 15 years that support more efficient and flexible pharmaceutical manufacturing operations that reliably produce high-quality products, with less regulatory oversight. Despite these efforts, the global spread of industry to regions with divergent regulatory requirements has greatly complicated the post-approval change process, noted Christine Moore, global head and executive director of CMC policy at Merck. She explained at the June 2018 ISPE Quality Manufacturing Conference in Arlington, VA, how variability in regulatory policies around the world adds years and costs to implementing post- approval changes, ruling out many initiatives that could make pharmaceutical production more efficient and reliable.

	A main component of the Q12 guidance is to define established conditions that are critical to product safety and efficacy and should be reported to regulatory authorities when making manufacturing changes, explained Robert Iser, vice-president of Parexel Consulting, formerly with FDA. Established conditions for manufacturing operations include critical process parameters and sequences, Iser pointed out at the ISPE conference. The ICH guidance describes how manufacturers can develop a product lifecycle management strategy that presents a summary of established conditions, reporting categories, and post-approval change management protocols to address expected changes. These approaches may be most appropriate for new drugs and biologics and may be more controversial for managing change to existing products.

	The hope is that ICH Q12 will provide manufacturers with more uniform reporting requirements and greater clarity on what and how to submit changes in dossiers. This approach would promote continual improvement in manufacturing and controls and enable more efficient regulatory evaluation of proposals and facilitate inspections. Although the current guidance does not establish set timelines for regulatory reviews or common requirements for regulators, the expectation is that authorities will move toward common approaches over time. FDA and other authorities are accepting comments from industry on the guidance, with the aim of finalizing the document next year. If implemented as intended, the approach outlined in Q12 could promote drug quality and consistency, encourage innovation in production processes, and help ensure a reliable global supply of needed medicines.

Regulatory authorities have published draft guidance on strategies to facilitate pharmaceutical lifecycle management.

Global Standard for Managing Post-Approval Changes Moves Forward

	Pressure to assess and approve a growing volume of promising new drugs and biologics in accelerated and compressed timeframes is prompting a major reorganization of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER). The aim is to help CDER staff deal with a “staggering pace of work,” that involves attention to detail and the need to keep up with emerging scientific advances in genomic medicine, targeted therapy, digital health, drug-device combination, and more global drug development, commented CDER director Janet Woodcock. She has been spearheading the initiative for the past year, with an eye on encouraging team-based reviews and streamlined processes that will make the oversight process more efficient and consistent.

	In announcing the pending reorganization last week, Woodcock outlined 

 to increase OND’s drug review offices from five to nine and to expand specific review divisions from 19 to 30. Likely changes are to split OND’s hematology division into two units and to divide the gastroenterology team into three groups. Additional divisions would focus on diabetes, obesity products, and ophthalmology.

	Such structural changes would “ultimately flatten the overall matrix of our review process,” observed FDA Commissioner Scott Gottlieb, in a

supporting the OND reorganization. The creation of more therapeutic-specific divisions will promote more efficient reviews, he said, while also deepening internal collaboration and enhance external scientific exchange.

	Each new drug application, moreover, will be reviewed by a cross-disciplinary team comprised of OND reviewers plus experts from CDER’s Office of Translational Sciences, Office of Surveillance and Epidemiology, and Office of Pharmaceutical Science. Additional staff from field inspection and compliance offices also may be involved. OND also will form a centralized project management function to establish a single, consistent review process for all divisions. Enhanced IT systems will improve access to information that can support scientific reviews and help ensure consistent regulatory decisions. And a more uniform post-market safety surveillance framework will better monitor the benefits and risks of drugs before and after approval.

	Implementing this reorganization will entail expanding OND’s staff, a process enhanced by provisions in the 21

 Century Cures legislation. An important benefit of the proposed reorganization, Woodcock emphasizes, is that CDER scientists and physicians would gain more time to collaborate with external researchers, physicians, and patient communities to better inform drug development and oversight.

	Gottlieb similarly emphasized the role of FDA scientists and medical officers in dealing with new adaptive approaches to clinical development and to processes for evaluating new medical products. He highlighted the importance of providing review staff with more time to provide feedback to sponsors on clinical protocols and development processes and to engage with researchers and patient groups in identifying risks and benefits of new therapies. He estimated that the new staff alignment and review processes will “improve efficiency by 20% at a minimum” due to better workflow and workforce management and greater internal collaboration across review functions.

	Maintaining a speedy, efficient new drug review process is vital for FDA to be able to spur innovation and bring new breakthrough therapies to patients, Gottlieb 

 at the recent meeting of the American Society of Clinical Oncology (ASCO). He described a number of innovations FDA is piloting to accelerate the review and approval of applications and supplements for cancer therapies. FDA’s Oncology Center of Excellence is implementing a real-time oncology review of data strategy to support added indications for already approved cancer drugs. These and other new efficiencies to the oncology review process should lead to broader improvements in oversight for all new drugs.

The agency is encouraging team-based reviews and streamlined processes that will make the oversight process more efficient and consistent. 