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

Jill Wechsler

	Pharmaceutical manufacturers that can ensure a reliable supply of high-quality therapies should be able to command higher prices needed to maintain modern production systems able to avoid drug shortages, according to an FDA expert panel. Drug quality issues account for nearly two-thirds of recent shortage situations, which usually involve low-priced, low-profit sterile injectables that companies would rather abandon than finance the long-term upgrades needed to meet standards. 

	This is the main conclusion of a comprehensive FDA report by an inter-agency task force on ways to address the financial, manufacturing, and policy issues underlying 

short supplies of important prescription medicines in the United States

. Ongoing shortages of common, but critical, therapies such as epinephrine and widely used cancer drugs, continue to generate outrage on Capitol Hill and from the public.

	Unfortunately, earlier efforts by the Center for Drug Evaluation and Research (CDER) to encourage a greater industry focus on quality and reliability in drug manufacturing met strong opposition. Several years ago, CDER officials proposed that manufacturers assess a series of performance measures defined by an FDA Quality metrics program. The idea then, as now, was that firms could command higher prices for drugs able to document high quality achievement. Even efforts to further the initiative through voluntary programs had little success, as manufacturers objected that FDA rating of production operations and quality programs would be arbitrary, costly, and unlikely to provide useful information to inform drug production and sales.

	Now the new drug shortages report revives the call for a rating system to help drug purchasers, hospital buying groups, and consumers identify quality products that warrant higher prices. The analysis documents that drug shortages arise most often from quality production problems involving low-priced sterile products, often made by just one producer. 

	In unveiling the report, FDA Acting Commissioner Ned Sharpless and CDER Director Janet Woodcock 

highlighted the call for a system to measure and rate a facility’s “quality management maturity”

that informs the public about its commitment to reliable quality production, instead of just meeting the basic standards set by current good manufacturing practices (cGMPs).

	Manufacturers should “sell quality-not just medicine,” Woodcock stated in 

. She maintains that a firm’s ability to reliably make a product in sufficient quantities and with sufficient speed to “ensure that supply consistently meets demand over sustained periods of time” should be a strong selling point-something that now is not rewarded due to limited quality product information for purchasers. The team of economists and scientists preparing the report found that of 163 drugs that first went into shortage between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality problems. Only a few had problems due to increased demand or natural disasters. 

	In addition to detailing the harms of drug shortages and need for more reliable solutions, the task force proposes some specific actions to prevent and address shortages, such as permitting longer expiration dates where justified. Legislation should increase penalties on firms failing to provide timely and adequate notification of a likely interruption in production. Here FDA will help with additional guidance that spells out more clearly requirements for manufacturers to notify FDA of expected production interruptions or discontinuance. 

	Congress also should authorize FDA to require application holders of certain drugs to conduct periodic risk assessments to identify vulnerability in their manufacturing supply chains and plans to mitigate such risks. New guidance will outline how firms should develop and maintain such risk management plans. 

	Manufacturers would be more likely to invest in modernizing facilities and improving formulations if regulatory approval of such post approval changes was faster and more efficient. To this end FDA supports efforts by the International Council for Harmonization (ICH) to finalize a new guideline (Q12) to harmonize procedures governing product lifecycle management. The new standard aims to simplify and support a more efficient global system for regulating manufacturing changes to approved products, a complex process that is often extremely costly and time-consuming for a pharmaceutical company to modernize or alter a production facility that serves multiple markets. 

Articles

A recent report released by an FDA task force highlights the financial, manufacturing, and policy issues underlying the drug shortages of important prescription medicines in the United States.

FDA Highlights Quality, Cost Issues in Campaign to Reduce Drug Shortages

	Because federal investigators cannot inspect every drug test site or production facility, FDA relies on manufacturers to submit complete and accurate information in all submissions and market applications, especially for innovative cell and gene therapies. Evidence that Novartis submitted manipulated data from certain preclinical tests related to its production process for breakthrough therapy Zolgensma recently produced a strong, public warning from FDA, with implications that the agency may pursue civil or criminal charges. 

also blasted Novartis and demanded a full accounting of its actions (1).

from FDA to Chinese over-the-counter drug manufacturer, Ningbo Huize Commodity Co., similarly cited egregious data integrity lapses (2). In a statement issued on Aug. 20, 2019, FDA said it was banning the import of all the company’s products following a plant inspection where local staffers provided FDA investigators with documents that were clearly falsified, including cleaning validation reports and batch production and control records for multiple drugs (3).

	In highlighting this enforcement action, FDA Acting Commissioner Ned Sharpless stated that efforts to “prevent, uncover, and combat data integrity lapses” is a continuing commitment of the agency and involves increased global inspections, updated guidance, and additional staff training. FDA published 

 in December 2018 for ensuring data integrity in compliance with current good manufacturing practices (CGMPs) (4), which emphasizes the importance of company top management establishing a “quality culture” that acknowledges the importance and value of data integrity in all aspects of drug development and production.

	Data integrity issues involving manufacturing activities are cited regularly in warning letters related to manufacturing facility inspections at home and abroad. A 

dated July 9, 2019 warned Indoco Remedies Ltd. of Mumbai, India of GMP and data integrity violations at a facility in Goa (5). It cited problems with batch production and control records for products intended for the US market. And a June 13, 2019 

 to Akorn Inc. raised concerns about the firm’s failure to ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of its products (6). FDA cites a previous warning letter regarding inadequate quality controls at another Akorn production site and demands prompt correction of all cited violations or risk legal action and delays in product approvals.

	In the Novartis case, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), sharply rebuked the company, emphasizing the importance of FDA having confidence in all tests and data provided by sponsors, particularly to support the rapid development and accelerated approval of innovative therapies. The submission of “truthful, complete, and accurate data” is critical for FDA to be able to protect the public health, and the law requires it, Marks asserted in a statement on Aug. 6, 2019 (7).

	FDA’s pronouncements aim to provide clear warnings to manufacturers that data manipulation is a serious offense, and that data quality is critical for product approval and continued marketing. Marks said that Zolgensma would remain on the market, as the faulty information involved early animal studies related to developing the production process for Zolgensma and did not compromise product safety. But he acknowledged that if the agency had been aware of the data manipulation by Novartis’ AveXis unit, it probably would have delayed approval of the lifesaving $2-million drug.

	Although Novartis claimed that it quickly investigated allegations of data manipulation when the issues first surfaced internally, the timing and disclosure of these problems raise questions. The company evidently knew of the data errors as early as March 2019 but did not launch a formal investigation until May and did not reveal its concerns until June. And that was after the May 24, 2019 approval of Zolgensma, based on limited, but convincing evidence that it dramatically improved the health of infants suffering from the most severe form of the neurodegenerative disease spinal muscular atrophy.

	FDA compliance officers continue to investigate whether Novartis and AveXis staffers intentionally hid evidence of data manipulation until after approval. According to press reports, FDA inspectors raised questions about a mouse essay at an inspection of a Novartis manufacturing facility in Illinois earlier this year, but company staff said they had been corrected. However, FDA’s 

 in July 2019 of AveXis’ San Diego control test lab found evidence that management failed to thoroughly review unexplained discrepancies in potency assays, had incomplete records, and failed to follow quality control and test procedures (8).

	Novartis dismissed the AveXis scientists linked to the data manipulation, but FDA holds corporate management responsible for ensuring adherence to rules at all levels. Although only a small portion of product test data in the market application appears to be manipulated, FDA says that a thorough assessment of all information will determine if further warnings or limits are warranted for this new therapy that has limited patient experience.

Warning Letter to NingBo Huize Commodity Co., Ltd.

, Aug. 2, 2019.
	3. FDA, “FDA Warns Company for Putting Consumers at Risk with Drug Manufacturing Data Integrity Violations,” Press Release, Aug. 20, 2019.
	4. FDA, 

Data Integrity and Compliance with Drug CGMP Questions and Answers, Guidance for Industry

Warning Letter to Indoco Remedies Limited

, June 13, 2019.
	7. Dr. Peter Marks, MD, Statement on Data Accuracy Issues with Recently Approved Gene Therapy, Press Release, August 6, 2019.
	8. FDA, 


	Vol. 43, No. 10
	October 2019
	Pages: 14-15

	When referring to this article, please cite it as J. Wechsler, "Data Integrity Violations Draw Strong FDA Rebukes," 

Falsified documents and manipulated test results prompt warnings and investigations.

Data Integrity Violations Draw Strong FDA Rebukes

	After months of planning and explaining, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), finally gained approval for broad changes in its process and procedures for evaluating and approving new drugs. In the works for nearly two years, this effort to modernize and reorganize CDER’s Office of New Drugs (OND) establishes additional new drug review offices and divisions more aligned to assess therapies for interrelated diseases and conditions. In addition, new administrative offices aim to better manage policy development and program management [see 

https://www.fda.gov/drugs/regulatory-science-research-and-education/reorganization-office-new-drugs-corresponding-changes-office-translational-sciences-and-office

]. The new structure “will strengthen operations in a number of CDER offices,” said Woodcock, and “promote a more efficient review process,” with “stronger alignment of administrative, regulatory project management, program operations, policy, and drug development tool services.” 

	Under the new structure, an OND deputy director for clinical operations will oversee eight (up from six) offices with 27 review divisions (vs. 19 divisions now). The aim is to better align staff expertise with more defined therapeutic areas, while also reducing workloads so that scientists and physicians can better respond to changes in biomedical science [see 

https://www.fda.gov/media/131102/download

 ]. The new Office of Oncologic Diseases expands to five review divisions, while neuroscience is separate from cardiology. There’s a new division for rare diseases and medical genetics, and a new Office of Nonprescription Drugs, but with limited staff pending Congressional approval of a new user fee program in this area. The clinical review offices will work more closely with relevant divisions of clinical pharmacology/toxicology from CDER’s Office of Translational Sciences (OTS). And all these groups will be linked to a new Office of Drug Evaluation Sciences with divisions for clinical outcomes assessments and biomarker qualification and biomedical informatics. 

	To further reduce the need for medical reviewers to spend time dealing with administrative tasks, new OND cross-functional support offices for regulatory operations, program operations, and administrative operations will manage business functions, financial accounts, and with regulatory developments [see 

https://www.fda.gov/media/131107/download

 ]. The Office of New Drug Policy will lead the development and publication of new guidance documents and regulations. And an Office of Therapeutic Biologics and Biosimilars will oversee policy and product development in this high-profile field. 

	CDER’s Office of Pharmaceutical Quality (OPQ) will experience structural changes to better align with the new review structure. This includes establishing a new Office of Administrative Operations and renaming two existing offices and creating seven new divisions to fit the assessment of the chemistry, manufacturing, and controls aspects of new drug applications (NDAs) to OND offices and divisions. 

	For manufacturers with applications already filed and under review, CDER officials say there will be no changes in review teams, although the name of the responsible division may shift, depending on where a submission stands in the review process. FDA anticipates it will be updating policies and procedures to clarify new division names and processes and promises to regularly communicate with industry about new points of contact. The plan is to have the new structure fully established by early next year. For additional background and information on these changes, see CDER’s webpage [see 

https://www.fda.gov/drugs/regulatory-science-research-and-education/modernizing-fdas-new-drugs-regulatory-program

After months of planning and explaining, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), finally gained approval for broad changes in its process and procedures for evaluating and approving new drugs. 

FDA Gains Approval to Revamp New Drug Review Operations

	Time is running out on Ned Sharpless’ term as FDA acting commissioner, generating much talk as the administration shows interest in naming a new head for the agency. While there has been wide expectation that Sharpless would gain the nomination, nothing is simple in Washington these days. Another cancer specialist, Stephen Hahn, chief medical officer at the MD Anderson Cancer Center in Houston, has emerged as a likely contender. Gaining Congressional confirmation at a very busy time on Capitol Hill could be tricky, though, and everyone is waiting for word from the White House on how President Donald Trump wants to go.

	The issue has moved to center stage because Federal law sets a 201-day limit on acting officials in positions requiring Senate confirmation. That means Sharpless’ temporary term ends Nov. 1, 2019, and he’s likely to depart before then. It would be surprising if he stays during the confirmation process of another candidate, and if he is nominated, he would step down as acting, while another agency official fills the job temporarily, as has occurred in the past.

	Sharpless has broad support for continuing to lead the agency from former FDA commissioners and numerous disease and patient groups. But Hahn, also a prominent cancer researcher with leadership experience, is a long-time Republican donor, but one without damaging ties to the pharmaceutical industry. Yet the recent scrutiny of his potential candidacy has brought to light some past controversies related to radiation oncology treatment safety, federal rule violations, and employee dismissals.

	Hahn’s ties to the White House, though, may be key, as the administration has become more closely involved in FDA issues, namely efforts to combat teen vaping following the emergence of a lethal condition apparently linking to e-cigarette use. And the FDA’s role in allowing the widespread marketing and distribution of opioids remains in the spotlight as the legal battles expose details on manufacturer and distributor involvement in the opioid epidemic. Anticipated resolution of some court cases will continue to raise questions about why and how FDA approved these drugs for market and what changes can prevent opioid abuse and misuse while ensuring access to treatment for patients with serious pain.

	The clock is ticking, as Congressional leaders face pressure to address a host of critical issues, including numerous proposals related to healthcare and treatment access. First up is the deadline for funding federal agencies-including FDA-for the fiscal year that begins Oct. 1, 2019. The likely scenario is that multiple drug marketing and regulatory proposals, including provisions on drug pricing and regulation, may be added to year-end must-pass legislation to keep the government going. The tight legislative calendar leaves little time for politicians to wrangle over the appointment of a new FDA commissioner; if that becomes contentious, FDA may have an acting commissioner for months to come.

Time is running out on Ned Sharpless’ term as FDA acting commissioner, generating much talk as the administration shows interest in naming a new head for the agency. 

Who Will Head FDA?

	Attacks on high-priced medicines clearly play well with voters on all sides of the political spectrum and have featured prominently in political debates and policy negotiations. This discussion will continue through the rest of the year, as polls show that Americans consider healthcare and the rising cost of prescription drugs a top consumer issue. All the Democratic candidates back some kind of drug pricing legislation and are pushing cost control issues on the campaign trail, as leading Democrats in the House and Senate seek consensus on reform legislation.

	A major political problem for Democrats is that President Trump has been vocal in castigating the rise in prescription drug prices, despite a lack of support from Republicans in Congress. So, the politics surrounding drug pricing legislation are murky, as House speaker Nancy Pelosi (D-Calif) may not want to hand the White House a political win by enacting drug reform legislation.

	While the politics plays out, a broad range of reform measures continue to emerge, even as the pool of Democratic candidates scales back. Progressive reformers want to empower Medicare to negotiate drug prices, to link reimbursement for drugs to prices posted overseas, and to set limits on how much pharma companies can raise prices each year. More moderate proposals aim to spur competition in the pharmaceutical industry by bolstering the development of generic drugs and permitting importation of medicines from Canada and elsewhere.

	The Senate Finance Committee and the House Energy & Commerce Committee have approved drug pricing packages that would generate significant savings for Medicare and Medicaid-a strong incentive for Congress to act. But several other legislative panels still have to act to move forward with a consensus measure.

	Meanwhile, the legislators face tight deadlines for approving multiple appropriations bills needed to fund federal agencies for the fiscal year that begins Oct. 1, 2019, and that will be the top priority on Capitol Hill in coming months. No one wants to delay action on spending measures with disagreements over healthcare coverage and costs, which may postpone action on health reform measures.

	Even so, the multitude of health reform measures emerging on Capitol Hill has accelerated lobbying action across the board, along with campaign donations to candidates from all sides. Hospitals and health plans are vigorously opposing popular proposals to limit “surprise billing” of patients. Pharma companies are anxious to halt drug reimportation, international reference pricing, and reform of curbs on Medicare price negotiations. But proposals to cap out-of-pocket outlays for prescription drugs for Medicare beneficiaries may be more attractive to industry. The trick for reformers is to maintain a distance from Trump pronouncements while developing bi-partisan consensus on legislation that can be approved before year-end.

The multitude of health reform measures emerging on Capitol Hill has accelerated lobbying action across the board, along with campaign donations to candidates from all sides.

Drug Pricing and Politics

	Regulatory officials in the United States, Europe, and other regions are collaborating with manufacturers to advance a new framework for managing chemistry, manufacturing, and controls (CMC) changes more efficiently across the product lifecycle. The process is outlined in the Q12 guideline developed by an expert working group formed under the 

 (ICH) (1). ICH is expected to approve a revised core Q12 guideline at the November 2019 ICH meeting in Singapore, along with more detailed annexes and a global training plan for industry and regulators.

	Support for a harmonized approach for authorizing new manufacturing and testing methods on approved drugs and biologics reflects general agreement on a risk-based system for categorizing and managing changes, despite continuing differences among authorities over specifics for reduced oversight of certain variations. In the works formally since 2014, the Q12 guideline is expected to provide flexible oversight of post-approval changes with reduced regulatory reporting for manufacturers able to demonstrate enhanced knowledge about product, manufacturing process, and analytical procedures, as provided by a company’s product quality system (PQS).

	A key feature of Q12 outlines how manufacturers should define those established conditions (ECs) that are considered necessary to assure product quality. Thus, a change to an EC would require a regulatory submission, explained Chikako Torigoe, biologist in the office of the director of FDA’s Center for Biologics Evaluation and Research (CBER). At the same time, those parameters that have less risk of impacting product quality or process consistency would not be considered ECs and could be managed by a manufacturer’s internal PQS and implemented without prior approval, Torigoe noted at the July 2019 CMC Forum sponsored by CASSS (2).

	Manufacturers may reduce ECs requiring regulatory approval through development and submission of a post-approval change management protocol (PACMP) that describes anticipated changes to a product or products. The PACMP would provide the basis for agreement between the applicant and regulatory authority about information required to support certain changes. PACMPs could involve multiple products, as with establishing a new process to improve product sterility assurance, upgrades to a vial wash room, or introducing a new product to a manufacturing facility. FDA is launching a pilot program to gain experience in assessing proposed ECs, with the aim of reviewing nine submissions of new drugs, generics, and biotech products to see how much time and effort is involved in identifying ECs at time of approval.

	An approach similar to Q12 already has been established in Japan, pointed out Tomonori Nakagawa, API project manager at Otsuka Pharmaceutical Co., at the CASSS Forum. This initiative by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has produced a more efficient program for overseeing a robust change management system, he noted, based on a demonstration of product and process knowledge. And Health Canada is ready to implement ICH Q12, reported senior regulatory scientist Anthony Ridgway at Health Canada’s Biologics & Genetic Therapies Directorate. That agency has issued guidance on categories, conditions, and data expected for different reporting categories, and policies already are aligned to provide flexibility in defining ECs and in justifying reduced reporting. Health Canada encourages adoption of risk-based categorization of post-approval changes that require only notification or listing in an annual report, Ridgway said, adding that more work is needed to better define and align with ICH recommendations for PACMPs.

	Kavita Vyas, policy lead in the Office of Policy for Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER), described ongoing FDA efforts to prepare to meet Q12 challenges. An agency group is examining case studies related to established conditions and anticipates gaining useful learnings from the upcoming pilot project. Alexey Khrenov, senior staff fellow at CBER’s Office of Tissues and Advanced Therapies (OTAT), noted that training is being developed to familiarize reviewers with Q12 approaches. Greater regulatory flexibility should benefit manufacturers, he commented, although the specifics for defining ECs and for assessing PACMP and product lifecycle management (PLCM) documents remains uncertain.

	Despite the challenges, manufacturers hope to move forward with Q12 as more products are tested, produced, and distributed in multiple regions, creating complex supply chains that trigger diverse testing requirements and inspection processes. It can take four to six years to add a new site or comply with a new standard for a product that is approved and distributed globally, noted Nakagawa. Similarly, consultant Moheb Nasr, formerly with FDA and Amgen, described how the current system discourages firms from adopting more efficient laboratory test methods and modern production systems.

	Many manufacturers look to advance strategies for managing CMC changes under the firm’s PQS, as supported by a series of earlier ICH quality guidelines (Q8–11). Leslie Bloom, executive director of regulatory CMC at Pfizer, described efforts to develop PLCM plans to manage ECs over the product lifecycle even before Q12 is finalized. And ongoing efforts aim to provide more justification for a range of risks related to ECs and non-ECs, especially in process and analytical methods.

	Kimberly Wolfram, director of global regulatory affairs CMC at Biogen, described herself as a “realist” in anticipating the benefits from Q12 after years of effort. While she hopes for less confusion in regional adoption of ECs and guidelines, she and others acknowledge challenges in gaining global alignment on change management protocols based on risk assessment to enhance access to therapies.

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

	2. CASSS, “The Future of Post-approval Changes is Coming–Are You Ready for ICH Q12?” Conference (Gaithersburg, MD, July 2019).


	Vol. 43, No. 9
	September 2019
	Pages: 14-15

	When referring to this article, please cite it as J. Wechsler, "More Predictable Post-Approval Change Policy on Horizon," 

Industry and regulators seek global system that reduces regional differences. 