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

Jill Wechsler

 to enact a second version of the 21st Century Cures Act, building on the landmark measure approved by Congress in 2016. Reps. Diana DeGette (D-CO) and Fred Upton (R-MI) again have teamed up to advance a comprehensive (170 pages) bill that would provide billions to establish the new Advanced Research Projects Agency for Health (ARPA-H), enhance pandemic preparedness, and provide added authorities and resources for FDA [see]. Many of its provisions have been applauded by the medical community and biopharma manufacturers, but enactment is not likely any time soon, as a host of legislative priorities already are backing up on Capitol Hill.

A likely scenario is that next year, Cures 2.0 will be incorporated into a broader legislative package to reauthorize several FDA user fee programs that provide critical funding for the agency. Revised fee programs for drugs, generic drugs, biosimilars, and medical devices need to be approved by next summer to meet the Sept. 30, 2022 deadline, a scenario that encourages policymakers to add to the fee measure a wide range of pet projects and policy updates related to public health, biomedical research, and access to medicines and care.

 by including provisions that relate to the COVID-19 pandemic, support patients, enhance FDA programs, and expand Medicare coverage of services and products. The bill seeks further study of factors underlying long COVID, along with development of a national strategy for responding to future pandemics and new models to support development of novel antimicrobial drugs. There’s added support for caregivers and patients and provisions to improve diversity in clinical trials and make broader use of patient experience data in research.

FDA would advance digital health technologies, expand the use of real-world evidence, and support novel trial designs, such as decentralized trials. The policymakers also call for FDA to accelerate designations for breakthrough and regenerative medicines, with specific attention to developing more information on CMC (chemistry, manufacturing, and controls) for expedited programs. FDA and the Centers for Medicare and Medicaid Services would communicate earlier on breakthrough therapies to facilitate coverage, and sponsors could utilize a broader range of evidence to fulfill postapproval study requirements for drugs receiving accelerated approval.

The measure also looks to continue certain more flexible coverage policies authorized for the health emergency, notably wider use of telehealth under Medicaid and Medicare and continued coverage for breakthrough devices and other innovative technologies. It facilitates diagnostic genetic testing of children with rare diseases and authorizes pharmacogenetic consultations for the elderly.

The House Energy & Commerce Committee will consider the measure with an eye to gaining agreement on a package likely to win Congressional approval next year. In budget deliberations earlier this year, the legislators dropped the Biden administration’s pricey ARPA-H proposal, and that may occur again as federal funds get tight. Industry supports the overall bill but will not want any extensive policy debate to delay user fee reauthorization.

Articles

Leading legislators have launched the campaign to enact a second version of the 21st Century Cures Act.

New Cures 2.0 Legislation Advances Biomedical Research and Care

The White House finally decided to nominate Robert Califf to once again take the reins of this complex and vital regulatory agency, acknowledging the difficulty of finding an experienced and capable administrator without visible industry ties. Califf’s appointment has been discussed and analyzed for months and now moves forward at the last moment.

Under federal rules, Acting Commissioner Janet Woodcock has to leave that position by Nov. 15, 2021. Now, however, she can remain in place during the Senate confirmation process for Califf, which could take some time in the face of a very packed year-end schedule for Congress. Although many policy makers and medical leaders backed Woodcock for the top job, she ran into opposition from some legislators and consumer groups that considered her too close to industry and blamed her for authorizing market approval of opioid pain killers, later found to fuel addiction and deaths.

Califf had a brief stint as FDA commissioner in the waning months of the Obama administration, taking the helm following the departure of Margaret Hamburg from the top spot in 2015. His confirmation at that time met only minor opposition in the Senate and was supported by then majority leader Mitch McConnell. Most research advocates consider Califf’s long experience in overseeing clinical trials a plus, while public health groups applaud his strong opposition to tobacco use. Califf has extensive academic credentials, as well valuable experience as a consultant to drug developers and most recently as top official at health tech firms, Verily Life Sciences.

 ends months of uncertainty about the future path for the high-profile agency. FDA has played a central role in orchestrating the development of vital COVID-19 vaccines and therapies, along with facilitating supplies of critical diagnostics and medical equipment, and the new commissioner may face the early challenge of vetting and approving important new therapeutics to combat the virus. 

The Friends of Cancer Research, a leading advocate for biomedical R&D, called for quick confirmation of Califf to provide the agency with “a strong and respected leader” who can ensure that FDA will continue “to be patient-centered and driven by science and not politics.”

Woodcock has provided FDA with such capable, experienced leadership, which has been key to mounting an effective response to the challenges imposed by the ongoing public health emergency. Now, with many agency staffers exhausted and key agency operations in flux, a commissioner who knows the agency is important for dealing with continuing criticism from anti-vacciners, as well as disease advocates demanding fast approval of potential therapies. Early challenges for Califf will be to shepherd FDA’s budget plan for 2022 through the legislative process and to gain Congressional approval of vital new user fee plans in the coming year. As a confirmed commissioner, Califf will gain the authority and the imperative to continue efforts to rebuild and restore the agency to handle such challenges and expectations.

The White House has nominated Robert Califf to head FDA, ending months of uncertainty about the future path for the high-profile agency. 

Califf Named to Head FDA

The Democratic legislative proposal to authorize price negotiations on costly medicines covered by Medicare and to penalize firms that raise prices faster than inflation has drawn vehement opposition from brand pharmaceutical and biotech companies. More surprising is that manufacturers of generic drugs and biosimilars also are objecting loudly to those policy changes on the table.

Dan Leonard, president of the Association for Affordable Medicines (AAM),

 says that the reforms under consideration by Congress would limit patient access to more affordable generics and biosimilars by thwarting competition. 

AAM opposition specifically challenges the proposed compromise approach to Medicare price negotiations and inflation-based rebates.

To gain support from moderate Democrats, Congressional leaders agreed to limit Medicare price negotiations to 20 costly drugs, starting with 10 in 2023. The program, moreover, would apply to expensive drugs that had been on the market for enough time to have lost patent protection or exclusivity status (e.g., small molecules available at least nine years and biologics for at least 12 years).

Reformers also want to require drug makers to pay higher rebates on drugs that boost prices faster than the consumer price index, including medicines sold in the private insurance market. Leonard notes that generics will be hit harder than brands by this inflation-based rebate due to their basically low prices:a 1-cent increase on a 20-cent pill could exceed the rate of inflation and trigger a penalty. And if downstream purchasers boost prices, the generics maker could be penalized, even it does not increase its price.

The basic problem with the price negotiation scheme for generics is that they could face big price reductions on a brand medicine just when they’re poised to bring their competitive medicine to market. Generic-drug makers must start the process of testing and planning for mass production of follow-on products years before patents expire, expecting to recover that investment by providing lower-cost alternatives to a costly brand. 

But the spread between the brand and generic prices would shrink if Medicare can negotiate a lower brand price at that time of patent expiration

The situation would have an even greater impact on biosimilar makers, where the testing and development of follow-on biotech therapies can cost $100–250 million and involve 10 years of investment, Leonard points out. But the proposal before Congress could lead to a price reduction in the brand biologic by 60% right before the biosimilar is set to launch. Moreover, the added uncertainty about what drugs the government would decide are subject to price negotiation could forestall development of multiple biosimilars as well as generics.

Pharmaceutical Research and Manufacturers of America (PhRMA) 

continues to loudly oppose any kind of Medicare price negotiations as a threat to future innovation. Brand firms prefer a cap on annual out-of-pocket costs for patients, reduced cost-sharing, plus reforms in the payment and coverage system for Medicare Part B.

AAM warns that misguided reforms on generic-drug coverage in the past have led to drug shortages and predicts that the current proposal similarly will undermine the development of low-cost products. Yet, generics makers appear caught between a rock and a hard place. They don’t want to appear to side with Big Pharma in opposing drug price reform, yet the changes contemplated by Congress could radically alter the industry’s basic mode of operation:it’s the very high prices on brand drugs that provide an opportunity for generics and biosimilars to come to market at lower prices and still make a profit.Narrowing the spread upends that business model.

The Democratic legislative proposal to authorize price negotiations on costly medicines covered by Medicare has drawn opposition from brand pharmaceutical and biotech companies. 

Generic-Drug Makers Also Fight Price Controls

After extensive debate and discussion, Democratic leaders in the House and Senate appear to have reached a compromise on a relatively modest plan for controlling prices on certain prescription drugs. The latest deal greatly reduces the scope of medicines that would be subject to price negotiations, penalizes firms that raise prices faster than inflation, and sets a $2000 annual cap on out-of-pocket (OOP) drug costs for Medicare beneficiaries. An added sweetener is a $35 OOP monthly maximum on patient outlays for insulin, a high-profile consumer issue.

The modified plan addresses several main concerns raised by moderate Democrats in the House and Senate. Rep. Scott Peters (D-Ca) has been most visible in proposing to limit Medicare price negotiations to older medicines with expired patents to protect investment in small biotech firms. Peters has been receptive to caps on price increases and on patient OOP costs, but also opposed to taxing firms that don’t negotiate.

The latest compromise authorizes negotiations for only 20 drugs per year and only for older products that have exceeded exclusivity periods, with exceptions for small biotech companies. The package won support from Sen. Kyrsten Sinema (D-Ariz), who has been a main opponent of drug price negotiations, but broader Senate backing remains unclear.

However, industry continues to object to any Medicare price negotiations. Such action gives the government the power to dictate drug value and threatens the development of new treatments, according to the 

Pharmaceutical Research and Manufacturers of America (PhRMA)

. The Biotechnology Innovation Organization (BIO) urges its members to carefully assess the latest pricing plan, reminding them that any kind of price controls threatens continued funding for biopharma R&D. Generic-drug makers also object to language that sets inflation-based rebates on generics and biosimilars.

The ongoing debate highlights the complexities of drug pricing, which has faced Congressional reform efforts for decades. Going forward, policy makers still will consider additional options for reallocating rebates, reducing patient costs, skewing payments to high-value therapies, boosting contributions from the wealthy, and subsidizing those who can’t afford needed medicines.

Analysts at the Medicare Payment Advisory Commission (Medpac) also are examining for its June 2022 report to Congress potential policies for reimbursement of Aduhelm for Alzheimer’s disease due to its potentially large impact on Medicare Part B. Options include curbs on payment for new first-in-class drugs with limited clinical evidence, reference pricing to spur competition from therapeutic alternatives, and changes in the coverage policy for Part B drugs. None of these proposals are new, and most would require legislative change. The Biden administration also seeks to promote competition in the pharmaceutical market through executive orders and policy initiatives. The Innovation Center in the Centers for Medicare and Medicaid Services (CMS) is examining new pilots to test changes in both Part D and Part B reimbursement, as well as increased price transparency.

Manufacturers, moreover, are adopting value-based pricing deals with insurers to address opposition to high launch prices for new treatments. Pfizer has 

to patients and payers if its lung cancer drug Xalkori fails to deliver promised effects. Similarly, Takeda Pharmaceuticals has an arrangement with Point32Health in New England (recently formed by Tufts and Harvard Pilgrim) to provide a rebate on patients that don’t respond or can’t tolerate lung cancer treatment Alunbrig. The two drugs cost $15,000–$20,000 a month per patient, and the deals aim to support prescribing of therapies that may have benefit for some individuals.

Democratic leaders in the House and Senate appear to have reached a compromise on a relatively modest plan for controlling prices on certain prescription drugs.

Will Pharma Accept the Democrats’ Drug Pricing Deal or Continue to Fight Reform?

Over the past 18 months, FDA officials have tested and adopted a range of procedures to overcome restrictions on visiting facilities in person to evaluate pharmaceutical production and clinical testing operations. Many of these alternative compliance methods now are being retained even with the end of the current health emergency in sight. FDA has devised ways to monitor industry operations and to collaborate more routinely with foreign regulatory authorities to assess facilities and products, efforts important for ensuring continued patient access to needed therapies, vaccines, and medical diagnostics.

With some 8000 site inspections of drug manufacturing facilities postponed during the height of the pandemic in 2020, FDA regulatory officials plan to retain key operational changes as they work to catch up on their vast oversight obligations. During the hiatus in facility inspections, FDA’s Office of Regional Affairs (ORA) looked to evaluate the inspection status of a facility largely through the review of historical inspection records from the site plus reports conducted by reliable regulatory authorities. Now, even with the return to more normal inspections for domestic manufacturing facilities, ORA will continue to pre-announce domestic inspections “for the foreseeable future,” explained Alonza Cruse, director of the Office of Pharmaceutical Quality Operations in ORA at the PDA/FDA Joint Regulatory Conference in September 2021. The aim is to avoid having inspectors turn up at a facility that is not fully operational, has altered hours, or has limited staff available.

While ORA aims to send inspectors to more facilities in the United States, the agency will continue to limit foreign inspections to those deemed “mission critical,” Cruse noted. FDA also will utilize the tools expanded during the pandemic to assess product safety and quality more efficiently. This includes more extensive analytical testing and sampling of drugs, particularly at US borders with an eye to denying entry to products with quality problems. In addition, FDA continues to request documents from facilities to review compliance histories off site and to conduct video livestreaming “visits” to plants. The agency updated information on how it was managing and revising its inspection program, initially in a Q&A guidance issued in August 2020 and expanded extensively through the following months through May 2021 (1).

A main initiative has involved greater use of Remote Interactive Evaluations (RIEs) of drug manufacturing, compounding, and bioresearch monitoring facilities, a process that FDA compliance offices plan to continue, as outlined in guidance issued in April 2021 (2). Cruse highlighted FDA’s process and policies for how the agency will notify, conduct, and conclude RIEs and the impact on regulatory
timeframes. And Donald Ashley, director of Center for Drug Evaluation and Research’s (CDER’s) Office of Compliance (OC), reported at the PDA/FDA conference that the agency completed more than 50 REIs for Bioresearch Monitoring operations programs and eight for outsourcing facilities since Oct. 1, 2020, as part of its effort to utilize all available oversight tools.

Even with reduced onsite inspections, manufacturers may gain regulatory flexibility in expanding or altering production or updating manufacturing methods by gaining FDA recognition for having high-quality operations as described in its Quality Management Maturity (QMM) program. FDA has encouraged biopharma companies to establish QMM systems able to measure outcomes that reflect control of problems that lead to complaints, shortages, and adverse events, noted Patrizia Cavazzoni, director of CDER, at the PDA/FDA conference. Now manufacturers stand to benefit from advancing QMM in gaining greater flexibility in scheduling facility inspections and for making post-approval changes in production and product characteristics.

Although industry has challenged earlier CDER efforts to devise measures and “report cards” on manufacturing operations, the pandemic has magnified the need to focus on risk management and to expand efforts by manufacturers to ensure the operation of more mature quality systems, Cavazzoni explained. A critical issue during the public health
emergency has been to overcome shortages in medical products due to supply chain constraints and drug quality problems. To facilitate the development and timely production of new
COVID-19 therapeutics, CDER expanded the data and analytics employed by its drug shortages program to assess risks of supply disruptions earlier and more effectively.

In the wake of the pandemic, FDA is looking to further support and encourage QMM initiatives at firms able to demonstrate having consistent, reliable, and robust business processes to achieve quality objectives, added Ashley Boam, director of CDER’s Office of Policy for Pharmaceutical Quality at the PDA/FDA conference. FDA is launching two pilot programs to test how QMM may be implemented by domestic drug product manufacturers and by foreign producers of APIs. The pressures created by the pandemic, Boam observed, have supported alternative approaches for plant inspections, streamlined assessment of proposals to add or change manufacturing facilities and suppliers, and increased global collaboration and harmonization in these areas.

Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers, Guidance for Industry 

(CDER, CBER August 2020 Updated on May 17, 2021).

Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency, Guidance for Industry 


Volume 45, Number 11
November 2021
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, “Pandemic Alters FDA Inspections and Quality Oversight,”

New methods and policies necessitated by the global pandemic are slated to become permanent fixtures in FDA enforcement and regulatory programs. 

Pandemic Alters FDA Inspections and Quality Oversight

Despite broad enthusiasm for wider use of real-world data (RWD) and real-world evidence (RWE) in developing and assessing the efficacy and safety of new drugs and medical products, this approach presents significant challenges in assuring that the information is valid and germane to the research involved.

FDA has worked to clarify how drug development can gain from tapping into information in health care systems and claims databases, as outlined in our 

October 1 posting on “advancing reliance on real-world data and evidence” 

report discusses the agency’s September 2021 guidance

, which addresses a range of issues involved in sponsor utilization of RWD and RWE in clinical research.

Now, FDA seeks to address the added complexities for incorporating such information into submissions to the agency, while addressing concerns about its relevance and reliability. Such challenges are evident in a more recent FDA 

 on how sponsors should submit RWD to support research submissions to the agency for drugs and biologics, which acknowledges numerous difficulties that arise from utilizing data from a wide range of information systems with different formats, terminologies, data aggregation methods, and overall quality measures.

These issues reflect FDA efforts over the past decade to require electronic submission of data to support market applications based on agreed-on standards. The aim is to make it easier and faster for the agency to receive, review, store, and analyze the wide range of research, manufacturing, and safety information submitted to in applications. Now, to further support increased use of RWD and RWE in applications, FDA outlines here how sponsors should collect and convert or “map” such data collected outside of clinical trials to fit agency e-standards for submitting information in investigational new drug applications, applications for generic drugs and biotech therapies, and applications for new drugs.

The guidance addresses how sponsors should format data elements so that they can be exchanged between computer systems in ways to minimize inconsistencies and increase clarity to facilitate FDA review and archiving of the information. The agency recognizes the importance of sponsors being able to utilize data from electronic health records, medical claims systems, disease registries, and mobile digital tools, among other sources. Problems arise, though, because such information systems have diverse standards and policies, such as differing diagnosis codes set by national and international data standardization entities. FDA and sponsors acknowledge considerable challenges in mapping data from source systems to fit FDA standards, noting added difficulties raised by differences in definitions and in key variables, even basics such as sex and diagnosis.

For now, FDA advises sponsors to document data sources and conversion processes and decisions, acknowledging that the field is in flux and faces many adjustments and challenges ahead. Collaborative industry efforts are working to develop data standards and mapping tools for electronic health records, but all parties concede that this will be a lengthy and difficult process. FDA acknowledges that its advice is limited by current uncertainties and that sponsors should anticipate changes in policies for collecting and submitting RWD to support applications.

Some assistance may arise from multiple efforts to advance standards for this field. The Professional Society for Health Economics and Outcomes Research (ISPOR) is launching a real-world evidence registry to provide added transparency into the analysis and reporting of RWE in health research, here through a platform for researchers to register study protocols so other experts may assess the potential for biases, sufficient randomization, and uniform data quality.

Additionally, FDA looks to enhance its use of RWE for more rapid assessment of therapies to treat COVID-19 through its partnership with 

. The agency is expanding the use of Aetion’s platform-based approach for utilizing data from EHRs and other sources to define key research questions, identify fit data sources, and validate ways to capture data on subgroups outside clinical trials. This builds on projects with Aetion for assessing data fitness for use, identifying good practices in working with RWD, and advancing rapid-cycle analytics to address critical health questions.

FDA has worked to clarify how drug development can gain from tapping into information in health care systems and claims databases.