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

Jill Wechsler

After months of negotiations, Congress approved a massive federal government spending package in March 2022, spurred by bipartisan support for including $13.6 billion in aid for Ukraine. The $1.5 trillion omnibus funding bill for fiscal year 2022, which began Oct. 1, 2021, increases funds to combat the opioid crisis and extends telehealth provisions, while also directing resources to a broad range of programs to advance health and medicine.

The measure increases FDA’s budget by $102 million to $3.3 billion in discretionary budget authority. FDA’s total funding amounts to $6.1 billion, with almost half of that—$2.8 billion—provided by approved user fees. The boost in federal funds is smaller than proposed earlier by Congressional committees, but sufficient to “reflect continued Congressional support for a strong, well-funded FDA,” commented 

The added $102 million allots $29 million to medical product oversight, $29.5 million to food safety activities, and retains $41 million for cross-cutting initiatives. The legislators direct FDA to use the increase for medical products to better track medical device shortages, tackle the opioid crisis, provide unannounced inspections of foreign drug manufacturers, bolster orphan and rare disease drug development, and support FDA data modernization, field inspections, and minority health programs. The funding committees highlight the importance of conducting real-time, unannounced plant inspections and instruct FDA to spend $5 million on hiring additional foreign-based investigators for this purpose.

are provided in the report from the House Appropriations Agriculture subcommittee. Of the $2.8 billion to be collected in user fees, $1.2 billion comes from fees on drugs and biologics, $540 million from generic drugs and $40 million from biosimilars. The budget plan calls for FDA to do more to regulate cannabis-derived products, advance strategies to combat the opioid crisis, develop a comprehensive food traceability system, and take steps to protect against adulterated dietary supplements.

In the broader health and medicine arena, 

 increases support for the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC) and other agencies in the Department of Health and Human Services (HHS). Of note, Congress provides $1 billion to establish the Advanced Research Projects Agency for Health (ARPA-H) as part of NIH. The amount is way less than the $6.5 billion initially sought by the Biden administration for this new entity, but an important first step in moving it forward.

More controversial is the Democrats’ decision to approve the broad spending package without including President Biden’s $30 billion request for additional COVID-19 relief funds. That amount had already been reduced to $15.6 billion to purchase and continue research on more anti-COVID vaccines, therapies, and test kits, but the provision was dropped due to dissension among Democrats over the proposed cuts. Budget increases at CDC, NIH, and the Biomedical Advanced Research and Development Authority (BARDA) are expected to support further R&D in this area, pending future agreement on COVID research activities, but researchers fear significant reductions in these programs.

At the same time, the broader budget bill provides support for a host of specific initiatives, such as a measure limiting access to flavored vaping products by clarifying FDA authority to regulate these products. There are provisions to prevent domestic violence and billions to support thousands of pet projects favored from individual legislators.

Resolution of this federal spending bill clears the way for Congress to start considering legislation to reauthorize a packet of FDA user fee programs by Sept. 30, 2022. That deadline opens the door for the legislators to include multiple proposals affecting FDA and biomedical research in the fee package, as seen in a long list of bills already being considered by the House Energy & Commerce Health subcommittee.

The proposals include the Cures 2.0 Act (HR 6000) to advance a range of biomedical research programs plus multiple measures that fall under the heading of “encouraging innovation and improving oversight.” There are bills to 

overhaul FDA’s accelerated approval process

, encourage drug production in the United States, advance diversity in clinical trials, support development of certain orphan drugs and rare disease treatments, and ensure access to affordable medicines. The House panel will begin the evaluation process for these and other proposals at a hearing March 17, 2022.

Articles

The US Congress approved a federal spending package that increases funding for a range of programs to advance health and medicine.

Federal Budget Bill Boosts FDA Funding, Supports New Research Institute

Amidst continued bombing, death, and destruction from the Russian invasion of Ukraine, biotech companies and medical product manufacturers have condemned the aggressive tactics of Vladimir Putin, while also looking to maintain supplies of essential medicines to the beleaguered populations. As the invasion of Ukraine has escalated since late February 2022, prompting more than 2 million citizens to seek safety outside its borders, international energy suppliers, global manufacturers, leading retailers, and major financial institutions halted trade and interactions with Russia. But most international pharma companies have remained in Russia, claiming humanitarian reasons for continuing to supply patient populations with needed therapies and health products, including those dependent on vital new treatments.

Biotech industry leaders, however, have been vocal in calling for a halt to investment in Russian companies and support for research and marketing in that country. In a letter dated Feb. 27, 2022, company CEOs acknowledged likely delays in clinical trials in both Ukraine and Russia and difficulties in producing vaccines and drugs needed in those countries. 

Venture capitalists joined with manufacturers

 in anticipating supply chain disruptions, but emphasized the importance of condemning Russia’s deliberate “criminal act” for disrupting the global economy and ruining the lives of so many.

Decisions to maintain Russian manufacturing and marketing operations by industry leaders such as Johnson & Johnson, AstraZeneca, Pfizer, Novartis, and Abbott, however, have drawn fire. Many US and European firms have multiple facilities in Russia and sponsor hundreds of clinical studies in the region. Some CEOs say they will not expand investment in Russia but will continue to produce medicines to meet public health needs.

In an interesting move, a former FDA official and rare disease advocate Tim Cote petitioned the agency to freeze all regulatory requests and actions from firms in Russia or controlled by Russian parties. The aim is to prevent Russian biopharmaceutical companies from building a presence in the US market, one way to emphasize the economic consequences of their nation’s actions.

A major concern is how the invasion threatens to limit or halt clinical trials for drugs and biologics in both Ukraine and Russia, often cutting off research programs that enable patients with critical conditions to access advanced therapies. Ukraine-based drug companies and clinical trial sites have all but collapsed, as the Russian invasion has destroyed hospitals and research facilities. And biopharma companies are halting enrollment in many clinical trials in Russia, as the outlook continues to deteriorate.

Analyses by Clinical Trials Arena and others 

document a sizeable number of research programs

 had been underway in those nations, many part of global research programs. San Francisco-based Tricida pharma, for example, 

that the horrifying situation in Ukraine prompted it to delay expectations for clinical trial results for its chronic kidney disease drug candidate veverimer. Many clinical trials in the region, though, involve approved drugs seeking broader markets for therapies already available in the United States.

Russia’s actions are slated to have a visible impact on pharmaceutical and vaccine production in India, where vaccine makers have extensive contracts to produce Russia’s Sputnik V COVID-19 vaccine for global distribution. India’s Dr. Reddy’s Laboratories, Serum Institute of India, and Hetero are leading distributors for the Sputnik vaccine, according to press reports. But Sputnik production has been slow and far below earlier expectations, even before the Ukraine crisis, as the Russian product gained only limited market acceptance. The situation is unlikely to change, as efforts by Russia to gain approval from the World Health Organization (WHO) for its Sputnik vaccine appear to be on hold.

In addition, analysts anticipate supply disruptions and price increases for certain raw materials and supplies imported from Russia. Rising prices in oil and natural gas could boost the cost of certain plastics used in syringes and medical bottles. And the higher cost of transportation may curb access to certain materials over the long term, further heightening efforts to boost US production of medical supplies and products.

Biotech companies and medical product manufacturers have condemned the invasion of Ukraine, while also looking to maintain supplies of essential medicines.

Ukraine Invasion Challenges Biopharma Research and Operations

The heightened political debate that delayed his Senate confirmation, plus continued challenges created by the COVID-19 pandemic, ensure that Dr. Robert Califf’s tenure leading FDA will be much more contentious than his previous stint. His Senate confirmation process was punctuated by sharp queries from both sides of the aisle about access to COVID-19 tests and therapies, agency policies for speeding new drugs to market, and FDA’s role in facilitating access to both long-acting opioids and to medicine to induce abortions, as the politicians sought to make points with constituencies leading up to mid-term Congressional elections in November.

A previous version of this article was published online at 

That partisan tone was apparent in January 2022 as the Senate Health, Education, Labor & Pensions (HELP) Committee voted to advance his nomination as FDA commissioner by a close 13 to 8 margin (1). Final Senate approval by an historically narrow 50–46 vote came only after the White House and Califf’s supporters lobbied hard to gain sufficient support, a success that is very different from Califf’s 89–4 approval back in 2016. Four Democrats and independent Bernie Sanders opposed the nomination, citing Califf’s close ties to industry and his failure to halt access to opioids. Califf won the vote of Sen. Elizabeth Warren (D-Mass) and some others by agreeing to extend ethics restrictions on his future involvement with industry.

Only six Republications voted for confirmation, led by HELP Committee ranking Republican Richard Burr of North Carolina, who championed the appointment of his fellow Carolinian as a knowledgeable scientist and experienced policymaker. Most Republicans preferred to rail against FDA’s recent decision to remove curbs on prescribing and dispensing medications that induce abortion at early stages of pregnancy.

Califf’s first order of business is to support the development and approval of drugs, vaccines, and diagnostics vital to taming the ongoing coronavirus pandemic. FDA’s recent decision to delay consideration of a COVID-19 vaccine for very young children indicates that many difficult scientific and legal issues remain on the agency’s agenda. Califf will benefit considerably from the experience and assistance of Acting Commissioner Janet Woodcock, who as agreed to remain at the agency as his principal deputy commissioner (2).

An immediate challenge for the commissioner is to revisit and clarify the risks and benefits of the agency’s accelerated approval (AA) programs and to ensure completion of required confirmatory trials. Califf promised such an effort to several uncertain Senators concerned about FDA’s approval of and access to the Alzheimer’s drug Aduhelm and about a proposal from the Centers for Medicare and Medicaid Services (CMS) to limit prescribing Aduhelm to patients participating in clinical trials. If adopted, the Coverage with Evidence Development requirement could apply to similar Alzheimer’s treatments moving through the R&D pipeline, which has raised fears of discouraging further research in the Alzheimer’s field by both patient groups and biopharmaceutical companies. The situation has fueled debate over FDA’s reliance on limited evidence in assessing new products under the AA process and the scope and timing of postapproval confirmatory studies. Meanwhile, the Department of Health and Human Services (HHS) inspector general is investigating the Aduhelm approval decision by the Center for Drug Evaluation and Research (CDER) and whether reviewers behaved properly in weighing the risks and benefits of the therapy.

Patient advocates also want FDA to increase diversity in medical product research and to advance treatments for rare diseases, improved antibiotics, and safer gene and cellular therapies. Pressure to help control the high cost of prescription drugs will continue to drive FDA support for developing complex generic drugs and biosimilars. FDA has taken action against scores of clinics and operations promoting unapproved COVID-19 treatments, many presenting serious health risks to consumers.

Oversight of drugs and medical products is only one of many hot-button issues for FDA’s leadership to track and tackle. There is pressure to clarify rules governing e-cigarettes amidst concerns about flavored products luring young people into tobacco use. FDA also has to address serious health problems arising from contaminated food and seafood, including significant volumes of imported products. The safety of cosmetic products, dietary supplements, sunscreens, and other non-prescription products raise additional complex issues, many described in FDA’s annual report for 2021, which outlines these and several other high-priority regulatory programs (3).

Amidst all these programs, probably the most consequential assignment for FDA’s leader is to win Congressional support for agency funding and resources. This year that entails the timely approval of new user fee agreements on drugs, generic drugs, biosimilars, and medical devices as part of a larger legislative package that must be passed by Sept. 30, 2022. Califf comes to the job with valuable experience in these areas, which he will need to manage the many controversial decisions and heavy political pressures ahead.

“HELP Committee Advances FDA Nominee Dr. Califf, Others,


Vol. 46, No. 3
March 2022
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, “A Rocky Road Ahead for Commissioner Califf,” 

Califf will face challenges that include COVID-19, opioids, and user fees.

A Rocky Road Ahead for Commissioner Califf 

FDA officials and their scientific advisors have come down hard on clinical development programs that rely on study results from a single foreign country, instead of from multi-regional trials following harmonized R&D standards. Even though in the past FDA has approved certain therapies based on limited foreign data, those decisions usually involved new drugs for serious diseases lacking effective treatment. Now regulatory officials seek to clarify that applications are inadequate if they present data from a single foreign study for “me-too” drugs to treat conditions that already have approved therapies.

The issue made headlines recently following a February 10, 2022 meeting of FDA’s Oncologic Drugs Advisory Committee (ODAC) that addressed the degree of generalizability and applicability of data from one country to support approval of a drug for patients in the United States. Here, the debate involved a supplemental application for the PD-1 inhibitor Tyvyt (sintilimab) sponsored by Eli Lilly and Innovent Biologics of China to treat metastatic non-small-cell lung cancer (NSCLC) based on one pivotal trial conducted in China.

FDA officials and its advisors strongly opposed approval of the drug, citing concerns that the drug’s pivotal study in China had limited applicability to the US population. The drug’s broader study design, moreover, raised objections for utilizing an outdated chemotherapy as the control arm, as opposed to the standard of care, Merck’s Keytruda (pembrolizumab).

FDA officials cited a strong preference for multi-regional trials able to support broader drug approval and use, as mapped out by the International Council of Harmonisation (ICH) in its E-5 and E-17 clinical efficacy standards. FDA noted in its 

for the ODAC meeting that the more recent E-17 document advances the use of multiregional clinical trials as optimal for global registration of drugs, and that data from a single country trial does not allow for evaluation of treatment effects across geographic regions and subpopulations.

FDA’s main points also are presented by Richard Pazdur, director of FDA’s Oncology Center of Excellence, and Harpreet Singh, director of the Division of Oncology 2 in the Center for Drug Evaluation andResearch (CDER), in 

 journal. Pazdur emphasized at the advisory meeting that while the trial for Tyvyt closely resembles earlier NSCLC trials that had established checkpoint inhibitors as important treatment regimens in the past, the results are less impressive at this time when similar drugs are available to patients.

A broader concern for FDA and the research community is that the Innovent-Lilly study appears to reflect “an increasing number of oncology development programs based solely or predominantly on clinical data from China.” At least 25 such applications are in development, headed for submission or currently under review by FDA, and Pazdur made clear that such drug development programs may similarly meet objections from FDA, particularly for subsequent indications of already-approved treatments.

The sponsors emphasized that the Tyvyt clinical trial, which was originally designed to support approval of the drug in China, followed the guidelines presented in ICH E5 on efforts to expand the acceptability of foreign clinical trial data as a way to reduce duplicative research programs and promote international harmonization. While FDA and other regulatory authorities have accepted foreign trial data for highly novel therapies that treat underserved patients, they regard multiregional clinical trials and bridging studies as important for ensuring ensure that data from one country is applicable to broader populations. In this case, FDA further pointed out that the China-only study failed to reflect the racial diversity of the US population.

FDA also emphasized the need to compare Tyvyt to a checkpoint inhibitor that is approved in the US in order to demonstrate a statistically significant improvement in overall survival—and not just progression-free survival. In light of growing efforts to broaden clinical trials to represent a full range of ethnic and racial patient groups, a drug tested only in China appears to be “a step backward,” Pazdur said at the meeting.

In an unusual strategy, Lilly executives sought to win broader support for Tyvyt approval by pledging to market the drug at a deep discount in the US. That message, however, appeared to further alienate the scientists, as FDA emphasizes that it does not consider price in its review and approval decisions. The ODAC 14-1 vote in support for additional testing for the drug makes it likely that FDA will send Lilly and Innovent back to the drawing boards—and that the agency and others will take a similar stance with additional applications seeking approvals based on single-country trials—many from China.

FDA officials and their scientific advisors have come down hard on clinical development programs that rely on study results from a single foreign country, instead of from multi-regional trials following harmonized R&D standards. 

FDA Nixes Approvals Based Only on Foreign Data

FDA quietly announced last week that it was resuming domestic surveillance inspections for drugs and other regulated products after another hiatus due to the pandemic. Regular FDA field inspections have been halted several times since March 2020, most recently at the end of 2021; the spread of the omicron variant boosted COVID-19 infections, raising fears that FDA inspectors as well as local plant personnel could be exposed to the virus from such interactions.

FDA has determined that new infections are declining sufficiently

 to restart more routine site visits. FDA’s Office of Regulatory Affairs (ORA) had continued to conduct “mission critical” inspections, both foreign and domestic, during these inspection shutdowns, but the numbers were low. Now the task of catching up is considerable, with some 8000 site inspections of drug manufacturing facilities postponed during the height of the pandemic, and many more since then.

For foreign inspections, FDA aims to start conducting prioritized site visits in April 2022. Agency inspectors will go to locations that have received “country clearance” and meet the Level 1 or Level 2 travel recommendations from the Centers for Disease Control and Prevention (CDC).

For both US and foreign facilities, the agency will continue to provide “effective oversight” of foods, drugs, medical products, and tobacco through remote assessments and by utilizing “a variety of tools.” This includes more extensive analytical testing and sampling of drugs, particularly at US borders. FDA also is requesting documents from facilities to review compliance histories off-site and plans to continue visiting plants via video livestreaming.

Even before the pandemic forced a halt to most FDA inspections, the scope and effectiveness of the agency’s drug inspection program was under scrutiny by federal watchdogs. Members of Congress and domestic manufacturers have long complained that infrequent and pre-announced foreign inspections fail to ensure that drugs made overseas meet the high quality standards required for products made in the United States and create an uneven playing field between US and foreign firms. The issue has been assessed regularly by the Government Accountability Office (GAO), and 

 provides additional advice on how FDA should improve the program.

GAO has found that FDA succeeded in increasing foreign inspections in 2019, as the analysts had advised. However, the COVID-19 pandemic halted almost all that activity; FDA conducted only three foreign inspections in most of 2020, and 18 high-priority inspections through April 2021, compared to some 600 foreign inspections in previous years. Now GAO is looking for FDA to assess whether some of the inequities between foreign and domestic inspections can be addressed by conducting unannounced foreign site visits and by utilizing independent translation services, as opposed to relying on translators engaged by the host site. GAO notes that sound methods are needed for evaluating the results of these pilot programs for FDA to be able to determine if such approaches can be applied more effectively to its broader inspection program.

GAO also continues to emphasize the need for FDA to fill the many “persistent” vacancies in its inspection workforce, particularly personnel specializing in foreign inspections. Staff shortages are serious for both FDA’s US-based foreign inspection cadre as well as in overseas offices in China and India.

It’s no news that throughout its operations, FDA has many unfilled positions, and that recruiting is a major challenge for both foreign and domestic inspection work. Agency officials also have long recognized the drawbacks of pre-announced inspections, as well as the complexities in planning, supporting, and carrying out unannounced foreign site visits. The goal of creating a more “level playing field” between US and foreign manufacturers is important but will remain a clear challenge for some time to come.

With new COVID-19 infections declining, the agency is resuming domestic inspections of drug manufacturing facilities.

FDA Faces Huge Task Catching Up on Inspections

Just a few weeks ago, it looked like FDA would finally gain a permanent commissioner after a year of waiting and that industry agreement on revised drug user fees would begin a steady march through Congress to timely approval this year. Now a range of contentious political issues have jeopardized these and other initiatives vital to the agency’s effectiveness and stature, both at home and on the important global stage. Democrats and Republicans are questioning the capabilities and credibility of Robert Califf as a leader for the agency, despite his valuable experience in biomedical R&D and as the head of FDA several years ago. Moreover, the legislators appear willing to delay action on new user fee agreements to air a broad range of grievances about agency decisions and policies.

The House Energy & Commerce Health subcommittee 

 to officially kick off the debate and review process for renewing new user fee programs to support FDA regulation of drugs (PDUFA VII), generic drugs (GDUFA III), and biosimilars (BsUFA III). The session provided a forum for FDA officials and industry leaders to

 and to emphasize the importance of renewing the fee programs by Sept. 30, 2022. The legislators unveiled both their continued support for the program, as well as concerns and complaints about FDA’s performance and priorities.

The agreed-on fees are significant, even by federal spending standards:$1.4 billion a year for prescription drugs, $600 million to speed approvals of generics, and approximately $50 million to advance biosimilars. The considerable fee amounts generate concerns about industry influence on the agency, along with praise for enabling cutting-edge advances and efficient operations by FDA’s staff. Notably absent was any discussion of fees for medical devices, due to continued disagreement over program parameters by manufacturers and FDA’s Center for Devices and Radiological Health.

The range of complaints and concerns with FDA decisions and actions raised by the legislators signals the shape of the debate to come. The agency’s accelerated approval (AA) process is at the top of the list, as seen in both vocal challenges to FDA’s approval of the Alzheimer’s treatment Aduhelm, along with complaints that Medicare patients will be denied access to the drug due to the proposed coverage-with-evidence-development policy under consideration by the Centers for Medicare and Medicaid Services (CMS). In response to some heated questions, Center for Drug Evaluation and Research (CDER) Director Patrizia Cavazzoni emphasized that FDA did not influence CMS on its controversial coverage proposal. However, she acknowledged the need for improvements in the AA program, notably in requiring sponsors to begin confirmatory studies at time of approval and in facilitating FDA’s authority to pull products that fail to provide timely follow-on evidence.

The legislators also voiced concerns about limited development of new antimicrobials and treatments for rare conditions and on the lack of diversity in clinical trials. Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), outlined efforts to address drug development policies for future pandemics and the need for reliable real-world evidence to support new products. Several legislators raised questions about how FDA will transition to “normal” procedures and practices for field inspections and remote meetings when the Public Health Emergency is declared over.

Meanwhile, prospects dimmed for quick Senate confirmation of Robert Califf as FDA commissioner. His strong record as an expert in clinical research and FDA policies, as seen in his previous stint as commissioner during the last year of the Obama administration, was supposed to speed his nomination through the Senate process. But lingering concerns about his ties to the pharmaceutical industry have generated opposition, as have complaints that he failed to tackle FDA’s involvement in the approval of lethal opioids. Califf recently moved to offset “revolving-door” charges by pledging to recuse himself from industry involvement for four years after his time as FDA commissioner—instead of the required two years. That won over some Democrats, but not all.

At the same time, Republican support fell off with an attack by right-to-life groups on FDA’s “pro-abortion agenda.” A main target is the agency’s recent decision to remove curbs on prescribing medications that induce abortion at early stages of pregnancy. In response to heated questions, Califf said he would review that policy, but not necessarily revoke it, prompting most Republicans to withhold support for the candidate. Even the editors of the 

objected to such criticisms of Califf from the pro-life movement, noting that FDA is not an abortion regulator and that Califf doesn’t deserve such abuse from the left or the right.

Califf’s most vocal supporter is HELP Committee ranking Republican Sen. Richard Burr of North Carolina. Burr championed the appointment of his fellow Carolinian as a knowledgeable scientist, experienced policymaker, and greatly needed leader for FDA, attributes also praised by former FDA commissioners and leaders of the biomedical research community.

Evidently, the White House expected Burr to bring in sufficient Republican support to move Califf’s confirmation through the Senate. But with much of the opposition coming from Democrats, the Biden administration has had to put more pressure on waffling legislators or risk leaving FDA in limbo once again. Acting Commissioner Janet Woodcock can remain in her post for much of the year if all else fails, but that temporary status is not fair to her or to FDA.

A range of political issues have impacted FDA initiatives vital to the agency’s effectiveness and stature, both at home and on the important global stage.