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

Jill Wechsler

 this week, presenting a host of strategies to strengthen the nation’s transportation, housing, jobs, education, and home healthcare, while also advancing research and science in multiple industries. The aim is to appeal broadly to Americans in all regions and across the political spectrum with the promise of better lives post-pandemic. With a cost of $2.3 trillion over eight years, and possibly up to $4 trillion over the next decade, the administration seeks to fund much of the tab with the hefty boost in the corporate tax rate over 15 years and to increase taxes on companies’ foreign earnings, changes that notably would affect biopharma companies.

The largest investments provide funds to modernize transportation infrastructure, expand affordable housing, bolster utilities, and expand home and community-based care for the elderly and disabled. Within these initiatives are multiple programs related to R&D and technology, such as funds for electric vehicle development, to expand high-speed broadband, and to improve the power grid. An emphasis on boosting support for research and development aims to make American industry more competitive with China and other advanced nations, while also creating more high-wage jobs and maintaining American global leadership in manufacturing and economic development.

A number of innovation and R&D programs fall under the $280 billion allotted for jobs creation and expanded research infrastructure to support the “technologies of the future” important to American competitiveness “on the global stage.” There’s $50 billion for the National Science Foundation to collaborate and build on high-tech programs in fields like biotechnology, semiconductors, advanced computing, and advanced energy technologies. There’s another $35 billion to address the climate crisis and advance clean energy technology. Efforts to retool and revitalize American manufacturing include a new office to monitor domestic industrial capacity and support production of critical goods such as semiconductors. And there’s more than $50 billion available for investment in US manufacturers and a plan for “regional innovation hubs” to spread new opportunities across the country.

Advancing American manufacturing also supports activities to “protect Americans from future pandemics.” That initiative provides $30 billion to invest in medical countermeasures manufacturing, shore up the strategic national stockpile, accelerate the timeline for R&D and testing of new therapeutics, and train personnel for epidemic and pandemic response. One notable proposal is to accelerate the nation’s ability to respond quickly to a medical emergency by developing prototype vaccines through Phase I and II trials. Biopharma manufacturing also would gain from investment in new technologies for rapid scale up of vaccine production, in expanded emergency production capacity and enhanced US infrastructure for biopreparedness, and in greater production onshore of APIs. 

The main source of funding for the massive program is to boost the corporate tax rate to 28%, up from the current 21% that was part of a major Trump administration tax cut. That’s still lower than the 35% corporate tax rate before the change in 2017, but still projected to provide up to $3 trillion to pay for the jobs and infrastructure package. President Biden explained that the plan aims to end “the race to the bottom on corporate tax rates” around the world. And reformers maintain that corporations actually pay only about a 16% tax rate, largely due to incentives for shifting production and jobs overseas.

Biden aims to fix that by revising current policies that exempt from US taxes most foreign assets and higher taxes paid overseas. A range of policy changes would discourage foreign based companies from shifting profits from US operations to avoid taxes, while also discouraging foreign takeovers of US firms. The global operations of most biopharma companies means that any changes in the international tax arena will have a significant impact on industry operations and business decisions.

Republicans already are loudly opposing the tax changes, and the package is slated to undergo significant changes to gain sufficient support for enactment.

Articles

The White House’s American Jobs Plan includes investment in new technologies for rapid scale up of vaccine production, in expanded emergency production capacity and enhanced US infrastructure for biopreparedness, and in greater production onshore of APIs.   

Biden Infrastructure Package Would Boost R&D and Corporate Taxes

With Senator Bernie Sanders (D-Vt) leading the charge on Capitol Hill, the campaign to limit US outlays for prescription drugs have accelerated, now aiming to include a number of cost-control measures in the massive economic development bill under development. Although such efforts have petered out in the past, the need for added revenues to fund billion-dollar infrastructure improvements has fueled challenges to industry pricing practices.

 hearing in March before the Senate Health, Education, Labor and Pensions (HELP) subcommittee

 chaired by Sanders. He and colleagues are sponsoring a 

 that would peg US drug prices to those in other industrialized nations, facilitate broader reimportation of prescription drugs from certain countries, and permit Medicare to negotiate prices paid by drug plans. 

Another popular proposal would require manufacturers to conduct comparative studies to justify “substantial” price increases related to product improvements. Debate continues over additional reforms involving rebates paid to Medicare drug plans and the role of patents in thwarting competition from low-cost generics and biosimilars. Broader disclosure of marketing expenditures and pricing decisions also have gained support.

None of these cost-cutting measures are new, and policy changes under the Trump administration already permit reimportation under certain circumstances. Industry and its Republican allies continue to push back with claims that limits on drug prices would stymie innovation and delay the development of critical new therapies. They prefer specific strategies for reducing patient out-of-pocket expenses through access to rebates and co-pay support programs. There is some agreement on policies to encourage biosimilar prescribing and the development of complex generic medications. Analysts acknowledge, moreover, that high-cost biotech therapies are driving cost trends, but that these can be life-saving treatments for seriously ill patients.

Despite concerns that price controls would block new drug development, the prospect that such reforms would create $450 billion in savings to offset trillion-dollar expenditures in economic development legislation may be sufficiently potent to drive reform forward. The House passed a broad drug pricing measure in 2019, but it never came up for a vote in the Republican-controlled Senate.

Now with public support growing for controlling medical costs, Senate moderates may join with progressives to lessen restrictions on the government’s role in limiting drug prices. They may be attracted by proposals to use some of those gains to fund new community health centers and further expand the Medicaid program to more low-income consumers. Moreover, Democrats may look to circumvent Republican opposition to pricing measures by including such reforms in budget reconciliation legislation, which requires only a majority to win Senate approval—and not 60 votes. Industry lobbyists will seek to foil that strategy, but there is concern that the rising outcry from individual patients hit by huge costs for vital medicines will sway Congressional action.

In addition to enacting legislation to challenge manufacturer pricing, reformers in Congress and consumer advocates are weighing a number of avenues to change. Biden administration officials are considering expanded use of Medicare demonstration programs and of the Center for Medicare and Medicaid Innovation (CMMI), as did the Trump administration, to test new payment models, discount drug vouchers, and other cost-cutting programs. The Department of Health and Human Services (HHS) also may propose new rules, payment policies, and waivers to alter current Medicare reimbursement and coverage requirements, as discussed in a white paper prepared by the 

Congressional reformers also want federal agencies to investigate pharma pricing practices. A group of House Democrats recently sent a letter to Federal Trade Commission acting chair Rebecca Slaughter urging a probe of possible collusion among leading insulin marketers. The request is similar to one made by Senator Sanders in 2016, but may get more attention from Slaughter, who recently announced increased scrutiny of drug industry mergers. The legislators cite reports on coordinated price hikes of insulins since 2012 by Eli Lilly, Sanofi, and Novo Nordisk, and note how the high cost of diabetes medicine is particularly harmful to minority patients [see 

(20) Rep. Katie Porter on Twitter: "Just 3 companies control nearly all of our insulin supply: Eli Lilly, Sanofi, and Novo Nordisk. Shocker: it turns out they raise prices in tandem—at least 13x in 10 years—while patients are rationing or starving themselves to try to cut costs. I want answers. https://t.co/AtkH3OonTs" / Twitter

Separately, consumer advocates are urging the National Institutes of Health (NIH) to “march in” and claim patent rights to medicines developed in collaboration with government-funded researchers. NIH scientists have been visibly involved in the research underlying the mRNA vaccines that have proven so effective in combatting COVID-19. A coalition of non-profit public interest organizations is urging NIH to ensure that the new vaccines, which advanced with notable support from the National Institute of Allergy and Infectious Diseases (NIAID), will be made available on an affordable basis to global health organizations for delivery to less developed nations around the world.

The great success of the biopharmaceutical industry in speeding to patients innovative vaccines and therapies able to combat COVID-19 has boosted public confidence in and regard for biopharma companies to notable highs. Industry leaders have highlighted the cutting-edge science and dedicated researchers that have produced these critical new therapies. This success has raised concerns about upsetting the underlying economic and scientific factors driving innovation, but that continues to be offset by vivid reports of patient hardship in accessing vital medicines.

The need for added revenues to fund billion-dollar infrastructure improvements has fueled challenges to industry pricing practices. 

Drug Pricing Moves to Top of Legislative Agenda

Is FDA approving too many new drugs and added indications too quickly based on surrogate endpoints that fail to pan out? While patient advocates and the research community have been strong backers of early access to treatments that demonstrate potential effectiveness for serious and life-threatening conditions that lack effective treatment, some consumer advocates and research experts believe that FDA has been lax in approving medicines with insufficient supporting data.

Now the agency is reviewing the record of its accelerated approval (AA) program following the recent withdrawals of certain key indications for several leading cancer therapies based on the failure of postapproval studies to document extended benefits of treatment. That development has raised questions about the broader FDA policy, including frequent difficulties in conducting postapproval clinical trails and the relatively few therapies that have had approvals withdrawn by the agency.

These issues will be reviewed by FDA’s Oncologic Drugs Advisory Committee (ODAC) at a 

three-day meeting on April 27–29, 2021,

 a notably long session to discuss several supplemental biologics license applications (sBLAs) where confirmatory trials failed to verify clinical benefit. The experts will assess advanced cancer indications for Roche/Genentech’s TECENTRIQ (atezolizumab), Merck’s KEYTRUDA (pembrolizumab), and Bristol Myers Squibb’s (BMS) OPDIVO (nivolumab). Since December 2020, these sponsors voluntarily withdraw these immunotherapies for certain indications based on failure to meet primary endpoints in confirmatory trials, as did AstraZeneca for use of IMFINZI (durvalumab) to treat advanced bladder cancer.

These monoclonal antibodies target PD-1/PD-L1 proteins to boost immune response against cancer, raising questions about the broader efficacy of such treatment. The confirmatory studies aimed to document overall improved survival compared to standard-of-care chemotherapy, after gaining accelerated approval based on tumor response in early studies. The ODAC meeting will examine the status of efforts by Genentech, Merck, and BMS to confirm additional indications for their therapies, and, in the process, will scrutinize the AA program more publicly for a range of cancer types.

The meeting is part of a broad, ongoing effort by FDA’s Oncology Center of Excellence (OCE) to review AA policies and the role of surrogate endpoints in evaluating new therapies. Sponsors are anxious to know whether the agency is focusing on this small subset of treatments or on the use of surrogate endpoints and other accelerated research strategies more broadly. Over its 30-year history, FDA’s AA program has led to speedy approvals of dozens of products, primarily for oncology and hematology in recent years. Although FDA may withdraw an accelerated approval for a product, the manufacturers did so voluntarily in the above cases, and for some dozen other therapies in previous years. There are only two cases where the agency initiated a withdrawal, following a complex and time-consuming process.

white paper issued by the Friends of Cancer Research (FOCR)

 at its annual meeting in November 2020 that outlines ways to update the AA policy to provide FDA with greater flexibility in both approving and in withdrawing approvals of innovative drugs. Prepared by a multi-stakeholder working group, the report emphasizes the importance to patients of early access to new treatments, the benefits and risks of utilizing surrogate endpoints to streamline research, and challenges in conducting post-approval studies to confirm early evidence. There is discussion of differences and similarities between FDA’s policy and the European Medicines Agency’s conditional marketing authorization policy, particularly related to market withdrawal actions. The panel recommends added flexibility in policies governing AA approval decisions, including the role and design of confirmatory trials and expanded use of real-world evidence to better confirm benefits and risks with broader use of a medicine. Such approaches aim to assist FDA in understanding factors that contribute to failed confirmatory studies and the need for a more efficient process for making withdrawal decisions.

The ODAC meeting will provide an opportunity for sponsors to provide updates on ongoing studies for their therapies and to examine whether further testing could revise the withdrawal actions. A long-debated issue is industry’s poor record in conducting and reporting results from postapproval studies, and FDA appears to be taking a harder line on requiring confirmatory trials to support clinical benefit.

Is FDA approving too many new drugs and added indications too quickly based on surrogate endpoints that fail to pan out? 

FDA Reviews Gains and Risks of Accelerated Approval Process

The Federal Trade Commission announced this week that it is launching a broad review of drug-company mergers, with an eye to examining how such actions can harm competition in the biopharmaceutical industry. The Commission is 

 that will include lead competition officials from Canada, the United Kingdom, and the European Commission, as well as the US Department of Justice Antitrust Division and state attorneys general.

The goal of the initiative is to identify “concrete and actionable steps” to review and update how the Commission analyzes pharmaceutical mergers, as one way to address “skyrocketing drug prices” and concerns about anticompetitive conduct in the industry. Although the FTC and the Justice Department share oversight of industry mergers, the FTC has the lead related to the biopharmaceutical industry. The project was spurred by Acting FTC Chair Rebecca Kelly Slaughter, who has called for closer scrutiny of pharma competition as member of the commission for several years.

In response to industry claims that company mergers foster innovation, the FTC project will address the need to “refresh” current assessment of harm related to industry conduct and what types of remedies can best prevent conduct involving price fixing, reverse payments and other regulatory abuses. The Commission wants to consider what evidence is needed to challenge transactions and how to assess the scope of assets and characteristics of firms for successful divestiture requirements.

The initiative reflects the Biden administration’s concerns about anticompetitive business practices, beyond much-discussed challenges to market control by high-tech industry leaders. The FTC is currently evaluating AstraZeneca’s proposed $39 billion acquisition of Alexion Pharmaceuticals, and scrutiny of the proposal is likely to be more stringent as a result of the new initiative. In most larger mergers, the FTC requires the divestiture of certain products or company assets to maintain competition in select markets, but many Democrats support stronger action to prevent excessive industry consolidation. Industry innovation has been driven in recent years by large companies buying up multiple small biotech firms, moves that critics claim leads to plan closings and reduced work forces.

Slaughter recently indicated that the review may examine the impact of past pharma merger reviews by the FTC, with an eye to assessing whether errors were made. While the Commission seldom reverses earlier consolidation decisions, that possibility has raised industry concerns.

The Federal Trade Commission is launching a broad review of drug-company mergers, with an eye to examining how such actions can harm competition in the biopharmaceutical industry. 

FTC Eyes Crackdown on Pharma Mergers

A few weeks ago, it looked like the race was narrowing to name a new head for FDA, with Acting Commissioner Janet Woodcock the lead candidate. But with no final nomination coming from the White House, concern has mounted among regulated industry and interested stakeholders that FDA operations and stature will suffer without a permanent commissioner able to articulate new policies and gain support for innovative programs—while also fending off critics and challenges to FDA’s science-based decision-making.

The cost of delay was spelled out recently 

 from six former FDA commissioners, who state that the absence of strong agency leadership endangers the independence and authority of this critical agency. The letter is signed by Robert Califf, Scott Gottlieb, Margaret Hamburg, Jane Henney, Mark McClellan, and Andrew von Eschenbach. Although they don’t support any specific candidate for commissioner, they applaud Janet Woodcock for her commitment to FDA’s scientific mission and career staff and note the benefits of the experienced leadership that she has demonstrated as acting commissioner.

In February, it appeared that Woodcock was headed for the permanent job. Her experience and efforts to spur the development and approval of innovative therapies generated support from regulated entities and the research community. A long list of patient advocates, including leading cancer and rare disease organizations, urged her nomination. That applause, however, was countered by consumer advocates who faulted Woodcock for being too ready to speed unproven therapies to market, including long-acting opioids that subsequently fueled the devastating opioid abuse epidemic.

The public health community called for former FDA official and public health advocate Joshua Sharfstein to take the lead at FDA in order to fully restore the agency’s reputation for scientific integrity. Although he had support from many Democrats in Congress, Sharfstein raised objections from others for being divisive and hostile to innovation, and his nomination has dimmed in recent weeks.

The potential damage to FDA from continued delay and uncertainty over its leadership was further emphasized by several former commissioners in a recent online 

 interview. Peggy Hamburg commented that the uncertainty over who will head the agency hurts morale and creates problems for sponsors planning R&D programs. Scott Gottlieb noted that real benefits do come with Senate confirmation related to making broader policy decisions.

The former agency leaders also agreed that FDA would be better off as an independent agency, similar to the Federal Trade Commission. Gottlieb sees little of value in FDA being part of the Department of Health and Human Services (HHS). And the group said that FDA would be a more nimble and streamlined operation if it did not have to go through additional stages of approval and sign-off from HHS, which only opens up opportunities for outside intrusions into policy making.

But as FDA still is part of HHS, there is some expectation that Senate confirmation of Xavier Becerra as secretary of this vast department this week may open the door to naming an FDA commissioner. Most other top HHS positions already have been proposed, and multiple confirmation hearings will occupy the Senate for some months ahead.

One factor delaying the Biden administration’s decision on FDA leadership has been its focus on enacting massive legislation to further fight COVID-19. Although the prime objective of the $1.9 billion American Rescue Plan is to provide support for millions of Americans and businesses facing financial hardship, 

the massive bill also provides billions to improve testing and disease surveillanc

e to combat the pandemic, including $7.5 billion to promote, distribute, and administer COVID vaccines..

Of note, FDA gains an extra $500 million to support the fast and efficient evaluation of vaccines, therapeutics, and diagnostics to combat the pandemic and to distribute needed medical supplies. Congress also authorizes FDA to use the funds to further advance continuous manufacturing of drugs and vaccines, to bolster drug inspection programs, and to prevent drug shortages and better oversee the biopharmaceutical supply chain. And FDA is instructed to further review the large volume of medical devices initially approved for emergency use.

Less welcome for industry is a provision that alters how Medicaid calculates limits on rebates for certain drugs. In eliminating a cap on total rebate amounts, manufacturers of some drugs used heavily by Medicaid patients may face big increases in payments owed the program. However, the change is calculated to save the federal government $14 billion over eight years to 2030, making it an attractive addition to the measure for its advocates.

Also important for access to medicines are measures to expand access to health care for Americans under revisions to the Affordable Care Act (ACA). Key provisions expand Obamacare subsidies, including free health coverage to the unemployed and erasing the need to pay back excess health care subsidies by people who underestimated their income.

With no final nomination of FDA commissioner coming from the White House, concern has mounted among regulated industry and interested stakeholders that FDA operations and stature will suffer without a permanent commissioner able to articulate new policies and gain support for innovative programs.

Where’s FDA’s Permanent Commissioner?

Despite critical disruptions and added challenges posed by the coronavirus pandemic in 2020, FDA annual reports on drug regulatory programs and policies confirm successful efforts for meeting review time frames and updating policies and programs. These reviews of FDA initiatives and activities recapitulate efforts to assess and approve new drugs, generic drugs, and biologics, as well as strategies for advancing new initiatives. These efforts appear timely as FDA continues to renegotiate revisions and expansion of user fees paid by manufacturers to support FDA oversight and review activities.

 This article was originally published online on Feb. 15, 2021

Several reports from the Center for Drug Evaluation and Research (CDER) summarize efforts to ensure drug quality and to maintain a steady pace in new drug review and approvals despite limitations and pressures imposed by the pandemic. A report on new drug approvals in 2020 documents the 53 novel drugs and biotech therapies approved in 2020, describing a range of innovative oversight strategies to evaluate product safety and efficacy (1). The report also notes approval of additional uses for certain existing therapies, evaluation of new biosimilars, and the importance of expedited review programs in facilitating patient access to critical medicines.

More specific demographic information on the clinical trials supporting the review and approval of these novel drugs is provided in the 2020 Drug Trials Snapshots Summary Report (2). That report presents data on demographic groups participating in these key studies and how such enrollment may inform product safety and efficacy. In addition, CDER activities for protecting public health during the pandemic are outlined in an annual drug safety report that describes efforts to ensure appropriate tracking and reporting of safety issues, some related to broader uses of the agency’s Sentinel System (3).

Separately, an annual report from CDER’s Office of Product Quality (OPQ) highlights the use of alternative tools for on-site facility inspections to support the timely approval of new drugs, an effort that avoided the need for 153 site visits (4). OPQ notes its role in advancing CDER’s emerging technology program and efforts to bolster continuous and semi-continuous manufacturing and continued development of its knowledge-aided assessment and structured applications (KASA) program for evaluating new drugs, starting with solid oral dosage forms. Another main goal is to move forward with a new framework for assessing and identifying mature quality management systems by manufacturers.

OPQ also cites its efforts to support the approval of 942 generic drugs in 2020, including more first generics, complex generic therapies, and biosimilars. This involves coordination with CDER’s Office of Generic Drugs (OGD) in bringing new generics to market quickly and efficiently, especially to offset shortages in medicines critical to treating patients infected by COVID-19, as is outlined in the OGD annual report (5). The report discusses efforts to update the Orange Book, publish guidance documents on specific product development standards, advance the science on complex generics, and collaborate with foreign regulatory authorities to support wider global access to generic drugs. OGD is poised for a major reorganization beginning this year, which aims to update operations to better handle a steady rise in
abbreviated new drug applications.

The challenges in continuing to speed new oncology therapies to patients are presented in an annual report from FDA’s Oncology Center for Excellence (OCE), which enumerates its achievements in overseeing the approval of multiple new indications and market approval of cancer treatments, including several new formulations (6). OCE Director Richard Pazdur emphasizes the importance of addressing the needs of cancer patients during the pandemic with initiatives to permit more flexible clinical trials and remote communications. OCE also is continuing its Project Orbis collaborative review of new cancer therapies with other regulatory authorities to speed access to cancer treatments around the world.

Similarly, the annual report from the Center for Biologics Evaluation and Research (CBER) outlines how it met milestones for reviewing new therapies and for ensuring product safety (7). CBER Director Peter Marks highlights the Center’s involvement in the development and evaluation of vaccines against COVID-19. In addition, CBER approved several novel biologics and blood reagents, provided advice to sponsors through virtual meetings, and continued to support pilot programs to advance modern manufacturing and regenerative medicine. Separately, Marks issued CBER’s list of new guidance documents slated for release in 2021 (8). This relatively short list of only 14 planned advisories reflects the considerable progress made in 2020 in issuing more than 20 guidance documents, including several related to development and emergency use of new COVID-19 vaccines and therapies.

In January, CDER also published a much longer list of more than 100 planned guidance documents for 2021, including 42 new items (9). The largest categories involve clinical studies, generic drugs, and agency procedures, and new categories were added for biosimilars, compounding, pharmacology/toxicology, and the animal rule. New guidance documents on the list involve the use of real-world data, developing antisense drug products, and demonstrating efficacy in a single trial.

FDA may gain some added resources for its evaluation of new treatments to combat COVID-19 from a Congressional proposal to make an extra $500 million available to the agency this year, on top of its budget for 2021. The funding boost recognizes the considerable added work that FDA has taken on to support the development and oversight of new vaccines, therapeutics, and medical products, as multiple applications for emergency use authorizations and product approvals have overloaded the agency.

1.FDA, Advancing Health Through Innovation: New Drug Therapy Approvals 2020, 

Office of Pharmaceutical Quality, 2020 Annual Report: Assuring Quality Medicines are Available to the American Public

Office of Generic Drugs 2020 Annual Report: Ensuring Access to Safe Effective, High-Quality, and More Affordable Generic Drugs

Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2021

CDER Guidance Agenda, New & Revised Draft Guidance Documents Planned for Publication in Calendar Year 2021

Washington editor, jillwechsler7@gmail.com.

When referring to this article, please cite it as J. Wechsler, "FDA Documents Achievements and Plans for Future," 

Reviews of FDA initiatives and activities recapitulate efforts to assess and approve new drugs, generic drugs, and biologics and strategies for advancing new initiatives.