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

Jill Wechsler

The escalating attack on too-high prices for prescription medicines has heightened debate over the government’s authority to revoke licenses for medical products that are developed with support of public funds. The Department of Health and Human Services (HHS) and Department of Commerce (DOC) 

 a broad review of the “march-in” authority provided in the Bayh-Dole Act of 1980 in the wake of its controversial decision to let stand licensing rights to a widely used cancer drug.

The review will be conducted by a new Interagency Working Group for Bayh-Dole, which is charged with updating the framework for altering march-in provisions spelled out in that legislation. A main issue is whether a high price for a product provides sufficient reason to revoke a manufacturer’s license. HHS will hold a workshop later this year to discuss when it might be appropriate to implement march-in rights, with input from patient groups, industry, academic, nonprofit organizations, and legal and policy experts. And the discussion will be informed by a recent publication from National Institute of Standards and Technology (NIST) that proposes changes to streamline and clarify licensing procedures for federally funded inventions.

This issue hit the headlines recently when the National Institutes of Health (NIH)

 to initiate march-in proceedings for the prostate cancer drug Xtandi (enzalutamide), marketed by Pfizer and Astellas Pharmaceuticals. Public interest groups had filed a petition in 2021 that called on NIH to take ownership of the patents on the drug due to its much higher cost in the United States than in Canada and other countries, which limited patient access to the therapy.

At the same time, Congressional leaders highlighted the substantial NIH funding of Moderna’s COVID-19 vaccine in challenging the company’s plan to raise the price of the preventive when federal subsidies end in May. In testimony before the Senate Health, Education, Labor and Pensions (HELP) Committee on March 22, 2023, Moderna CEO Stephane Bancel 

emphasized the years of research and billions

 invested by his company to devise methods for quickly testing and producing such a vaccine. Committee chair Bernie Sanders (I-Vt) 

highlighted the $1.2 billion invested by the federal government

 in the project in blasting the company’s plan to boost the price from $26 to $130 per shot with the end of the COVID health emergency.

The Bayh-Dole Act of 1980 provides a pathway to facilitate commercialization of inventions, including biomedical products, that are developed with support from federal agencies such as NIH. The program permits the government to “march in” to rescind licensing rights if it determines that the benefits of such inventions are not available to the public on reasonable terms. Over the years, various organizations have petitioned NIH and other agencies to initiate march-in proceedings when a product’s high cost might be considered a barrier to access. But federal officials have rejected such pleas, as with several petitions related to Xtandi.

In rejecting the latest filing on Xtandi, NIH stated that the aim of Bayh-Dole is to promote commercialization and public availability of government-funded inventions, and not necessarily to ensure a low price for a covered medical product. NIH noted that Xtandi is widely available to patients, and that instituting march-in rights was unlikely to lower the price. Sen. Sanders and patient advocates clearly disagreed with the NIH decision, pointing out that Xtandi can be purchased in Canada for one-fifth the US price. But manufacturers and industry experts counter that without private sector investment and know-how, most government-funded research would never move from the laboratory to the marketplace—at any price.

Articles

A new Interagency Working Group for Bayh-Dole will review the government’s authority to revoke licenses for medical products.

Feds to Review March-In Authority on Drug Patents

After more than a decade of delay tactics, it appears that FDA may finally bring about the withdrawal of its earlier approval of the controversial drug to prevent preterm birth. Even after an FDA 

advisory panel voted 14–1 in October 2022 

to remove the drug, Makena manufacturer Covis Pharma continued to press for some continued access to the therapy. In a long submission, the firm’s attorneys argued that the weak trial results were inconclusive and that more studies should be done, and that there is no other drug available to prevent preterm birth, so Makena is better than nothing.

Officials at the Center for Drug Evaluation and Research (CDER) disagreed, 

stating that it undermines public health to offer a drug to patients that offers only risks and no benefits and that Makena should exit the market immediately

. FDA explains that Makena was approved under the accelerated approval process, but that postmarketing clinical studies had failed to confirm its effectiveness in reducing the risk of premature birth in its target patient population. Therefore, CDER analysts urge Commissioner Rob Califf and the agency’s chief scientist, who are charged with deciding the issue, to support immediate withdrawal of the drug and any generic versions to avoid exposing patients to further risk. And in specific response to Makena’s proposal to continue treatment for those patients already using the drug, agency experts emphasize that there is no evidence of patient harm from discontinuing Makena, and only further risks from continued treatment.

The 12-year Makena saga illustrates how difficult it is for FDA to cancel marketing of an approved therapy, even when test data fails to confirm efficacy, and the need for reform of the accelerated approval process to ensure patient use of effective treatments. An FDA advisory committee that met in October 2019 was divided on whether to withdraw the drug. Even though postapproval studies of Makena by then-manufacturer AMAG Pharmaceuticals failed to confirm substantial evidence of effectiveness, some panel members supported leaving the product on the market pending further evidence. The company objected to additional trials, and FDA proposed to remove the drug from the market in October 2020.

That led to the more recent advisory committee meeting in October 2022. With little new evidence to support the drug’s efficacy, this time the panel voted unanimously that a confirmatory study showed no benefit, and it agreed 14–1 to remove Makena from the market. Covis 

initially objected to that course of action

 and sought to continue to make the drug available to very high-risk patients. Only when FDA issued a much harsher report this month did the company agree on March 7, 2023 to “voluntarily withdraw the product” in an “orderly wind-down,” said

 Covis Chief Innovation Officer Raghav Chari

Just how long that “wind-down” takes remains to be seen. Covis continues to point to the lack of any alternative treatment to prevent miscarriage, and that that some treatment—even its ineffective one—is better than nothing. And the company has highlighted the higher rates of miscarriage among black women, and that removing the drug discriminates against this minority patient group.

FDA and the research community, however, recognize that it’s impossible to conduct any placebo-controlled study if any approved treatment is available to patients. Leaving the drug on the market all these years now is seen as a deterrent to developing more effective therapies for this condition. But the therapy generated some $1.5 billion in sales since its approval in 2011, according to press reports. If Califf and his staff agree with CDER’s recommendations, the marketing of Makena may finally end.

Even after an FDA advisory panel voted 14–1 in October 2022 to remove the drug, Makena manufacturer Covis Pharma continued to press for some continued access to the therapy.

Makena Saga Shows How Hard It Is to Remove Unproven Drug from Market

The spotlight on rising prescription drug costs also is focusing more attention on the role of drug plan middlemen in shaping patient access to and outlays for medicines drugs. Congressional leaders are investigating how pharmacy benefit managers (PBMs) determine health plan coverage and charges for medicines, as is the Federal Trade Commission (FTC). Independent pharmacists also are loudly protesting certain PBM practices, and pharma companies readily support the shift in focus toward PBM practices and away from manufacturer launch and list prices.

to examine PBM business practices and their impact on costs and coverage for consumers. Health care experts testified on the need for more transparency into harmful PBM business practices, including “fail-first” and prior authorization requirements that can delay or deny coverage, limits on co-pay assistance, and efforts to steer high-cost patients away from plans. Committee Chair Maria Cantwell (D-Wash) and Sen. Chuck Grassley (R-Iowa) have proposed legislation to enhance transparency in PBM practices seen to inflate drug costs and limit patient access.

More recently, the House Committee on Oversight and Accountability announced a probe of the role of PBMs in pharmaceutical markets, an effort begun by Republicans and now revived by the panel’s chairman, Rep. James Comer (R-Ky). Minority Republicans 

on the role of PBMs in stifling competition in pharma markets, and now Comer is following up with letters to PBMs and federal health plans on a range of policies and practices. Letters were sent March 1 to the top three PBMs—Express Scripts, CVS Caremark, and Optum Rx—requesting a long list of documents related to formulary design and management, rebates, and fees paid to companies and insurers. The Oversight Committee analysts want to better understand whether such PBM policies compel manufacturers to pay hefty fees and to offer steep discounts to the middlemen to gain favorable formulary placement and less restrictive coverage policies for patients.

The House panel also sent letters to the Centers for Medicare and Medicaid Services (CMS), the Office of Personnel Management (OPM), and the Defense Health Agency (DHA) 

 on how these federal health programs interact with PBMs related to rebates, fees, and other charges involving government prescription drug coverage programs. And in response to retail pharmacists, the investigators seek information on tactics allegedly used by PBMs to steer business to those pharmacies that accept reduced reimbursement and pay retroactive rebates and fees, which shift costs from PBMs to insurers and pharmacies. The National Community Pharmacists Association (NCPA) 

to challenge PBM practices “that are distorting the pharmaceutical market and limiting high quality care for patients.” 

The FTC is analyzing similar issues in its investigation of whether a few large PBMs exercise excessive control of the pharmaceutical market. In February 2022, the Commission announced a formal inquiry into the effects of PBM consolidation and vertical integration with large health insurance companies. The resulting volume of comments and criticisms of PBMs sent in prompted the 

for ramping up enforcement against illegal rebate schemes involving drug companies and drug middlemen.

The stated goal for the legislators is to better understand whether PBMs actually reduce drug costs and save money for health plans and consumers by negotiating rebates and discounts with manufacturers—or if the middlemen merely pocket those savings and limit access to important medicines from firms that fail to ante up. Manufacturers support these efforts, insisting that PBM demands for rebates and discounts drive up list prices for all medicines. And while patients in covered health plans may benefit from the lower negotiated prices, higher list prices can boost their insurance premiums and copays.

PBMs are fighting back, as seen in efforts by the industry’s Pharmaceutical Care Management Association (PCMA). The industry maintains that the proposed Senate legislation would raise costs for employers and patients and do little to limit deceptive practices.

Congressional leaders are investigating how pharmacy benefit managers determine health plan coverage and charges for medicines.

Congress Probes PBM Link to Higher Drug Prices

The remarkable success of utilizing messenger (mRNA) technology to combat the severity and spread of COVID-19 is transforming the world of vaccine discovery and testing, stimulating a new generation of vital preventives for global diseases. Industry’s ability to deliver COVID-19 vaccinations in the United States and internationally is generating multiple initiatives to further compress the timeframe for vaccine development and production. New vaccines to combat cancer and to better prevent a range of infectious diseases are being tested, as are more efficient seasonal influenza shots that more closely match prevalent viral strains.

These developments are fostering new partnerships among vaccine makers and initiating more clinical trials to develop mRNA therapeutics and preventives for a range of serious conditions, including melanoma, Zika, malaria, and shingles. New shots to prevent pneumococcal disease are in development from several firms. Moderna made waves with data indicating 84% effectiveness for a new preventive for RSV (respiratory syncytial virus) as well as progress in developing a vaccine to help combat melanoma (1). Takeda is gearing up to launch a new dengue vaccine that provides several years of protection in anticipation of FDA approval later this year (2).

And despite plans to end the COVID-19 public health emergency, additional preventives for that virus continue to emerge. Novavax gained FDA approval of its protein-based COVID-19 vaccine only in July 2022 and recently announced the sale of 1.5 million vaccine doses to the federal government to cover the transition from government-supported shots to a commercial market (3,4). But a vaccine to prevent HIV appears as elusive as ever, as Johnson & Johnson’s Janssen unit recently reported failure to show effectiveness in clinical trials, adding to the list of disappointing efforts to block continued spread of this lethal disease (5).

These developments speak to the need to review research and regulatory approaches for testing, assessing, and marketing potential vaccines. FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) agreed on the value of a common bivalent anti-COVID shot for all patients that targets both the original COVID-19 strain and the Omicron subvariants.However, the expert panel was less certain about recommending annual vaccination against COVID-19 due to uncertainty about the continued effectiveness of the current shots and about what time during the year would be best for a national COVID-19 vaccination campaign (6).

Pfizer, Moderna, and Novavax reported to VRBPAC on efforts underway to produce reformulated bivalent vaccines and supported the plan for a common formulation for all manufacturers to simplify vaccination recommendations and reduce patient questions about the effectiveness and safety of vaccines from different manufacturers. The three firms also said that they are already studying combination shots for flu and COVID-19 and emphasized the need for specifics from FDA on the process for updating vaccine strains and the timing, process, and methodology for producing a data package for new licensure.

While the expert panel and officials from FDA and other health agencies acknowledged the value of utilizing mRNA platforms to produce anti-COVID vaccines so quickly and effectively at the start of the pandemic, some panel members called for further analysis of how well the new formulations provide long-term protection, avoid safety issues, and emphasized the need to assess whether more traditional vaccine production methods may have broader benefits moving forward. They urged additional research on the possible need for different vaccination schedules for both young children and older adults with health impairments.

In concluding the advisory committee meeting, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), reiterated the importance of a “data-driven approach” to achieve a vaccine regimen that is as simple as possible. But he also noted the value of monitoring vaccine safety and assessing product effectiveness in shifting to a next generation of COVID-19 vaccines able to provide “greater depth of protection.”

Despite these advances, criticism of FDA vaccination recommendations has escalated, generating vaccine hesitancy among broader population groups. A survey by the Kaiser Family Foundation in December 2022 found that one third of parents now oppose required vaccination of school-age children for measles and other infectious diseases (7).

Politics has driven vaccine hesitancy even more on the state level. Florida Governor Ron DeSantis made waves in December 2022 by disparaging vaccines and even charging vaccine makers for fraud in promoting their preventives—a strong about-face from a political leader who strongly supported vaccines during the Trump administration and sought millions to fund Florida’s vaccination campaign to combat COVID-19.

To bolster public confidence in decisions by FDA alongside federal and state health agencies, former FDA leaders from both sides of the aisle have joined FDA Commissioner Robert Califf in pressing for health professionals, disease advocates, and the academic community to ramp up efforts to counter such anti-vaccine fears and misinformation, much of it presented in online communications. There’s even talk of permitting manufacturers to directly address false or misleading information on their vaccines and medical products, provided that FDA permit firms to present clinical data and real-world experience on public platforms. Vaccine experts hope that a shift away from differing COVID-19 vaccine compositions and varying immunization schedules, along with clearer alignment between US and European vaccination recommendations, will generate wider support for preventing infection from old and new infectious diseases.

Moderna. Moderna Announces mRNA-1345, An Investigational Respiratory Syncytial Virus (Rsv) Vaccine, Has Met Primary Efficacy Endpoints in Phase 3 Trial in Older Adults. Press Release. Jan. 17, 2023.

Takeda. Takeda’s Biologics License Application (BLA) for Dengue Vaccine Candidate (TAK-003) Granted Priority Review by US Food and Drug Administration. Press Release. Nov. 22, 2022.

FDA. Coronavirus (COVID-19) Update: FDA Authorizes Emergency Use of Novavax COVID-19 Vaccine, Adjuvanted. Press Release. July 13, 2022.

Novavax. US Government and Novavax Extend Partnership, Securing Up to 1.5 million Additional Doses of Novavax’s COVID-19 Vaccine. Press Release.
Feb. 13, 2023.

Johnson & Johnson. Janssen and Global Partners to Discontinue Phase 3 Mosaico HIV Vaccine Clinical Trial. Press Release. Jan. 18, 2023.

Vaccines and Related Biological Products Advisory Committee Meeting, January 26, 2023. FDA Briefing Document. Future Vaccination Regimens Addressing COVID-19

. https://www.fda.gov/media/164699/download (accessed Feb. 16, 2023).

Lopes. L; Schumacher, S.; Sparks, G.; Presiado, M.; Hamel, L; Brodie, M. KFF COVID-29 Vaccine Monitor: December 2022. KFF.org. Dec. 16, 2022.


Vol. 47, No. 3
March 2023
Pages: 14–15

When referring to this article, please cite it as Wechsler. J. Vaccine Development Builds on COVID-19 Breakthroughs. 

Advances in vaccine development are creating partnerships and stimulating clinical trials to develop new mRNA applications.

Vaccine Development Builds on COVID-19 Breakthroughs

FDA should step up its oversight of institutional review boards (IRBs) to better assure the safety of participants in some 21,000 active clinical trials in the United States, according to the Government Accountability Office (GAO). 

examines the fairly limited scope of IRB inspections carried out each year by FDA and the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) and the resulting uncertainty created about clinical research activities.

FDA and OHRP oversee about 2300 US-based IRBs through routine or for-cause inspections that examine whether these boards appropriately review research protocols and programs to ensure adherence to federal rules and whether human subjects adequately understand study risks and benefits. A growing concern is that a small number of independent or single IRBs now review nearly 50% of investigational research in the US, up from 25% in 2012. The shift has been spurred by a National Institutes of Health (NIH) rule requiring the use of a single or central IRB to review multi-site funded studies to streamline and facilitate research review and operations. FDA also is considering how a single IRB requirement could apply to regulated research, despite concerns about the independence and integrity of commercial IRBs and whether they conduct hasty or inadequate reviews.

In this light, GAO questions whether FDA and OHRP inspect IRBs sufficiently to determine how well research sponsors and investigators follow federal regulations and ensure data integrity. OHRP conducts only three or four routine IRB inspections each year on the large number of IRBs based at hospitals and academic research organizations, while FDA completed nearly 1600 inspections on 1054 IRBs from 2010–2021, on average 133 inspections a year to reach 13% of IRBs that review research involving regulated drugs and medical devices.

But the analysts are unsure whether that volume of oversight is sufficient to accomplish stated objectives. The report notes that the agencies rely on inaccurate data on the number of protocols that IRBs review, making it difficult to identify those IRBs that monitor large numbers of research programs. An annual risk-based assessment of oversight objectives is needed, says GAO, as well as attention to the broader question of whether IRB reviews actually help protect human subjects.

To better address these issues, GAO advises FDA and HHS to bring together multiple stakeholders to identify best methods for evaluating IRB effectiveness and standards and to implement effectiveness measures for IRB operations. Similarly, FDA should conduct an annual risk assessment of whether IRBs are inspected frequently enough to help understand what volume of site inspections are needed to ensure appropriate program oversight, and what kinds of validated measures can further inform the issue. But GAO stepped back from setting a specific number of FDA IRB inspections each year to avoid undermining other agency inspection activities.

GAO calls for more oversight of institutional review boards in clinical trials.

IRBs Need More Monitoring 

Policymakers and biopharma companies acknowledge the importance of assessing drugs and medical products on a wide range of ethnic and racial populations to fully understand medical effects on patients. This has bolstered support for studies to enroll patients in proportion to the prevalence and burden of the disease in relevant subgroups, but achieving such equitable patient representation in clinical trials has been difficult and uneven, at best.

After years of FDA issuing guidance documents and launching programs to encourage sponsors to seek broader representation in clinical trials, policy makers have added a “stick” to the process: research sponsors now will be required to tackle this issue by submitting Diversity Action Plans (DAPs) to the agency when proposing and seeking approval of Phase III and pivotal studies. This provision was included in the 

, approved by Congress in December 2022 as part of the massive 

hat authorized federal spending for 2023.

Among a host of FDORA provisions, including those designed to modernize FDA’s accelerated approval program, bolster FDA inspections, and expand oversight of cosmetics, the legislation also requires DAPs that set specific enrollment goals for clinical trials of most drugs and certain medical devices under development. FDA has a year to issue guidance on the program, and there may be some waivers and exceptions, as for bioequivalence studies. But diversity plans will be required for most clinical development programs. FDA will hold a public workshop on the program, issue additional guidances on specific topics, and submit annual reports to Congress once the program gets going.

The need to mandate DAPs is supported by studies and analyses showing inadequate patient representation in many clinical trials. A 

 of demographic representation in 17 years of clinical trials (2002–2019), for example, paints an uneven picture of trial enrollment of various minority and ethnic groups and how that has varied among different drugs and treatment areas.

review of clinical trial demographic data 

from 495 clinical trials involving US-based participants. There was a greater proportion of Black/African American patients enrolled in trials for asthma drugs than that group’s share of patients for that condition. But a smaller percentage of Black/African American patients participated in studies for HIV drugs compared to the group’s high prevalence in that disease population. Very few Asian patients were included in studies for coronary heart disease, and only slightly more Hispanic patients. And all minority groups were underrepresented in vaccine trials.

analysis by the Government Accountability Office

 (GAO) issued in December 2022 found that certain population groups remain underrepresented in clinical trials despite years of efforts to improve research diversity. This analysis focused on cancer clinical trials and noted consistently low numbers for a range of patients, including those in certain racial and ethnic groups, adolescents and young adults, older adults, women, low-income individuals, and people from rural communities.

The report also described practices developed at certain cancer centers that helped advance diverse enrollment in research. These include assigning community ambassadors to increase awareness of clinical trials in a local area, better training and increased workforce diversity at centers to better explain clinical trial opportunities, and financial and logistical support to overcome barriers to patient participation in research programs.

in April 2022 on developing Race and Ethnicity Diversity Plans to further research enrollment of appropriate numbers of participants from underrepresented racial and ethnic populations, and that advisory may provide a basis for moving forward with final specifics on the now-required program. The guidance emphasizes the value of submitting diversity plans as part of initial investigational plans and later in market applications, noting successes and challenges.

In discussions on this and earlier FDA proposals on this topic, sponsors have queried the agency on specifics for applying diversity goals to global development programs and for assessing “adequate enrollment” of underrepresented populations. Another issue is whether diversity goals should apply to each individual study or to an overall development program. And sponsors particularly want to know more about how FDA will deal with research programs that fail to meet set goals for patient enrollment.

report issued by the National Academies of Sciences, Engineering and Medicine 

in May 2022 that assesses how the failure to include diverse populations in clinical studies leads to poor health and greater disabilities for populations not included in medical research. The expert panel proposed that FDA provide added incentives for sponsors to meet diversity goals in the form of tax credits, fast-track eligibility, reduced fees, and extended market exclusivity, similar to incentives provided firms developing orphan drugs. In addition, researchers could gain more leeway to reimburse minority study participants and to cover expenses for transportation, dependent care, and lost wages. Conversely, FDA might gain authority to refuse to file an application that fails to include appropriate patient representation.

After years of FDA issuing guidance documents and launching programs to encourage sponsors to seek broader representation in clinical trials, policy makers have added a “stick” to the process.