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

Jill Wechsler

In the face of a host of contentious and controversial policy decisions, President Biden appears poised to bring in an experienced and well-regarded hand to lead FDA. The agency has lacked a permanent leader for more than eight months, as the White House has been unable to identify a new commissioner acceptable to politicians and interest groups on all sides.

So as the clock has ticked down on the Nov. 15 deadline for Janet Woodcock to vacate her acting commissioner role, potentially forcing Biden to appoint another acting commissioner, word is out that the White House will name cardiologist and research pro Robert Califf to the top job, a position he held for almost a year at the end of the Obama administration.

Califf’s appointment will bring much-needed stability to FDA as it contends with a host of difficult policy decisions involving vaccines, new anti-COVID therapeutics, access to e-cigarettes, accelerated approval programs, and budget priorities. Califf may face opposition in the Senate, as partisan politics has come to the fore on all sides. Although he wins plaudits for his experience in medical research and his familiarity with FDA operations and requirements, some consumer advocates and liberals criticize his close ties to industry and pro-development attitude. He will need support from Republicans, which may be more tenuous in today’s hotly divisive climate on Capitol Hill.

Another factor driving the FDA nomination is the recent announcement of retirement plans by Francis Collins, long-time director of the National Institutes of Health (NIH). Biden will want to name a new leader for NIH before the end of the year, and that provides an opening to bring a woman scientist into the administration’s health and science leadership cadre.

Hopefully, the politicians will recognize the importance of experienced leadership for the nation’s leading health agencies and put aside partisan politics to agree on a new FDA commissioner, and then a new leader at NIH. FDA has been well-served by acting commissioner Woodcock, but her tenuous position has exposed her to criticism and second-guessing on all sides. With a global pandemic still raging, a seasoned hand is needed to stabilize FDA’s exhausted workforce, ensure funding continuity, and steer debate and decisions on many difficult scientific and policy issues.

Articles

After months of deliberation, Biden plans to appoint cardiologist Robert Califf as FDA commissioner.

Can Califf Bring Clarity and Enhanced Credibility to FDA?

In an important step for modernizing drug formulation and biopharmaceutical development, FDA is launching a program to test the safety and suitability of novel excipients for use in new drugs and biologics. This final initiative, first proposed two years ago, will support a pilot program to test up to four novel excipients likely to improve the effectiveness and safety of important new drugs (1). The aim is to encourage sponsors of clinical trials to test new drugs formulated with excipients that FDA finds acceptable for use under this program.

FDA announced the pilot program Sept. 7, 2021, and spelled out the application process in a Federal Register notice (2). The notice explains that the pilot is open to novel excipients that have not been used previously in food or in FDA-approved products. Excipient manufacturers seeking to participate in the pilot should submit information on the novel inactive ingredient and its potential for enhancing health by offering pharmacokinetic characteristics important to developing new drugs, as described in an outline for an initial proposal (3). The sponsor also must show it can produce a complete information package in the set time frame for weighing pilot proposals. Initial pilot review proposals are due at FDA by Dec. 7, 2021.

FDA defines a novel excipient as an inactive ingredient that is not fully supported by existing safety data related to a proposed level of exposure, duration of exposure, or route of administration. Manufacturers should describe how the product addresses a public health need and advances drug development, such as by increasing solubility for an oral formulation taken chronically. Sponsors also, should describe available quality and toxicology information that support the product’s safety, such as pharmacokinetic/toxicokinetic data and other nonclinical information, as presented in FDA guidance issued in 2005 (4).

From these submissions, FDA will select four products for full review under the pilot, planning for two during the first year. Selected participants then should provide a full data package of toxicology and chemistry, manufacturing, and controls (CMC) quality data, as required for excipients. If the excipient passes muster, FDA will determine that it may be used in the formulation for an experimental drug undergoing clinical trials, provided that the sponsor demonstrates that it is safe to use in that therapy. After FDA approves a new drug or biologic utilizing the new excipient, that excipient would then be added to FDA’s Inactive Ingredient Database, making it available for use by other manufacturers, including those producing generic drugs.

Manufacturers of drugs and biologics, as well as excipient developers, have long sought a process for FDA to evaluate new inactive ingredients prior to use in a new drug or biologic. A perennial difficulty is that new drug sponsors are reluctant to delay or complicate FDA review and approval of an investigational new drug (IND) for an experimental therapy due to the need to assess an untried inactive ingredient in the product formulation. Yet, these firms increasingly face difficulties in formulating innovative products with available, established excipients. Biopharma companies have expressed support for the pilot as a way to address these development challenges, such as the need for new ways to stabilize proteins for bioavalability in new formulations. Excipient makers similarly acknowledge that they would be more willing to invest in production, controls, and characterization of novel excipients if it’s possible to gain FDA review of the product’s benefits outside of clinical testing for a new molecular entity.

FDA first proposed this process for evaluating novel excipients separate from new drug applications in a Federal Register notice posted in December 2019 (5). That draft plan asked manufacturers to comment on the proposed program, its definitions and scope, and FDA sought to address these issues in this final proposal.

It appears fitting that FDA is launching this novel excipients pilot program as the International Pharmaceutical Excipients Council, IPEC-Americas, marks its 30th anniversary. IPEC held its first meeting in March 1991, with the aim of harmonizing excipient standards set by different pharmacopeias and to address worldwide issues important to excipient use. Manufacturers of these essential ingredients in pharmaceutical formulations note that many well-known excipients that have been used for decades are not suited to the novel dosage forms and parenterals under development today (6). Industry also would like to see an update of FDA’s 2005 guidance on excipient safety testing, mentioned previously. These initiatives, as well as ongoing efforts to set international standards for excipient use, have potential to enhance drug formulation and support modern manufacturing and quality control efforts.

Novel Excipient Review Pilot Program, FDA.gov

Center for Drug Evaluation and Research Office of New Drugs Novel Excipient Review Pilot Program

Novel Excipient Review Pilot Program Initial Proposal Model Content Online, FDA.gov.

Guidance for Industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients

Novel Excipient Review Program Proposal; Request for Information and Comments

, Federal Register, 84 FR 66669, Dec. 5, 2019.

Jill Wechsler is Pharmaceutical Technology’s Washington editor, 


Volume 45, Number 10
October 2021
Pages: 14–15

When referring to this article, please cite it as J. Wechsler, “FDA Moves to Advance Innovative Excipients

A new program will test the safety and suitability of new inactive ingredients to encourage the accelerated adoption of FDA-accepted excipients in drug development.

FDA Moves to Advance Innovative Excipients

Demand for more efficient and faster development of medical products is prompting regulatory authorities to incorporate additional sources of information into the research and approval processes, notably data provided by patient registries and medical records able to inform traditional clinical trials. FDA and the European Medicines Agency (EMA) are looking to tap real-world data (RWD) and real-world evidence (RWE) more broadly to accelerate the research and market approval process.

A notable advance was FDA’s recent reliance on RWE to approve an added indication for an important medicine. In July 2021, 

the agency extended the use of Astella’s liver transplant drug, Prograf, to also prevent the rejection of lung transplants

, which was based on data from a US registry of lung transplant recipients. FDA determined that this non-interventional “study” with historical controls met FDA standards for being adequate and well-controlled and precluded bias as an explanation of results, explained John Concato, associate director for RWE analytics in the Office of Medical Policy at the Center for Drug Evaluation and Research. Concato also described at the Sept. 13 & 14, 2021, Convergence meeting sponsored by the Regulatory Affairs Professionals (RAPS) how FDA demonstration projects are advancing the use of RWD/RWE in different types of studies.

 advises sponsors on strategies for accessing RWD from electronic health records (EHRs) and medical claims to help demonstrate the safety and effectiveness of a drug or biological product to support regulatory decisions. While such records are used to track medical product safety and to support additional uses and post-approval study requirements, the diversity and limitations of this information have stymied broader adoption for documenting drug effectiveness. Now, FDA is asking biopharmaceutical developers to weigh in on strategies utilizing RWD to support regulatory decisions and to help define treatment exposure, outcomes, data quality assurance, and data quality control procedures.

The potential for wider use of RWD and RWE in drug development has moved up on FDA’s agenda since it was featured in the 21st Century Cures Act of 2016 to support the approval of new indications for a drug and for meeting post-approval study requirements. 

FDA published a framework for wider evaluation of RWE in regulatory decision making in 2018

guidances on using data from EHRs in submissions and on submitting RWD and RWE in applications

. The agency also expanded its Sentinel surveillance system to help assess how health system data can inform research projects. FDA efforts to streamline clinical research during the pandemic have highlighted the potential for wider use of RWE to inform research protocols, identify research subjects, and track outcomes and responses remotely. Upcoming revisions in the Prescription Drug User Fee program (PDUFA VII) further expand the use of RWE in these and other initiatives.

Similarly, EMA looks to make wider use of RWE in regulatory submissions. At the recent RAPS meeting, EMA director of surveillance and epidemiology, Xavier Kurz, described a new study on the issue, noting the frequent use of information from disease registries and hospital records, while also acknowledging limitations in the data and confusion over terminology and methods.

Concato and other FDA officials have addressed these developments at numerous meetings and conferences this past year. At a July 2021 symposium on how RWE is changing scientific standards, experts also noted the limitations and need for caution in interpreting studies utilizing RWE. Long-time RWD skeptic, Steven Nissen of the Cleveland Clinic, warned that RWE is a “dangerous delusion” and should not be viewed as providing “conclusive evidence” on a treatment—citing the failure of early claims of cardiovascular benefits to women of hormone replacement therapy. He argued that wider use of RWE largely aims to save money on clinical development and that a better strategy is to find more efficient ways to conduct randomized trials.

Most experts, however, look to more advanced data analytical methods to validate data in this area. The rising demand for highly personalized therapies to treat very small patient populations, such as for rare conditions and neonatal populations, makes it vital to devise methods for the accurate assessment of RWE. In addition, efforts to include more data on patient minorities and other sub-populations in biomedical research look to tap RWD to make research more inclusive and representative.

FDA and EMA are looking to tap real-world data and real-world evidence more broadly to accelerate the research and market approval process.

FDA to Rely on Real World Data and Evidence for Future Research and Market Approvals

Despite the agency’s remarkable success in speeding vital new vaccines and therapies to patients to combat the COVID-19 pandemic, while also continuing to advise on and approve a broad range of vital medicines, FDA officials have been under attack. The regulators either are acting too fast and risking public safety or too slow, mired in rules while ignoring important scientific findings.

A main difficulty is that the agency has lacked a confirmed leader for the past 10 months, making it difficult to set priorities and explain actions within the Biden administration and to the public and policymakers. As acting commissioner, Janet Woodcock has maintained a steady hand on this diverse agency that oversees a vast range of products vital to public health. In addition to vaccines and new drugs, FDA has been in the spotlight recently over its efforts to limit marketing of e-cigarettes to halt the dangerous vaping epidemic among young people. The agency is responsible for assuring the safety of much of the nation’s food supply, veterinary medicines, and dietary supplements. Plus, its regulation of cannabis products and cosmetics is under debate. FDA’s oversight of medical devices and diagnostics has put it in the hot seat for shortages of critical products for protecting medical personnel and for providing fast and accurate public testing for COVID infection. And there’s the continuing wave of false claims about popular treatments to combat the pandemic, some dangerous and most ineffective.

Earlier in the year, it looked likely that Woodcock would become FDA’s permanent commissioner, but that was sidelined by some Democrats and public health officials upset by the agency’s earlier approval of what turned out to be deadly opioid pain killers that are easily abused. As the long-time head of drug development and approval at the Center for Drug Evaluation and Research (CDER), Woodcock also was accused of working too closely with biopharma companies in accelerating the development and marketing of important new therapies, some turning out to have limited long-term benefits and many posting high price tags. Although patient advocates and research groups have championed Woodcock for providing strong leadership in shifting FDA away from a more risk-averse stance, that approach has been challenged. The result is that the White House has delayed in selecting an FDA commissioner, even though federal rules require Woodcock to vacate her acting position by mid-November unless the administration nominates a new commissioner, permitting her to continue on during the Senate confirmation process.

The situation has hampered FDA in articulating future priorities and pushing back against miscommunications and outside complaints. The recent debate over approval of booster shots for anti-COVID vaccines is a case in point, with FDA compelled to manage President Biden’s promise to provide third shots by late September amidst highly publicized internal agency dissension on the issue. Leading FDA vaccine officials contended that the agency was ignoring the scientific evidence in authorizing booster shots and that such a policy was inappropriate when initial vaccines were desperately needed by much of the Third World.

That dispute over vaccines followed an even more blistering debate over FDA approval of a costly new treatment for Alzheimer’s disease, Biogen’s Aduhelm, based on questionable and very limited clinical evidence. The approval decision by CDER officials was blasted by members of Congress, the medical community and even some patient groups, but justified by the reviewers as likely to provide some benefit to some patients who lacked any alternative treatment for this devastating disease. Continued charges of FDA officials caving to industry pressures, though, prompted Woodcock to seek an independent review of the approval process for the drug from the Health and Human Services (HHS) Inspector General.

These developments have generated media reports on tumult and dissension at FDA and continued criticism about the agency putting industry interests above the needs of public health. The Aduhelm decision was blamed for undermining FDA’s “gold standard” for ensuring drug safety and efficacy and linked to the agency’s dependence on industry-paid user fees for shifting the balance away from careful oversight and toward too-speedy approvals.

Such charges gain support from several departures of long-term agency. Most visible was the recent announcement of retirement by top vaccine approval officials, Marion Gruber and Phillip Krause, director and deputy director of the Office of Vaccine Research & Review (OVRR) in the Center for Biologics Evaluation and Research (CBER). At the same time, many leading staffers who have been at FDA for decades have announced retirement plans, such as Theresa Toigo, CDER associate director for drug safety operations.More departures are expected, as many FDA officials past retirement age are exhausted from the pressures of the past year and now seek to move on after postponing their departures during the height of the public health emergency. Public scorn for the agency’s efforts to evaluate reams of data as fast as possible has tipped the balance in favor of leaving the public spotlight.

Meanwhile, agency veteran Woodcock has worked with her staff to keep review and regulatory decisions on track. Industry leaders have supported her for the top job but went quiet as the administration signaled that would not occur. Woodcock opened the recent annual “Convergence” conference sponsored by the Regulatory Affairs Professionals Society (RAPS) by citing FDA’s efforts to ensure access to needed diagnostics, vaccines, and therapeutics during the health emergency, and in meeting the challenges in conducting clinical trials, inspecting drug and food facilities, and issuing “reams of guidances” to facilitate emergency use authorizations for vital vaccines, drugs and diagnostics, while also keeping up with the usual volume of premarket reviews of innovative products.

Woodcock concluded by expressing hope that these efforts in dealing with the pandemic will create “at least among some people” a “renewed appreciation for the importance of science, technology, and data.” She said she looks forward to a greater understanding of the “essential role [played] by the FDA and other public health agencies” in responding to this crisis and in protecting and promoting public health.

The lack of a new permanent commissioner has hampered FDA in articulating future priorities and pushing back against miscommunications and outside complaints.

FDA Caught in the Political Crossfire

The stars finally may be aligned for Americans to gain greater access to alternative biotech therapies in the coming months. FDA recently approved important new biosimilars for market, updated guidance on follow-on development, and reached agreement with industry on an agenda for advancing biosimilar testing and production over the next five years. Of note will be 

o treat macular degeneration, providing an important alternative for patients experiencing serious vision impairment from this and related eye diseases. That advance follows 

of the first interchangeable biologic, a new treatment for diabetes that can be substituted for widely used Lantus insulin glargine.

The development of additional innovative follow-ons should gain from an FDA final guidance that updates recommendations for testing and documenting product similarity and interchangeability. The advisory 

 such as demonstrating similar strengths of injectable biosimilars, pediatric assessments, postapproval manufacturing changes, dealing with indications covered by exclusivity, and the need for biosimilars to have similar routes of administration, dosage form, and strength to a reference product.

These advances will be augmented by the proposal for advancing biosimilar development and approval under the third iteration of the Biosimilar User Fee Act (BsUFA III). FDA recently released the agreement with manufacturers for a revised and expanded BsUFA program as spelled out in a 36-page “

”. In posting the letter Sept. 21, 2021, FDA provided industry and interested parties with time to prepare comments and questions on this regulatory program for a 

public meeting to be held on Nov. 2, 2021 

via webcast. Information on these developments and on the process involved in ensuring reauthorization of the BsUFA program for 2023-2027 before it expires in a year can be found at 

The BsUFA III commitment letter describes a range of initiatives to facilitate the testing and oversight of biosimilar development, notably by issuing additional guidance plus findings from FDA scientific studies to advance interchangeable products. The program clarifies timelines for agency review of biosimilar applications and updates review goals for supplements, which vary based on the need to consider new clinical data. FDA authorizes additional meetings with sponsors during product development to address specific questions and gain timely clarification of agency requirements. And 

 sets timeframes for pre-approval inspections where needed and for electronic data submissions comparable to those provided in the updated user fee program for drugs and biologics (PDUFA VII) [see outline of BsUFA III goals letter from the Association for Accessible Medicine .

While these milestones are encouraging, the road ahead to widespread use of biosimilars remains uncertain. Physicians and patients in the United States continue to show reluctance in switching from brands to new alternatives, and insurers and formularies remain uneven in coverage and reimbursement practices. Although FDA has approved 31 biosimilars, only about 60% have come to market, as lengthy patent and exclusivity disputes delay the process. FDA’s July 30, 2021 approval of Mylan’s diabetes drug Semglee as interchangeable to Sanofi’s Lantus and eligible for substitution at the pharmacy should make it easier for patients to switch, even if initial savings are modest. That approval marks an important advance, opening the door to more widespread acceptance of follow-on biologics and potential cost savings for consumers.

Biosimilar approvals and the advance of biosimilar testing and production may lead to greater access to alternative therapies.

Biosimilars Gain Traction with Regulators and Manufacturers

If the debate has been heated over vaccines for adults and on the need for extra booster shots, FDA and its expert advisors will face even more scrutiny over the safety and value of vaccinating children under age 12. This population generally has had much lower COVID-19 infection rates than adults, but hospitalizations now have increased dramatically with the spread of the Delta variant, plus the return to school and other activities. The rise in pediatric COVID cases has alarmed the medical community, yet widespread vaccine hesitancy among many parents will make it critical to present strong safety results to gain broad protection for children.

The issue has moved to center stage as Pfizer-BioNTech announced plans to seek FDA approval this month of a smaller dose of its Comirnaty vaccine for children ages 5–11, as well as similar approval from the European Medicines Agency and other regulatory authorities. As Pfizer did in expanding use of its vaccine to younger adolescents, the 

company will file an Emergency Use Authorization

 (EUA) application with FDA, based on results from a Phase II/III study of a two-dose regimen on more than 4000 participants aged 6 months to 11 years [see ]. The study shows, according to Pfizer, that a lower 10-microgram shot for the 5–11 age group, one-third the dose for adults and adolescents, provides a sufficiently robust neutralizing antibody response, while also supporting safety and tolerability in these young subjects.

The clinical trial also enrolled similar numbers of younger children ages 6 months to 5 years and hopes to provide topline readouts for this group by year-end. Children under age 5 received a lower 3 microgram dose for each of two injections, and results will be evaluated for two age cohorts, children 2–5 years of age and those 6 months to 2 years old.

This initial Pfizer-BioNTech statement did not present specific study data, but the sponsor said it will submit its research results for publication in a scientific peer-reviewed journal, while also preparing its filing for FDA. The announcement specified that clinical trials in multiple regions enrolled 2268 children ages 5–11, with one-third receiving placebo. However, due to the generally lower infection rate among youngsters, there were too few numbers of ill participants to determine higher protection from the vaccine vs. placebo; that conclusion is based on a comparison of higher immune response levels in vaccinated vs. unvaccinated study participants.

The sponsor also notes that the lower dose for children can be linked to fewer side effects. In an early study that administered higher doses to young participants, adverse events were higher, although still comparable to older patients. But those children who received the lower dose experienced fewer incidences of fever, headache, and fatigue, while also showing a strong antibody response. Even after increasing the size of the pediatric trial at FDA’s request, Pfizer found no cases of heart inflammation or other serious side effects that have occurred after vaccination with some older individuals, although the sponsors continue to monitor study participants for ongoing effects.

FDA staff will review the Pfizer data closely following its submission and is expected to ask its Vaccine and Related Biological Products Advisory Committee to weigh the results and make recommendations. If approved, the Advisory Committee on Immunization Policy at the Centers for Disease Control and Prevention then will propose a specific vaccination schedule.

In response to earlier pressure from some quarters for FDA to quickly authorize preventives for younger children, agency leaders explained the need for very careful scientific evaluation to ensure that any vaccines for children are safe, as well as effective. FDA Acting Commissioner Janet Woodcock and Peter Marks, director of the Center for Biologics Evaluation and Research, penned a statement in early September emphasizing that FDA “will follow the science” to fully assess the safety of current vaccines. Woodcock and Marks also 

warned parents not to pressure pediatricians 

to provide their children with a vaccine approved for adults and adolescents:as far as vaccines go, children are not just young adults.

Pfizer-BioNTech announced plans to seek FDA approval this month of a smaller dose of its Comirnaty vaccine for children ages 5–11.