Journal of the Pediatric Infectious Diseases Society

SUPPLEMENT ARTICLE

Understanding the Regulatory Pathways Used to Develop,

Evaluate, Authorize, and Approve New Drugs and Vaccines
in the United States
Joseph B. Domachowske
Department of Pediatrics, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in
the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The
regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across
six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER) are the primary focus of this review.
Key words. CBER; CDER; FDA approval process; phases of clinical trials; vaccine development.

INTRODUCTION product, beginning with the submission of a “new drug applica-

The United States (U.S.) Food and Drug Administration (FDA) tion” has since undergone a series of updates and amendments
has had regulatory oversight over the safety, effectiveness, and but, even today, remains consistent with the 1938 regulations
quality of drugs used in the United States since the passage of the as originally outlined. The Drug Amendments Act of 1962 re-
1906 Pure Food and Drugs Act [1]. Administration of the FDA quired manufacturers to include evidence that the drug being
falls under the jurisdiction of the U.S. Department of Health evaluated was both safe and effective [3]. Then, in 1966, the
and Human Services (HHS). Currently, the roles and respon- agency reorganized to include the Office of New Drugs, which
sibilities of the FDA are divided across six main centers (Table included teams specifically dedicated to reviewing new applica-
1). The activities of two of these centers, the Center for Drug tions and the clinical testing of investigational drugs. Up to the
Evaluation and Research (CDER) and the Center for Biologics early 1980s, most available medical biologics were vaccines, and
Evaluation and Research (CBER) are the primary focus of this therefore used for disease prevention. By 1982, early advances
review. in biotechnology saw the emergence of therapeutic (rather
The 1938 Federal Food, Drug, and Cosmetic Act required than preventative) biologics, making it increasingly difficult to
that all new drugs be tested before marketing [2]. The legislation clearly distinguish between agents best classified as biologics
tightened regulatory controls over drugs and food and included and those best classified as drugs. To address these advances,
new consumer protection against unlawful, (often dangerous) the FDA’s Bureau of Drugs was merged with the FDA’s Bureau of
distribution of elixirs, cosmetics, and purported medical de- Biologics to form the National Center for Drugs and Biologics
vices. The Act also strengthened the government’s ability to [4]. Roles and responsibilities were again subdivided in 1987,
enforce the laws related to the sale and distribution of drugs. resulting in the formation of the Center for Drug Evaluation
For the first time, manufacturers and other stakeholders inter- and Research (CDER) and the Center for Biologics Evaluation
ested in evaluating new drugs for use in humans were required and Research (CBER) [5]. In 2002, the FDA transferred over-
to obtain FDA approval to do so. The year after the 1938 Federal sight of most biologic agents not considered to be vaccines from
Food, Drug, and Cosmetic Act was passed, the Drug Division of CBER to CDER, including most therapeutic proteins, immune
the FDA received more than 1000 applications for review. The modulators, growth factors, products designed to alter hemat-
process of gaining FDA approval to market a new medicinal opoiesis, and monoclonal antibodies. Those groups of products
that remain under the purview of CBER are shown in Table 2.
Representative examples and characteristics of biologic prod-
Received 8 February 2024; editorial decision 9 April 2024; accepted 15 April 2024 ucts and product categories, and the FDA agency assigned to
Corresponding Author: Joseph B. Domachowske, MD, E-mail: domachoj@upstate.edu.
their oversight, are shown in Table 3.
Journal of the Pediatric Infectious Diseases Society   2024;13(S2):S93–S102
© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the
Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact
Center for Drug Evaluation and Research
reprints@oup.com for reprints and translation rights for reprints. All other permissions can be Today, CDER remains the division of the U.S. FDA that regu-
obtained through our RightsLink service via the Permissions link on the article page on our
site—for further information please contact journals.permissions@oup.com.
lates the safety and use of most drugs as defined in the Food,
https://doi.org/10.1093/jpids/piae036 Drug, and Cosmetic Act. Some biological products are also

The US Drug and Vaccine Approval Process • JPIDS 2024:13 (Suppl 2) • S93
Table 1. The Six Main Centers of the U.S. Food and Drug Administration [7–9]. Phase I clinical trials evaluate a drug’s performance and
determine its maximum safe dose in a small number of healthy
Center for Drug Evaluation and Research (CDER)*
Center for Biologics Evaluation and Research (CBER)*
volunteers. Phase II trials are the first to include subjects with
Center for Devices and Radiological Health the condition the investigational agent is intended to treat. The
Center for Food Safety and Applied Nutrition evaluation of safety remains the priority while preliminary data
Center for Tobacco Products are also captured to evaluate efficacy/effectiveness trends. Phase
Center for Veterinary Medicine
III drug trials are designed to evaluate whether the drug is ef-
*Primary focus of this review.
fective in treating the condition of interest. For drugs that dem-
onstrate safety and efficacy through phase III clinical trials, a
legally considered drugs so they are (or historically were) comprehensive data package that includes results from preclin-
covered by the Center for Biologics Evaluation and Research ical studies and all clinical phases of evaluation are compiled

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

(CBER). CDER reviews applications for brand name, generic, and submitted to the FDA as a New Drug Application. If the
and over-the-counter (OTC) pharmaceuticals, manages U.S. drug is approved, stage IV trials may be conducted after mar-
Good Manufacturing Practice regulations for pharmaceutical keting to ensure there are no adverse effects or long-term ef-
production, evaluates for the presence of impurities in drug fects of the drug that were not identified during the prelicensure
substances, monitors advertising of approved medications, col- phase.
lects, and analyzes safety data about pharmaceuticals already In parallel with the efforts at CDER, the FDA’s Center for
FDA approved and in use, determines which medications re- Biologics Evaluation and Research (CBER) ensures that the
quire a medical prescription, and which are available directly FDA’s rigorous scientific and regulatory processes are followed
for consumers to purchase OTC. Its primary objective is to by those who pursue the development of vaccines. Broadly de-
ensure that all prescription and OTC medications are safe and fined, vaccines are biologic products that are given to patients
effective when used as directed. CDER’s Office of New Drugs with the goal to prevent infection by triggering a protective
is responsible for reviewing proposed clinical trial designs and immune response in the recipient [10]. As mentioned previ-
providing recommendations on the safety and effectiveness ously, the FDA transferred oversight responsibilities for sev-
monitoring and endpoints of clinical trials and for the evalua- eral non-vaccine biologic product categories from CBER to
tion of all new drug applications [6]. The Office of New Drugs is CDER in 2002. As such, for evaluation and oversight purposes,
divided into several departments based on the indication of the the FDA considers therapeutic proteins, most immune modu-
drug being evaluated. lators, growth factors, products designed to alter hematopoi-
esis, and monoclonal antibodies as drugs (not biologics) since
The Regulatory Path of an Investigational Drug most of the products included in these categories are used as
A four-phased series of human clinical trials to evaluate in- therapeutics. Vaccines (CBER) are biologics designed to pre-
vestigational drugs for safety and efficacy is generally accepted vent disease, while drugs (CDER) are chemicals or therapeutic
biologics designed to treat an existing condition. Using these
basic definitions, it’s straightforward to determine whether
Table 2. Biologics and Related Products Under the Oversight of CBER most products fall under the oversight of CDER or CBER
(Table 3). Monoclonal antibodies are the exception. While most
Blood and related products or devices
 Blood and blood components
monoclonal antibodies that are currently available for clinical
 Plasma and plasma derivatives use are designed to treat medical conditions, some of the most
  Immunoglobulins (but not monoclonal antibodies) recently approved monoclonal antibodies are designed to pre-
  
Hyperimmune products vent infection in the recipient by providing pathogen-specific,
  Antitoxins
passive immunity (eg, respiratory syncytial virus [RSV], severe
 Certain anticoagulants
acute respiratory syndrome coronavirus 2 [SARS-CoV-2]).
 Plasma volume expanders
 Reagents used for blood typing Despite this distinction, all monoclonal antibodies fall under
 Assays used to screen blood donations the oversight of CDER whether they are intended for use as
 Equipment used during blood donations therapeutics or for passive prevention of infection. For example,
 Blood bank instruments and computer software the clinical development oversight and evaluation of the mon-
Human cells, tissues, and cell-based products
oclonal antibody, nirsevimab was the responsibility of CDER
Xenotransplantation
Therapeutic and diagnostic allergenic extracts
even though its intended use is for the universal prevention of
Live biotherapeutics RSV infection in the infant population. Universal (passive) im-
Certain medical devices munization of all infants with a monoclonal antibody to prevent
 Diagnostic test kits for HIV a very common infection is a new and unique approach that
Vaccines for use in humans appears to blur the established distinction between drugs and

S94 • JPIDS 2024:13 (Suppl 2) • Domachowske

Table 3. Examples and Characteristics of Biologic Products Under the Oversight of the FDA’s CDER and CBER

Example of Condition FDA Oversight

Product Category Treated or Prevented CDER CBER

Insulin Therapeutic protein Diabetes ✔

Interferon γ Immune modulator Chronic granulomatous disease ✔
Human growth hormone Growth factor Growth hormone deficiency ✔
Granulocyte stimulating factor Alters hematopoiesis Chemotherapy-induced neutropenia ✔
Infliximab mAb to TNF-α Crohn disease ✔
Eculizamab mAb to C5 Paroxysmal nocturnal hemoglobinuria ✔
Cilgavimab mAb to SARS-CoV-2 spike protein COVID-19 ✔

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

Nirsevimab mAb to RSV prefusion F protein RSV ✔
RSV prefusion F protein Protein subunit vaccine RSV ✔
SARS-CoV-2 Spike mRNA mRNA vaccine COVID-19 ✔
Measles Edmonston-Enders strain Live attenuated vaccine Measles ✔
Hepatitis B surface antigen Recombinant vaccine Hepatitis B ✔
C5, complement component; COVID-19, coronavirus disease 2019; mAb, monoclonal antibody; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus
2; TNF-α, tumor necrosis factor-alpha.

therapeutic monoclonal antibodies regulated by CDER and the CBER to CDER [11]. At present CBER continues to have ju-
vaccines and biologics that are regulated by CBER. For now, all risdiction over human blood and blood-related products, sera
monoclonal antibodies (including nirsevimab) remain under used for allergic desensitization, live biotherapeutics (eg, pro-
the purview of CDER and its advisory committees. biotics, fecal microbiota transplantation), human cells and tis-
sues, diagnostic assays for HIV, devices used to transfuse/infuse
Center for Biologics Evaluation and Research blood and blood products, and vaccines (Table 2). As noted,
CBER was not originally part of the U.S. FDA. Instead, it began all monoclonal antibodies, whether intended for use as thera-
as one of several federal public health agencies that would even- peutics or for disease prevention, remain under the jurisdiction
tually merge to form the National Institutes of Health. From the of CDER.
beginning, its mission included a mandate to foster the devel-
opment of new vaccines. In 1972, CBER came under the juris- Advisory Committees to the FDA
diction of the FDA and was renamed the Bureau of Biologics. Federal laws and policies of the Department of Homeland
As part of this organizational restructuring, the agency retained Security outline the requirements for the CDER and the CBER
oversight of vaccines and gained an expanded regulatory role to establish and maintain advisory committees [12, 13]. The
that included blood products and allergy desensitization sera. size, purview, and designated responsibilities of these advi-
A decade later, as the biotechnology revolution took off and sory committees continue to grow, necessitating the formation
the distinction between a drug and a biologic became less clear, of subgroups, or panels of individuals, who together, have the
the Bureau of Biologics was merged with the FDA’s Bureau of multidisciplinary expertise to provide authoritative and com-
Drugs, to form the Center for Drugs and Biologics, although prehensive advice on questions posed to them about drugs and
the leaders from the two merged sections were charged with biologics under their review by their respective committees.
enforcing different public health laws and did so with philo- Each of the current technical and scientific advisory com-
sophical differences. In the early 1980s, CBER was declared the mittees and panels includes both scientific experts and mem-
primary agency for HIV/AIDS-related products, since blood bers of the public (Table 4). Applicants for available positions
products were already under their purview and a substantial on the advisory committee are selected based on their expertise
number of cases of HIV had been transmitted via the transfusion to meet the anticipated needs of the group [14]. FDA Advisory
of various blood products. Then, in 1987, the Center for Drugs committees typically include representation from most or all of
and Biologics was formally split into CBER and the CDER the following groups: physicians, physician-scientists, experts
under the leadership of FDA Commissioner Frank Young, the in biostatistics, biomedical engineers, physical chemists, bio-
organizational format that still exists today. The next substan- chemists, biologists, a consumer and/or patient representative,
tial shift in oversight responsibilities occurred in 2002 when the and a representative from industry.
FDA transferred regulatory responsibilities for certain biologic The primary role of an FDA advisory committee is to
products that were manufactured and used as therapeutics from provide independent, outside, expert advice on drugs and

The US Drug and Vaccine Approval Process • JPIDS 2024:13 (Suppl 2) • S95
Table 4. Current Advisory Committees to the Food and Drug Administration The Antimicrobial Drugs Advisory Committee
The Antimicrobial Drugs Advisory Committee (ADAC), (for-
Allergenic Products Advisory Committee
merly known as the Anti-Infective Drugs Advisory Committee)
Anesthetic and Analgesic Drug Products Advisory Committee
Antimicrobial Drugs Advisory Committee* is one of the largest and busiest advisory committees under
 Antiviral Drugs Advisory Committee CDER [15]. The group is responsible for reviewing data on
 Arthritis Advisory Committee the safety and efficacy/effectiveness of both marketed and in-
 Blood Products Advisory Committee vestigational human drug products that target infections. The
 Cardiovascular and Renal Drugs Advisory Committee
Committee is comprised of 13 voting members who are selected
 Cellular, Tissue, and Gene Therapies Advisory Committee
 Dermatologic and Ophthalmic Drugs Advisory Committee
by the FDA Commissioner or designee. The selected voting
 Device Good Manufacturing Practice Advisory Committee members may include one individual with consumer interests
 Digital Health Advisory Committee who is recommended by consumer stakeholder groups. A non-

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

 Drug Safety and Risk Management Advisory Committee voting member representing industry interests may be included
 Endocrinologic and Metabolic Drugs Advisory Committee at the discretion of the Commissioner [15]. Since nirsevimab
 Food Advisory Committee
is a monoclonal antibody, its clinical development evaluations,
 Gastrointestinal Drugs Advisory Committee
 Genetic Metabolic Diseases Advisory Committee
discussions, and regulatory approval disposition were the re-
 Medical Imaging Drugs Advisory Committee sponsibility of CDER. ADAC was the independent advisory
 Nonprescription Drugs Advisory Committee committee charged with reviewing the New Drug Application
 Obstetrics, Reproductive and Urologic Drugs Advisory Committee and advising CDER on its approval [16]. Of note, palivizumab
 Oncologic Drugs Advisory Committee
was evaluated and approved by the FDA in 1998 when mono-
 Patient Engagement Advisory Committee
clonal antibodies were still under the purview of CBER.
 Pediatric Advisory Committee
 Peripheral and Central Nervous System Drugs Advisory Committee
 Pharmaceutical Science and Clinical Pharmacology Advisory Committee The Regulatory Path of an Investigational Vaccine
 Pharmacy Compounding Advisory Committee The regulatory pathway for investigational vaccines (CBER)
 Psychopharmacologic Drugs Advisory Committee closely parallels those required for new drug candidates
 Pulmonary-Allergy Drugs Advisory Committee (CDER). Before a vaccine can be studied for safety and efficacy
 Medical Devices Advisory Committee
in humans, a series of tests must first be completed in vitro and
 National Mammography Quality Assurance Advisory Committee
 Risk Communication Advisory Committee
in animals. These preclinical efforts help to predict which inves-
 Technical Electronic Product Radiation Safety Standards Committee tigational products are likely to be safe and might work in hu-
 Tobacco Products Scientific Advisory Committee mans [17]. To move from preclinical efforts to human trials, the
 Toxicological Research, Science Advisory Board to the National Center for sponsor must submit an Investigational New Drug application
Toxicological Research
(IND) to the FDA [18]. The application includes results from
 Transmissible Spongiform Encephalopathies Advisory Committee
Vaccines and Related Biological Products Advisory Committee* all the required laboratory and other preclinical testing, and
 Veterinary Medicine Advisory Committee details regarding the vaccine’s manufacturing technology. The
*See further details in the text. FDA review includes assessments of the available preclinical
data and whether the tests were performed in accordance with
Good Laboratory Practices [17–19]. If the FDA allows the IND
biologic products under review. The committees evaluate application to proceed, the investigational vaccine can enter the
and discuss the New Drug (CDER) or Biologics License Clinical Development stage. At this stage, human trials begin
Application (CBER) submission they are charged to review, with phase I of testing. Investigational vaccines that are deemed
focusing on the safety and efficacy or effectiveness of the safe during phase I study are typically allowed to advance to
product under consideration [12]. During the meeting, ad- phase II evaluation. Clinical trials that meet phase II safety and
visory committee votes are taken, and a recommendation is proof of concept endpoints are usually eligible to advance fur-
made. The FDA takes the recommendation under advisement ther to large phase III efficacy studies. The three phases of study
as they work toward their final decision. In most circum- may progress sequentially, but it is also common for the phases
stances, the FDA decision agrees with the recommendations of development to overlap [20].
and advice made by the advisory group, but the FDA is not The evaluation of safety remains a high priority throughout
obligated to do so. Committee meetings are publicly acces- the Clinical Development stage of a candidate vaccine. Like
sible and now available to watch live via web streaming with clinical trials to evaluate candidate drugs, phase I, first in
dedicated time for public comment and questions. Materials human vaccine studies emphasizes safety as the primary out-
being reviewed and discussed during the meeting are open come measure. Other exploratory endpoints of interest may
access and usually made available to the public at least 2 days be included. Enrollment numbers for phase I clinical trials
before the meeting is scheduled. generally include between 20 and 100 healthy adult subjects

S96 • JPIDS 2024:13 (Suppl 2) • Domachowske

[20]. Stepwise dose escalation may be included to determine be reasonable markers of efficacy/effectiveness. For example, a
whether higher doses of vaccine antigens result in higher phase III clinical trial designed to evaluate a new candidate hep-
frequencies of side effects (in clinical trial jargon, “adverse atitis B vaccine might include post-vaccination measurements
events”), or are needed for different age groups to achieve sim- of serum antibodies against hepatitis B surface antigen (HBsAg)
ilar outcomes. An exploratory endpoint may include whether [28, 33]. Subjects shown to develop antibody titers of 10 mIU/
the study vaccine induces an immune response in the small mL or greater (the accepted surrogate of immunity) following
numbers enrolled. A successful phase I clinical trial allows a vaccination are considered protected. Documenting endpoints
research vaccine to be evaluated further in phase II. Phase II of infection or complications from infection, such as cirrhosis
studies are typically randomized trials using either a placebo or hepatocellular carcinoma, are impractical and logistically
or a standard-of-care active control vaccine as the comparator. impossible since they would likely require decades to accrue
Safety data continue to be collected. The study design includes meaningful numbers for analysis.

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

hundreds of participants in the age range or risk groups for Phase III trials may also be designed to support vaccine effi-
whom the vaccine is targeted. Phase II trials are designed to cacy using the outcome measure of immuno-bridging. To do so,
provide additional safety information on common short-term true efficacy and immunogenicity results from a prior phase III
side effects, examine the relationship between the dose(s) ad- study must first be available. For example, females 16–26 years
ministered and the immune responses observed among study of age who were enrolled in phase III clinical vaccine trials to
participants, provide early data regarding the effectiveness of evaluate the efficacy of HPV vaccine in preventing cervical
the vaccine, and/or to guide decisions about dose selection or dysplasia first underwent baseline Papanicolaou (PAP) smear
optimization for a larger efficacy trial. Phase III trials involve testing and had blood drawn to establish baseline anti-HPV an-
the enrollment of thousands of subjects. These large-scale, tibody titers [29]. The investigational vaccine series was admin-
multi-center trials are designed to establish the efficacy, effec- istered, and the subjects were followed over time. PAP smears
tiveness, and/or immunogenicity of the vaccine under eval- and serum HPV antibody titers were performed longitudinally
uation. Most phase III trials are randomized, double-blind at each scheduled research visit. Study results demonstrated
controlled studies. Enrollment goals are pre-determined by vaccine efficacy in preventing cervical dysplasia caused by the
performing a power analysis for determining the endpoint(s) HPV types included in the vaccine. The serum HPV antibody
of interest. Target enrollment numbers for most phase III range titers associated with that degree of efficacy were established
between 2000 and 3000 subjects [20]. Exceptions occur. For ex- for that age group. The same HPV vaccine was subsequently
ample, two of the largest phase III clinical vaccine trials ever tested in females between the ages of 9 and 15 years. At this
completed involved more than 60 000 infants each. Both trials younger age, PAP smear testing was not included in the study
were designed to evaluate the safety and immunogenicity of design for ethical reasons. Instead, immuno-bridging was used
candidate vaccines for the prevention of rotavirus gastroenter- to predict efficacy against cervical dysplasia for this younger age
itis in healthy infants [21, 22]. Such large enrollment numbers population. Vaccine immunogenicity across the 9- to 15-year-
were required for safety reasons as a previously licensed rota- old study population showed HPV antibody titers similar to, or
virus vaccine was linked to the uncommon, but potentially life- higher than those observed in the phase III efficacy trial among
threatening side effect of intussusception [23, 24]. females 16 years and older [32]. The agreed interpretation of the
results was that vaccine efficacy in 9- to 15-year-old females is
Evaluating Phase III Clinical Vaccine Trial Results: Efficacy, Bridging similar to, or better than the efficacy documented in the early
Efficacy, and Immunogenicity trial that included females in the 16- to 26-year-old range.
Safety assessments remain a high priority throughout any
candidate vaccine’s clinical development. The essential focus Lot-to-Lot Consistency and Oversight of the Vaccine Manufacturing
added during phase III evaluation centers on the effectiveness Process
(or potential effectiveness) of the product. Depending on the The processes involved in vaccine manufacturing are complex.
vaccine’s target, its effectiveness (or promise thereof) can be as- As the Clinical Development Stage of investigation (phase I, II,
sessed using different outcome measures. True efficacy studies and III of clinical trial activity) progresses, the FDA continues to
are preferred when evaluating vaccines for the prevention of assess the quality of the product at each step, and the condition of
disease in a target population (eg, influenza [25], RSV [26], the facilities used during the manufacturing process. Candidate
SARS-CoV-2 [27]). vaccines used for phase III studies are produced in batches
For vaccines being developed to prevent late complications called “lots” as the manufacturer prepares for commercial-scale
of infection (eg, hepatitis B [28], human papillomavirus [HPV] production. In addition to generating and reporting phase III
[29]) and for those with less predictable outbreak patterns (eg, clinical data to the FDA, manufacturers must also submit ev-
pertussis [30, 31], meningococcal disease [32]) study endpoints idence to support the quality of their manufacturing processes
more typically include surrogate measures thought or proven to and demonstrate the lot-to-lot consistency of their product [20].

The US Drug and Vaccine Approval Process • JPIDS 2024:13 (Suppl 2) • S97
The manufacturer, with guidance from the FDA, also develops a permission to market the vaccine in the United States for use in
protocol that lists the quality tests to be conducted on every vac- the approved population.
cine lot produced. For vaccines that earn FDA approval, each
item on this checklist must be performed and meet acceptable Regulatory Oversight Continues After Approval
standards before being released for public use. Prior to lot re- Despite the rigorous and comprehensive nature of the vaccine
lease, the FDA requires the manufacturer to submit their quality development process and regulatory approval pathway, over-
assurance protocols, a list of the agreed-upon tests to be per- sight, and surveillance continue after FDA approval. Federal
formed on each lot, and results of the testing that has been per- agencies (FDA, CDC) use both passive and active surveillance
formed, including assessments of purity, potency, and sterility. systems to monitor the safety of new and existing vaccines.
The manufacturer must also submit samples of the vaccine from The vaccine manufacturer, independent researchers, and other
the lot under evaluation. This permits the FDA to perform inde- stakeholders also regularly participate in these surveillance

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

pendent, confirmatory tests as they deem necessary. Even after activities. The FDA may require the manufacturer to conduct
a vaccine is licensed by the FDA, pharmaceutical companies post-marketing studies to further assess known or potential
are not permitted to distribute a specific lot of vaccine until the serious risks and/or monitor the real-world effectiveness of a
FDA releases it. new vaccine product. By definition, these formal post-licensure
Once all the Clinical Development Program require- studies are phase IV trials, but they are not always identified
ments have been completed, and the manufacturing process is as such. At the federal level, vaccine safety is tracked by the
deemed reliable and consistent, the vaccine developer submits Vaccine Adverse Event Reporting System (VAERS), the FDA
a Biologics License Application (BLA) to the FDA seeking Biologics Effectiveness and Safety (BEST) program, the FDA,
permission to distribute and market the product for use in and Centers for Medicare & Medicaid Services (CMS) part-
the United States [34]. CBER evaluates the data to determine nership, and the Centers for Disease Control and Prevention’s
whether the safety and effectiveness of the vaccine have been (CDC) Vaccine Safety Datalink [36–39].
demonstrated and whether the manufacturing and facility in-
formation assure product quality and consistency. Like CDER, Prescribing Information, Labeling, and the “Package Insert”
CBER relies on the separate, independent evaluation of an out- Prescribing information for a vaccine is based on scientific
side committee of experts to advise them on the disposition of data that are submitted by the manufacturer in the BLA and
the product. determined by the FDA to satisfy and support the approved
indication(s), usage, dosing, and administration [40]. The pre-
Vaccines and Related Biological Products Advisory Committee scribing information is updated as needed to include the most
Under CBER, the Vaccines and Related Biological Products current information available about the vaccine. Expanded FDA
Advisory Committee (VRBPAC) reviews and evaluates ap- labeling indications (eg, adding older or younger age groups) to
plications to the FDA regarding the safety, efficacy/effective- the label requires that the manufacturer submit a BLA supple-
ness, and recommended proper use of vaccines and related ment that includes evidence supporting the requested change.
biological products (but not monoclonal antibodies) [35]. The prescribing information (sometimes referred to as the P.I.)
Biologics, such as vaccines, are complex pharmacologic prod- is summarized in a paper document that is required to be in-
ucts meant to be used for the diagnosis, treatment, or preven- cluded with each unit of sale, whether it be a single unit dose
tion of disease. Separately, VRBPAC is charged with assessing or a multi-dose vial. The wording of the document must be re-
the quality and direction of the FDA’s research endeavors. The viewed and approved by the FDA [40, 41]. The document it-
Committee furnishes biomedical expertise and support for self is included with each unit of sale during packaging and is
how the products under their purview are regulated and im- therefore commonly referred to as the “package insert,” or “P.I.”
plemented. After each discussion and review, the committee Since the summarized information included in the detailed
votes on their recommendation(s), and conveys their advice to prescribing information is synonymous with the information
the FDA Commissioner via the CBER leadership. VRBPAC is included in the package insert, the abbreviation “P.I.” is used
comprised of 15 voting members who are selected by the FDA interchangeably.
Commissioner or their designee from outside experts in the
fields of preventive medicine, infectious diseases, pediatrics, ep- Emergency Use Authorization and the Accelerated Review Pathways for
idemiology, biochemistry, molecular biology, microbiology, im- Drugs and Vaccines
munology, biostatistics, vaccine development, policy, and safety Under circumstances associated with a public health emer-
[35]. After CBER completes its evaluation and considers the gency, and as outlined in section 564 of the Federal Food, Drug,
advice provided by VRBPAC, the CBER leadership and FDA and Cosmetic (FD&C) Act, the FDA Commissioner has the
Commissioner decide whether to approve (license) the vaccine power to issue Emergency Use Authorization (EUA) to use an
for use in the United States. FDA approval gives the company unapproved drug, device, or biological product under carefully

S98 • JPIDS 2024:13 (Suppl 2) • Domachowske

outlined conditions. Before an EUA may be issued, the Secretary investigational products deemed high priority and to ensure
of Health and Human Services must declare that circumstances that therapies for serious conditions are made available to pa-
exist justifying the authorization based on one of four categories tients as soon as reviewers can conclude that their benefits
summarized in Table 5 [42]. Under these conditions, the justify their risks. Each of the the FDAs formal designations
Secretary of HHS is empowered to declare that circumstances is meant to address specific needs, so a new drug application
exist to justify EUAs, allowing the FDA Commissioner to issue may receive more than one designation, if appropriate. There
them. Most recently, the Secretary of HHS declared a public are four expedited review programs issued jointly by CDER and
health emergency with significant potential to affect national CBER: Accelerated Approval, Priority Review, Fast Track, and
security or the health and security of United States citizens Breakthrough Therapy.
living abroad involving the novel coronavirus first detected in An Accelerated Approval designation is for drug candidates
Wuhan City, Hubei Province, China in 2019 (now referred to that address serious conditions and that have the potential to

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

as SARS-CoV-2 for severe acute respiratory syndrome corona- offer an important advantage over other available therapies.
virus 2, the pathogen that causes coronavirus disease 2019, or A key aspect of the Accelerated Approval Designation is that
COVID-19). The declaration of the public health emergency a surrogate endpoint, instead of a gold-standard clinical end-
allowed the FDA Commissioner to issue EUAs for many unap- point, is permitted in the design of the phase III clinical trial
proved diagnostic tests, vaccines, monoclonal antibodies, and used to support FDA approval of the drug [45]. As a rule, clin-
antiviral medications for use under strictly defined conditions. ical endpoints are used in the design of phase III efficacy trials.
Gradually, as some of these products completed formal Clinical Doing so requires that many study participants need to be fol-
Development Phase testing requirements, they underwent the lowed for a prolonged period before a definitive conclusion of
scrutiny required to gain full FDA approval. As the pandemic the study results can be made.
went on, EUAs for several other products were rescinded due to Surrogate endpoints are markers that are easy to measure
lack, or loss of efficacy of the investigational agent against pre- and follow over time and are generally accepted to predict clear
dominant circulating SARS-CoV-2 variants [42, 43]. clinical benefits.
Even in the absence of a declared public health emergency, Drugs granted a designation for Priority Review have com-
the FDA recognizes that some drugs and vaccines in develop- pleted all Clinical Development Stage requirements, and al-
ment should be prioritized for evaluation and possible approval. ready appear to demonstrate significant improvements over
When such agents are identified, the FDA considers whether existing medications in their safety, effectiveness, or both [47].
to review and approve (if appropriate) a new drug or vaccine A Priority Review designation promises completion of the re-
using an expedited timeline. For more than two decades, the view process within 6 months, instead of the more standard
FDA has employed expedited pathways aimed at speeding 10-month period.
the drug development and review processes so that therapies The FDA’s Fast Track designation debuted in 1997 as a new
that show early promise can reach patients faster [44, 45]. The process designed to facilitate the development and review of
popularity and value of these programs have grown so much certain drugs that show promise based on early clinical trial
during this time that over half of CDER’s 2015 novel drug ap- results [48, 49]. The designation and pathway are designed for
provals received some form of expedited review [45, 46]. An investigational products that are intended to treat a serious con-
accelerated approval timeline can be applied to promising ther- dition and that have already demonstrated the potential to ad-
apies that treat a serious or life-threatening condition and/or dress an unmet public health need during preclinical analyses.
provide therapeutic benefits over available therapies. FDA uses A Breakthrough Therapy designation expedites the devel-
several designations to encourage and/or incentivize those opment and review of drugs that are intended to treat a serious
condition and show preliminary clinical evidence indicating
that the drug may demonstrate substantial improvement over
Table 5. Categories Allowing for Emergency Use Authorizations to be
Considered available therapies. A drug with Breakthrough Therapy desig-
nation is also eligible for the Fast Track process [48, 50–53].
1. The presence of, or potential for a domestic emergency involving a height-
For example, the Fast Track and Breakthrough designations,
ened risk of attack with a Chemical, Biological, Radiological, or Nuclear
(CBRN) agent as determined by the Secretary of Homeland Security which must be requested by the pharmaceutical company, were
2. A material threat to national security or the health and security of U.S. citi- granted for both nirsevimab (Astra Zeneca) and for the ma-
zens living abroad, as determined by Secretary of Homeland Security
ternal prefusion F RSV vaccine (Pfizer) during the early stages
3. The presence of, or significant potential for a military emergency, involving
an elevated risk to U.S. military forces from a CBRN or similar agent, as of their clinical development.
determined by the Secretary of Defense Pharmaceutical stakeholders with a novel drug under devel-
4. Declaration of, or significant potential for a public health emergency af-
opment that has received a Breakthrough Therapy designation
fecting national security or the health and security of U. S. citizens living
abroad, that involves a CBRN agent or a disease or condition caused by are granted earlier and more frequent communication and input
such agents from senior leadership at the FDA [52, 53]. A cross-discipline

The US Drug and Vaccine Approval Process • JPIDS 2024:13 (Suppl 2) • S99
project lead is assigned to each Breakthrough Therapy develop- secretary is authorized to temporarily designate ex officio mem-
ment program to ensure that the review of the product’s data is bers as voting members, per the committee charter. Meetings
efficient across all disciplines. are announced, advertised, open to the public, and available on-
None of the four accelerated pathways/designations that line via webcast. Meeting minutes, and slide sets or supporting
have been described change the established requirements for materials used during the discussion are available on the CDC
gaining FDA approval. All products must demonstrate safety website within 90 days of the conference, often sooner.
and effectiveness in the same manner. The designations are, At the 2010 October meeting, the ACIP adopted the GRADE
instead, meant to move applications through the required pro- (Grading of Recommendations Assessment, Development, and
cesses by prioritizing and shortening review timelines [48, 50, Evaluation) framework to guide their discussions [58]. The
53]. Perhaps more importantly, some designations provide process includes a comprehensive review of the FDA-approved
for enhanced and more frequent communication between the labeling and prescribing information, a review of the scientific

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

pharmaceutical company and the FDA which facilitates a more literature on the vaccine’s safety and efficacy; an assessment
continuous process that can otherwise become fragmented and of cost-effectiveness; an overview of the disease burden and
lacking in optimal efficiency. mortality associated with the disease, a discussion of the re-
commendations from other groups (when available) and consid-
The Role of the Advisory Committee on Immunization Practices eration of the feasibility of vaccine use in the context of existing
The Advisory Committee on Immunization Practices (ACIP) programs. The strength of evidence to support each recommen-
was established in March 1964 by U.S. Surgeon General Luther dation is graded as very low, low, moderate, or high quality.
Terry to assist in the prevention and control of contagious dis- Weakness or deficiencies in data, lack of reliability, and/or po-
eases in the U.S. ACIP is comprised of a group of vaccine experts tential biases are considered during the grading of evidence.
that provide guidance and recommendations to the Director of A universal recommendation is used for vaccines that are
the U.S. Centers for Disease Control and Prevention (CDC) on suitable for all or nearly all individuals in a risk group or spe-
the safe and effective control of vaccine-preventable diseases cific age category, while a shared clinical decision-making rec-
across the U.S. civilian population [54]. As such, the ACIP de- ommendation is made when the evidence or cost-effectiveness
velops recommendations on the administration of vaccines to data for universal use are less clear. The Affordable Care Act
children and adults, including timing, doses, precautions, and requires that both tiers of recommendations be covered by in-
contraindications for their use. Once approved by the Director surance carriers.
of the CDC, ACIP statements are published in the Morbidity Much of the work involved in developing new or updating
and Mortality Weekly Report to become official federal docu- existing vaccine recommendations is done between meetings by
ments that guide the use of vaccines and immune globulins in ACIP-appointed working groups. These groups include ACIP
the United States. The ACIP includes 15 regular members with members, CDC staff, and other recognized experts. Each work
expertise in immunization practices and public health, use of group is charged with reviewing the available scientific informa-
vaccines and other immunobiologic agents in clinical practice, tion related to the vaccine and the disease it is designed to prevent
preventive medicine, clinical, or laboratory vaccine research, as- [58]. The efforts happen between scheduled ACIP meetings, so
sessment of vaccine efficacy and safety, and at least one member the findings are available for discussion during the next meeting.
with knowledge and experience in consumer perceptions or Draft recommendations are also developed by work groups.
community aspects of immunization programs [54–56]. When the workgroup has completed their assignment and the
Routine ACIP meetings are held three times a year. Ad hoc full committee has had the opportunity to discuss and comment
meetings are convened when deemed necessary (eg, discussions on the drafted guidance, the committee is called to vote.
and votes on implementation of EUAs related to early use of Following their vote on the wording of the final vaccine re-
SARS-CoV-2 vaccines). Meeting dates and agenda items are commendations, the ACIP may vote on whether the new vac-
published in the Federal Register in accordance with the re- cine should be included in the Federal Entitlement Program
quirements of the Federal Advisory Committee Act (FACA) known as Vaccines for Children (VFC). The VFC program
and are open to the public [54, 57]. Routinely scheduled meet- provides vaccines to individuals less than 19 years of age who
ings are 2–3 days in length and include detailed discussions on are un- or under-insured and cannot otherwise afford the cost
a broad array of vaccine topics. Some discussions involve final- of the vaccination. VFC was created by the Omnibus Budget
izing the proposed wording for new or updated vaccine recom- Reconciliation Act of 1993 and is required to be a new en-
mendations. A vote on each set of newly developed or revised titlement of each state’s Medicaid plan under section 1928 of
recommendations may be taken when a quorum of at least the Social Security Act. The program was officially launched
eight eligible ACIP members are present. Eligible voters are in October 1994 and serves eligible children in all the US
those members without significant conflicts of interest. If eight states, commonwealths, and territories [58, 59]. The impact is
eligible voting members are not present, the ACIP executive far-reaching as the federal government now purchases between

S100 • JPIDS 2024:13 (Suppl 2) • Domachowske

52% and 55% of all childhood vaccines that are administered in 16. https://www.fda.gov/advisory-committees/advisory-committee-calendar/
june-8-2023-meeting-antimicrobial-drugs-advisory-committee-meeting-
the U.S. Funding for the VFC program is approved by the Office announcement-06082023. Accessed February 7, 2024.
of Management and Budget (OMB) and allocated through the 17. https://www.fda.gov/patients/drug-development-process/step-2-preclinical-
research. Accessed February 6, 2024.
Centers for Medicare & Medicaid Services (CMS) to the CDC 18. https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-
[59]. CDC buys the vaccines at negotiated discount rates and application-procedures-overview. Accessed February 6, 2024.
19. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
distributes them to state health departments and other desig-
investigations/nonclinical-laboratories-inspected-under-good-laboratory-
nated public health agencies. The doses are then provided at no practices/1981-questions-answers-good-laboratory-practice-regulations.
cost to medical practices, clinics, and hospitals that are regis- Accessed February 6, 2024.
20. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-
tered as VFC providers. VFC providers are obligated to restrict CBER/vaccine-development-101. Accessed February 6, 2024.
the use of vaccine doses provided in this manner to their VFC- 21. Vesikari T, Matson DO, Dennehy P, et al; Rotavirus Efficacy and Safety Trial
(REST) Study Team. Safety and efficacy of a pentavalent human-bovine (WC3)
eligible patients [59–61]. ACIP voted in favor, and the Director reassortant rotavirus vaccine. N Engl J Med 2006; 354:23–33.

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

of the CDC approved, the inclusion of both nirsevimab and the 22. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al; Human Rotavirus Vaccine
Study Group. Safety and efficacy of an attenuated vaccine against severe rotavirus
maternal prefusion RSV-F vaccine in the VFC program. gastroenteritis. N Engl J Med 2006; 354:11–22.
23. Centers for Disease Control and Prevention (CDC). Intussusception among re-
cipients of rotavirus vaccine—United States, 1998–1999. Morb Mortal Wkly Rep
CONCLUSION 1999; 48:577–81.
24. Centers for Disease Control and Prevention (CDC). Suspension of rotavirus vac-
The regulatory processes used to evaluate, authorize, and ap- cine after reports of intussusception—United States, 1999. Morb Mortal Wkly
prove new drugs and vaccines are complex. The FDA, its ad- Rep 2004; 53:786–9.
25. Belshe RB, Edwards KM, Vesikari T, et al; CAIV-T Comparative Efficacy
visory groups, the ACIP, and other federal agencies perform Study Group. Live attenuated versus inactivated influenza vaccine in infants
independent reviews on product safety and effectiveness both and young children [published correction appears in N Engl J Med. 2007 Mar
22;356(12):1283]. N Engl J Med 2007; 356:685–96.
before and after licensure with the ultimate goal of assuring the 26. Kampmann B, Madhi SA, Munjal I, et al; MATISSE Study Group. Bivalent
ongoing safety and effectiveness of our pharmaceutical arma- prefusion F vaccine in pregnancy to prevent RSV illness in infants. N Engl J Med
2023; 388:1451–64.
mentarium. Regulatory pathways for drugs and vaccines are 27. Walter EB, Talaat KR, Sabharwal C, et al; C4591007 Clinical Trial Group.
similar, with key differences highlighted here. Evaluation of the BNT162b2 COVID-19 vaccine in children 5 to 11 years of age.
N Engl J Med 2022; 386:35–46.
28. Blondheim O, Bader D, Abend M, et al. Immunogenicity of hepatitis B vaccine in
Note preterm infants. Arch Dis Child Fetal Neonatal Ed 1998; 79:F206–8.
Supplement sponsorship. This article appears as part of the supplement 29. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to
prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–27.
“Preventing Infant RSV Infection,” sponsored by Sanofi Pasteur.
30. Pichichero ME, Badgett JT, Rodgers GC Jr, McLinn S, Trevino-Scatterday B,
Nelson JD. Acellular pertussis vaccine: immunogenicity and safety of an acellular
REFERENCES pertussis vs. a whole cell pertussis vaccine combined with diphtheria and tetanus
toxoids as a booster in 18- to 24-month old children. Pediatr Infect Dis J 1987;
1. Barkan ID. Industry invites regulation: the passage of the Pure Food and Drug Act 6:352–63.
of 1906. Am J Public Health 1985; 75:18–26. 31. Santolaya ME, O’Ryan ML, Valenzuela MT, et al; V72P10 Meningococcal
2. Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and B Adolescent Vaccine Study group. Immunogenicity and tolerability of a
Cosmetic Act. Ann Intern Med 1995; 122:456–61. multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy ado-
3. Steele H. The fortunes of economic reform legislation: the case of the Drug lescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled
Amendments Act of 1962. Am J Econ Sociol 1966; 25:39–52. study [published correction appears in Lancet. 2015 May 2;385(9979):1728].
4. https://www.fda.gov/about-fda/fda-history-exhibits/brief-history-center-drug- Lancet 2012; 379:617–24.
evaluation-and-research. Accessed February 5, 2024. 32. Iversen OE, Miranda MJ, Ulied A, et al. Immunogenicity of the 9-valent HPV
5. https://www.fda.gov/about-fda/histories-fda-regulated-products/history- vaccine using 2-dose regimens in girls and boys vs a 3-dose regimen in women.
biologics-regulation. Accessed February 5, 2024. JAMA 2016; 316:2411–21.
6. https://www.fda.gov/about-fda/CDER-contact-information/CDER-reference- 33. Block SL, Klein NP, Sarpong K, et al. Lot-to-lot consistency, safety, tolerability and
guide. Accessed February 5, 2024. immunogenicity of an investigational hexavalent vaccine in US infants. Pediatr
7. Diez Pascual C. Clinical drug trials: the path to the patient. Methods Mol Biol Infect Dis J 2017; 36:202–8.
2021; 2296:411–21. 34. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-
8. Jorda A, Zeitlinger M. Preclinical pharmacokinetic/pharmacodynamic studies CBER/biologics-license-applications-bla-process-CBER. Accessed February 6,
and clinical trials in the drug development process of EMA-approved antibacte- 2024.
rial agents: a review. Clin Pharmacokinet 2020; 59:1071–84. 35. https://www.fda.gov/advisory-committees/vaccines-and-related-biological-
9. https://www.fda.gov/vaccines-blood-biologics/development-approval-process- products-advisory-committee/charter-vaccines-and-related-biological-
CBER/vaccine-development-101. Accessed February 5, 2024. products-advisory-committee. Accessed February 5, 2024.
10. https://www.fda.gov/about-fda/fda-organization/center-biologics-evaluation- 36. Shimabukuro TT, Nguyen M, Martin D, DeStefano F. Safety monitoring in the
and-research-CBER. Accessed February 5, 2024. Vaccine Adverse Event Reporting System (VAERS). Vaccine 2015; 33:4398–405.
11. Schwieterman WD. Regulating biopharmaceuticals under CDER versus CBER: 37. Cope JU, Rosenthal GL, Weinel P, Odegaard A, Murphy DM. FDA safety reviews
an insider’s perspective. Drug Discov Today 2006; 11:945–51. on drugs, biologics, and vaccines: 2007–2013. Pediatrics 2015; 136:1125–31.
12. https://www.fda.gov/advisory-committees/about-advisory-committees. Accessed 38. McNeil MM, Gee J, Weintraub ES, et al. The Vaccine Safety Datalink: successes
February 5, 2024. and challenges monitoring vaccine safety. Vaccine 2014; 32:5390–8.
13. https://www.fda.gov/advisory-committees/about-advisory-committees/ 39. Meissner HC. Understanding Vaccine Safety and the Roles of the FDA and the
advisory-committee-laws-regulations-and-guidance. Accessed February 5, 2024. CDC. N Engl J Med 2022; 386:1638–45.
14. https://www.fda.gov/advisory-committees/advisory-committee-membership/ 40. Clarridge KE, Chin SJ, Stone KD. Overview of FDA drug approval and labeling. J
applying-membership-fda-advisory-committees. Accessed February 5, 2024. Allergy Clin Immunol Pract 2022; 10:3051–6.
15. https://www.fda.gov/advisory-committees/human-drug-advisory-committees/ 41. Shea MB, Stewart M, Van Dyke H, Ostermann L, Allen J, Sigal E. Outdated pre-
antimicrobial-drugs-advisory-committee-formerly-known-anti-infective-drugs- scription drug labeling: how FDA-approved prescribing information lags behind
advisory-committee. Accessed February 5, 2024. real-world clinical practice. Ther Innov Regul Sci 2018; 52:771–7.

The US Drug and Vaccine Approval Process • JPIDS 2024:13 (Suppl 2) • S101
42. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal- 51. Corrigan-Curay J, Stein P. FDA breakthrough therapy designation-trial design
regulatory-and-policy-framework/emergency-use-authorization. Accessed and more—commentary. Clin Pharmacol Ther 2021; 110:869–70.
February 6, 2024. 52. Corrigan-Curay J, McKee AE, Stein P. Breakthrough-Therapy Designation - An
43. Tran A, Witek TJ Jr. The emergency use authorization of pharmaceuticals: FDA Perspective. N Engl J Med 2018; 378:1457–8.
history and utility during the COVID-19 pandemic. Pharmaceut Med 2021; 53. https://www.fda.gov/drugs/nda-and-bla-approvals/breakthrough-therapy-
35:203–13. approvals. Accessed February 6, 2024.
44. Sachs RE, Donohue JM, Dusetzina SB. Accelerated approval—taking the FDA’s 54. Walton LR, Orenstein WA, Pickering LK. The history of the United States Advisory
concerns seriously. N Engl J Med 2022; 387:199–201. Committee on Immunization Practices (ACIP). Vaccine 2015; 33:405–14.
45. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated- 55. Smith JC, Hinman AR, Pickering LK. History and evolution of the advisory
approval-priority-review/accelerated-approval. Accessed February 6, 2024. committee on immunization practices—United States, 1964–2014. Morb Mortal
46. Reforming accelerated approval. Nat Biotechnol 2012; 30:293. Wkly Rep 2014; 63:955–8.
47. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated- 56. Hinman AR, Poland GA. Celebrating the ACIP at 50. Vaccine 2015; 33:403–4.
approval-priority-review/priority-review. Accessed February 6, 2024 57. https://www.cdc.gov/vaccines/acip/index.html. Accessed February 6, 2024.
48. Michaeli DT, Michaeli T, Albers S, Boch T, Michaeli JC. Special FDA designations 58. https://www.cdc.gov/vaccines/acip/recs/index.html Accessed February 6, 2024.
for drug development: orphan, fast track, accelerated approval, priority review, 59. Hinman AR, Orenstein WA, Rodewald L. Financing immunizations in the United
and breakthrough therapy. Eur J Health Econ 2023. States. Clin Infect Dis 2004; 38:1440–6.

Downloaded from https://academic.oup.com/jpids/article/13/Supplement_2/S93/7712668 by guest on 06 December 2024

49. https://www.fda.gov/drugs/nda-and-bla-approvals/fast-track-approvals. 60. Johnson KA, Sardell A, Richards B. Federal immunization policy and funding: a
Accessed February 6, 2024. history of responding to crises. Am J Prev Med 2000; 19:99–112.
50. Herink MC, Irwin AN, Zumach GM. FDA breakthrough therapy desig- 61. Smith PJ, Lindley MC, Rodewald LE. Vaccination coverage among U.S. children
nation: evaluating the quality of the evidence behind the drug approvals. aged 19–35 months entitled by the vaccines for children program, 2009. Public
Pharmacotherapy 2018; 38:967–80. Health Rep 2011; 126:109–23.

S102 • JPIDS 2024:13 (Suppl 2) • Domachowske