From the eradication of smallpox and near elimination of polio, to the notable reduction of morbidity and mortality associated with many other infectious diseases, vaccines have had an immense impact on public health and continue to save lives to this day.1,2 In the United States, advances in technology and research have allowed for an effective, rapidly expanding immunization program that routinely protects children from 16 serious and potentially life-threating diseases.3 Approximately 20 million illnesses and more than 40,000 deaths are prevented for each US birth cohort that receives the recommended childhood immunizations.4
Although the effectiveness of this public health intervention is clear, the behind-the-scenes process of developing vaccines and making them available to the public is complex and unknown to many. Each stage of discovery, development, evaluation, and regulation requires an intricate collaboration among academia, public and private organizations, and federal agencies.1,5 Although this coordinated effort ensures that safety is prioritized during each step, it also underscores why developing vaccines is a complicated, costly, and time-consuming process, often taking 10 to 15 years.6
After vaccines are developed and licensed, there is a robust system to continue monitoring their safety and effectiveness. In spite of the strong safety record of vaccines, the US and other countries face challenges with vaccine hesitancy and refusal.7 In 2019, the World Health Organization declared vaccine hesitancy as one of the 10 biggest threats to global health.7 Concerns about vaccine safety are especially relevant as we face the current coronavirus disease 2019 (COVID-19) pandemic and the accelerated speed with which candidate vaccines are being developed. Lack of confidence in both the vaccine development process and the safety of licensed COVID-19 vaccines could increase hesitancy, which may lead to insufficient uptake levels required to achieve herd immunity thresholds.8 Thus, public health officials and health care providers will need to emphasize that no compromises are being made in meeting the requirements to bring COVID-19 vaccines to licensure.8,9 An understanding of the comprehensive safety assessment networks and the process by which all vaccines are documented to be safe and effective will be important to improve public acceptance.
This review article aims to address the need for a better understanding of the vaccine development process, from basic science advances in the laboratory to recommendations and policy. A greater knowledge of this process and the safeguards in place is especially important for pediatricians and other health care providers, who serve as one of the most trusted and influential sources of vaccine information for patients and their parents.8,10 As such, providers must be well equipped to explain how vaccines are developed and tested thoroughly, to address concerns regarding their safety and effectiveness, and to express confidence in them.
Exploratory and Preclinical Stages
Development begins with the exploratory stage in the laboratory, where basic science researchers identify natural or synthetic antigens that could elicit immune responses to protect against disease.11 This discovery process involves understanding the pathogen's mechanism of survival and reproduction, the host-pathogen interaction, and the host response.1,11 Vaccines can consist of the whole pathogen, in a weakened (ie, live-attenuated) or killed version, or only its antigens that optimally stimulate the immune system.11 Advances in laboratory techniques and genetic engineering have led to the different types of vaccines listed in Table 1. Scientists continue to uncover novel investigational approaches to vaccination, such as DNA plasmid vaccines, mRNA vaccines, and adjuvants that stimulate an innate immune response.11 These advances are crucial for understanding how to create safer and more effective vaccines, especially for pathogens where traditional vaccine development programs have been unsuccessful.
Main Types of Vaccines Currently Available
After this initial period of discovery, researchers conduct extensive in vitro and in vivo testing in animals during the preclinical stage to measure safety and immunogenicity prior to introducing the vaccine to humans.12 Preclinical testing allows researchers to anticipate the cellular and humoral responses that may arise in humans, and is required to advance the candidate vaccine from the laboratory to the clinic. Many candidate vaccines do not elicit the desired immune response and fail to progress beyond the preclinical stage.6 This represents one of several hurdles along the path of vaccine development.
After assessing the safety and immunogenicity of the vaccine in cell-culture systems and animal models, the sponsor submits an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA).13 The FDA has 30 days to approve an IND application, which describes the vaccine, method of manufacture, preclinical data on safety and immunogenicity, and proposed clinical study.13 The institutional review board at the institution where clinical development will occur must approve the clinical protocol. Once approved, the vaccine moves onto the clinical development stage. However, basic science research does not stop at this stage, as findings in the laboratory continue to inform the development process.
Clinical development involves three consecutive phases of testing in human participants and rigorous oversight by the FDA. There can be overlap among the phases, and additional Phase I and II trials may be required by the FDA as new data become available.14,15 Studies are governed by good clinical practices and involve careful monitoring.15 If the FDA identifies any significant concerns about safety or efficacy, the Agency may request additional information or stop ongoing studies at any time.14,15
During Phase I trials, which aim to assess safety as the primary objective, the candidate vaccine is administered to healthy adults with low risk of vaccine-related adverse events.14,16 Preliminary immunogenicity information is also collected as a secondary objective. These normally nonrandomized and open-label studies involve fewer than 100 participants and measure tolerability and reactogenicity due to vaccination as the primary safety outcome.14–16
After Phase I studies have been successfully completed, the vaccine enters Phase II trials. These dose-ranging studies typically involve a few hundred healthy participants and collect further information on efficacy, immunogenicity, and safety.14–16 If the vaccine is ultimately for infants, then studies will be conducted in a step-down approach, assessing safety in adults first, then adolescents and children, and then infants.14 Phase II trials generate data on optimal dose, vaccine preparation, schedule, and factors such as age that influence immune response, all of which inform the study design of Phase III trials.15
By Phase III, there is an abundance of safety information collected from the preclinical stage and early clinical evaluation, albeit in relatively small study cohorts.1 Vaccines that raise acute safety concerns usually do not reach Phase III, which is when large-scale clinical studies are conducted with thousands to tens of thousands of participants from the population of interest.1,14,15 There is stronger statistical power for clinically meaningful outcomes and more precise characterization of safety and immunogenicity of the vaccine's final formulation.16 Sample size depends on the incidence of disease, with low incidence requiring a larger sample size and vice versa.
A randomized, double-blind, placebo-controlled trial is the “gold standard” during Phase III. This type of trial reduces bias and assesses the efficacy of the candidate vaccine compared with the control.16 The most common clinical endpoint is occurrence of disease, although endpoints can also include incidence of infection or be based on achieving correlates of protection.16 As an example of the latter, human serum bactericidal antibody titers were used as a correlate of protection to test immunogenicity for the meningococcal conjugate vaccine.17 Careful definition of endpoints increases the credibility of Phase III trial results, which are crucial for understanding the common side effects associated with the vaccine, weighing its risks and benefits, and providing support for licensure.16Figure 1 provides an overview of the steps leading up to licensure.
Overview of vaccine development before licensure: exploratory/preclinical stage and clinical development (Phase I, II, and III trials). Adapted from National Institute of Allergy and Infectious Diseases,11 Children's Hospital of Philadelphia,12 Baylor,14 Marshall and Baylor,15 and Hudgens et al.16
As COVID-19 vaccines enter Phase III trials, it is important to emphasize that no compromises are being made in evaluating safety or efficacy.8,9 Spearheaded by the National Institutes of Health, the ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) public-private partnership aims to safely and efficiently expedite the development and licensure of COVID-19 vaccines. This collaborative effort among academia, industry, and government addresses the need to establish consensus on the design of vaccine trials and accelerate data sharing, so that studies can be conducted in a harmonized manner.9 The ACTIV model also involves a common cross-trial Data and Safety Monitoring Board to coordinate these efforts and ensure that safety and efficacy are thoroughly and objectively evaluated.9
Approval and Licensure
The Center for Biologics Evaluation and Research (CBER) of the FDA oversees the vaccine approval process and enforces carefully designed regulatory requirements before and after licensure.15 Once all phases of clinical development are successfully completed, the vaccine manufacturer submits a Biologics License Application (BLA), which contains two main sections: a product license for the vaccine and an establishment license for the manufacturing facility.5,15 The manufacturer must show lot-to-lot equivalence of the product to demonstrate consistency of the vaccine manufacturing process.15 After licensure, every lot of vaccine produced must be tested for potency and meet FDA standards before release.15
While a multidisciplinary CBER team reviews the BLA, the Agency usually requires the manufacturer to present its findings to the Vaccines and Related Biological Products Advisory Committee (VRBPAC). This standing federal advisory committee, comprised of 15 experts knowledgeable in vaccinology-related fields, advises on licensure by evaluating the clinical data and determining whether they sufficiently support safety and efficacy or whether additional studies are required.14,15 The CBER strongly considers recommendations from the VRBPAC during the decision-making process to license a vaccine.14,15 The length of time from BLA submission to approval can range from 7 months to 2 years, as rigorous evaluation must be conducted before products can be offered on the market.5 For each licensed vaccine, the FDA produces prescribing information that describes indications, dosage, administration, storage and handling, contraindications, warnings and precautions, expected adverse reactions, observed or predicted clinically significant interactions with other vaccines, and patient counseling information.18Figure 2 provides an overview of the licensure process and the steps after licensure.
Overview of vaccine development after clinical evaluation: licensure, policy recommendations, and post-licensure monitoring. Adapted from Bloom et al.,8 Smith et al.,20 Centers for Disease Control and Prevention,24,26,27 and Shimabukuro et al.25
Expedited FDA review mechanisms available for vaccines against serious diseases include fast track, breakthrough therapy, accelerated approval, and priority review (Table 2). The fast track mechanism advances the development and review of vaccines that show potential to fill unmet medical needs for serious conditions.15,19 These vaccines may also be eligible for accelerated approval and priority review. As measuring clinical benefit can take many years, accelerated approval allows the FDA to approve a vaccine based on a surrogate endpoint, defined as any marker that is thought to predict clinical benefit but does not directly measure it.15,19 Due to this quicker approval process, an adequate and well-controlled post-marketing trial is required to confirm the vaccine's clinical benefit. Priority review indicates that the FDA aims to act upon an application within 6 months.15,19
Four Distinct FDA Approaches of Making Drugs/Vaccines Available as Quickly as Possible
Despite the speed of review, these expedited regulatory pathways do not have lower medical/scientific standards, quality of data, or length of clinical trial period.14,15 These approaches are used only in circumstances where the targeted disease is serious or life-threatening, such that expediting the availability of a vaccine is in the public's best interest. The current development of COVID-19 vaccines is using these pathways because an estimated 200 million Americans and 5.6 billion people worldwide will need to be vaccinated to end the pandemic.8
There is an important distinction between FDA licensure of a vaccine and development of federal recommendations by the Advisory Committee on Immunization Practices (ACIP) and the US Centers for Disease Control and Prevention (CDC). FDA licensure brings the vaccine to market and is based on data from clinical studies, whereas federal recommendations determine how the vaccine will be used and administered to the public (Figure 2). Specifically, these recommendations contain guidance on target populations for vaccination, route of administration, number of doses and dosing intervals, and precautions and contraindications.20 In addition to the criteria considered for FDA licensure, the ACIP and CDC consider disease epidemiology, vaccine supply, implementation issues, public acceptance, and cost.18 Thus, their recommendations for use of a vaccine sometimes differ from FDA-approved prescribing information.18
The ACIP, comprised of 15 nongovernmental experts in immunization and related fields, uses the Grading of Recommendations, Assessment, Development and Evaluation framework to develop evidence-based recommendations.21 The development process begins in subgroups, called work groups, that create precise policy questions in the PICO (Population, Intervention, Comparison[s], and Outcome) format.21 They then conduct an extensive review of the literature and assess the quality of evidence. Important factors to consider include balance of the vaccine's benefits with possible harms, type or quality of evidence, values and preferences of the target population, cost-effectiveness analyses regarding resource use, and feasibility of implementation.18,21 After gathering and evaluating vaccine-related data and literature, work groups prepare a presentation with evidence-based recommendation options to the full ACIP.20,21
ACIP members meet at least 3 times a year in an open, public forum to discuss, review, and vote on vaccine recommendations.20,21 The ACIP also collaborates with over 30 liaison organizations whose representatives serve in relevant work groups, attend ACIP meetings, and participate as nonvoting members. This ensures harmonization of immunization recommendations among leading professional medical societies, including the American Academy of Pediatrics, American Academy of Family Physicians, American College of Obstetricians and Gynecologists, and American College of Physicians.20,21 Recommendations that receive a majority vote are sent to the CDC director to be considered for approval.20 After adoption by the CDC director, ACIP recommendations become official policy when published in the Morbidity and Mortality Weekly Report (MMWR). Updated vaccine schedules for pediatric and adult populations are published every February in MMWR and the journals of the aforementioned medical societies.5,21
Post-Licensure Monitoring of Vaccines
A comprehensive safety surveillance system rigorously monitors vaccines and their administration to the public after licensure (Figure 2). Studies during clinical development may not have sufficient sample sizes to detect rare adverse events, or sufficient lengths of study to capture those with delayed onset. Because all possible adverse events cannot be predicted before the vaccine is distributed in the real-world environment, the FDA increasingly requires vaccine manufacturers to conduct Phase IV trials. These studies are an integral part of the post-licensure safety monitoring system and define the frequency of uncommon adverse events in specific risk groups.22 For example, a Phase IV study found a small increased risk of a febrile convulsion 5 to 12 days after administration of the combined measles, mumps, rubella, and varicella (MMRV) vaccine compared with separate injections of the MMR and V vaccines at the same visit.23 The ACIP used data from this study and other post-licensure trials to issue updated recommendations regarding use of the MMRV vaccine in different age groups.23
The Vaccine Adverse Event Reporting System (VAERS) is also crucial for monitoring vaccine safety. This passive reporting system, jointly maintained by the FDA and CDC, allows anyone to report adverse events that occur after vaccine administration. Health care providers are required by law to submit adverse event reports.24,25 These events may be coincidental or causally related to the vaccine, so VAERS is valuable as a hypothesis-generating system to detect possible safety issues.24,25 Subsequent hypothesis-driven study by the FDA and CDC is required to establish any cause-and-effect relationship.24,25 For example, VAERS reports of intussusception after administration of the RotaShield rotavirus vaccine (Merck & Co; Kenilworth, NJ), licensed in 1998, led the CDC to suspend its recommendation for the vaccine and conduct an investigation.25 Ultimately, this vaccine was withdrawn from the market, representing one of VAERS' earliest successes in monitoring safety.25
Other safety mechanisms include the Vaccine Safety Datalink (VSD), Post-Licensure Rapid Immunization Safety Monitoring (PRISM), and Clinical Immunization Safety Assessment Project (CISA). VSD is a collaboration between nine health care organizations and the CDC's Immunization Safety Office (ISO). Unlike VAERS, which relies on self-reports, VSD uses electronic health data from participating sites to evaluate vaccine safety and conduct studies about adverse events after immunization.26 Similarly, PRISM is a system that uses health insurance claims data, not self-reports, to monitor vaccine safety and identify any issues.10 CISA is a collaboration between the CDC's ISO and vaccine safety experts from seven medical research centers.27 In addition to reviewing rare adverse events after immunization and conducting clinical research to evaluate vaccine safety, CISA offers consultation to clinicians who have complex vaccine safety questions for specific patients.27 In summary, the post-licensure surveillance systems are robust and collect data from multiple sources, including self-reports, medical records, and health insurance claims, to ensure the highest level of safety and monitoring.
Vaccines have played a major role in improving public health, and they continue to save lives. After extensive characterization and testing in nonhuman subjects and human volunteers, vaccines undergo a highly regulated, active process of FDA licensure, development of ACIP recommendations, and post-licensure monitoring. There are many checkpoints along the path in adhering to regulatory requirements and receiving approval from various government agencies and advisory committees. These checkpoints emphasize that vaccine development is a coordinated effort that prioritizes safety during each step of the process, even with accelerated review.
For the success of the entire US vaccine program, it is imperative to build public trust and promote a clear understanding of the vaccine development process and the comprehensive safety systems. This is especially relevant in light of the COVID-19 pandemic and the pace with which vaccines are being developed. Despite efforts to rapidly develop a safe and effective vaccine, it must ultimately be accepted by and administered to a majority of the public to significantly decrease the spread of COVID-19 and its associated morbidity and mortality. Health care providers will be crucial for educating patients and promoting vaccination to achieve the necessary uptake of COVID-19 vaccines to return to pre-pandemic conditions. Efforts are needed to improve overall confidence in vaccines, reduce hesitancy, and maintain the remarkable successes that vaccinations have achieved in reducing the burden of infectious diseases.
- Curlin G, Landry S, Bernstein J, et al. Integrating safety and efficacy evaluation throughout vaccine research and development. Pediatrics. 2011;127(suppl 1):S9–S15. doi:10.1542/peds.2010-1722C [CrossRef] PMID:21502246
- Greenwood B. The contribution of vaccination to global health: past, present and future. Philos Trans R Soc Lond B Biol Sci. 2014;369(1645):20130433. doi:10.1098/rstb.2013.0433 [CrossRef] PMID:24821919
- Orenstein WA, Ahmed R. Simply put: vaccination saves lives. Proc Natl Acad Sci U S A. 2017;114(16):4031–4033. doi:10.1073/pnas.1704507114 [CrossRef]
- Ventola CL. Immunization in the United States: recommendations, barriers, and measures to improve compliance: part 1: childhood vaccinations. P T. 2016;41(7):426–436. PMID:27408519
- Pickering LK, Walton LR. Vaccines in the pipeline: the path from development to use in the United States. Pediatr Ann. 2013;42(8):146–152. doi:10.3928/00904481-20130723-08 [CrossRef] PMID:23910027
- The College of Physicians of Philadelphia. Vaccine development, testing, and regulation. Accessed November 16, 2020. https://www.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation
- World Health Organization. Ten threats to global health in 2019. Accessed November 16, 2020. https://www.who.int/news-room/feature-stories/ten-threats-to-global-health-in-2019
- Bloom BR, Nowak GJ, Orenstein W. “When will we have a vaccine?” - understanding questions and answers about COVID-19 vaccination [published online ahead of print September 8, 2020]. N Engl J Med. doi:10.1056/NEJMp2025331 [CrossRef] PMID:32897660
- Corey L, Mascola JR, Fauci AS, Collins FS. A strategic approach to COVID-19 vaccine R&D. Science. 2020;368(6494):948–950. doi:10.1126/science.abc5312 [CrossRef] PMID:32393526
- Edwards KM, Hackell JMThe Committee on Infectious Diseases; The Committee on Practice and Ambulatory Medicine. Countering vaccine hesitancy. Pediatrics. 2016;138(3): e20162146. doi:10.1542/peds.2016-2146 [CrossRef]
- National Institute of Allergy and Infectious Diseases. Vaccine types. Accessed November 16, 2020. https://www.niaid.nih.gov/research/vaccine-types
- Children's Hospital of Philadelphia. Making vaccines: process of vaccine development. Accessed November 16, 2020. https://www.chop.edu/centers-programs/vaccine-education-center/making-vaccines/process-vaccine-development
- US Food and Drug Administration. Vaccine product approval process. Accessed November 16, 2020. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-product-approval-process
- Baylor NW. The Regulatory evaluation of vaccines for human use. In: Thomas S, ed. Vaccine Design. Humana Press; 2016:773–787. doi:10.1007/978-1-4939-3389-1_51 [CrossRef]
- Marshall V, Baylor NW. Food and Drug Administration regulation and evaluation of vaccines. Pediatrics. 2011;127(suppl 1):S23–S30. doi:10.1542/peds.2010-1722E [CrossRef] PMID:21502242
- Hudgens MG, Gilbert PB, Self SG. Endpoints in vaccine trials. Stat Methods Med Res. 2004;13(2):89–114. doi:10.1191/0962280204sm356ra [CrossRef] PMID:15068256
- MacNeil JR, Rubin L, McNamara L, Briere EC, Clark TA, Cohn ACMeningitis and Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC. Use of MenACWY-CRM vaccine in children aged 2 through 23 months at increased risk for meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, 2013. MMWR Morb Mortal Wkly Rep. 2014;63(24):527–530. PMID:24941332
- Meissner HC, Farizo K, Pratt D, Pickering LK, Cohn AC. Understanding FDA-approved labeling and CDC recommendations for use of vaccines. Pediatrics. 2018;142(3):e20180780 doi:10.1542/peds.2018-0780 [CrossRef] PMID:30139807
- US Food and Drug Administration. Fast track, breakthrough therapy, accelerated approval, priority review. Accessed November 16, 2020. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review
- Smith JC, Snider DE, Pickering LKAdvisory Committee on Immunization Practices. Immunization policy development in the United States: the role of the Advisory Committee on Immunization Practices. Ann Intern Med. 2009;150(1):45–49. doi:10.7326/0003-4819-150-1-200901060-00009 [CrossRef] PMID:19124820
- Pickering LK, Meissner HC, Orenstein WA, Cohn AC. Principles of vaccine licensure, approval, and recommendations for use. Mayo Clin Proc. 2020;95(3):600–608. doi:10.1016/j.mayocp.2019.11.002 [CrossRef] PMID:32063358
- Pickering LK, Orenstein WA. Development of pediatric vaccine recommendations and policies. Semin Pediatr Infect Dis. 2002;13(3):148–154. doi:10.1053/spid.2002.125857 [CrossRef] PMID:12199610
- Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine. 2009;27(34):4656–4661. doi:10.1016/j.vaccine.2009.05.056 [CrossRef] PMID:19520201
- Centers for Disease Control and Prevention. Vaccine Adverse Event Reporting System (VAERS). Accessed November 16, 2020. https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html
- Shimabukuro TT, Nguyen M, Martin D, DeStefano F. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2015;33(36):4398–4405. doi:10.1016/j.vaccine.2015.07.035 [CrossRef] PMID:26209838
- Centers for Disease Control and Prevention. Vaccine Safety Datalink (VSD). Accessed November 16, 2020. https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html
- Centers for Disease Control and Prevention. Clinical Immunization Safety Assessment (CISA) project. Accessed November 16, 2020. https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html
Main Types of Vaccines Currently Availablea
|How the vaccine works
||Weakened pathogen, produces strong immune response without disease
||Pathogen is inactivated by heat/chemicals
Cannot replicate but is still recognized by immune system
||Toxin causing disease is modified
Immunologic response to toxoid protects against disease caused by pathogen
||Vaccine made of specific antigens of the pathogen (protein or polysaccharide based)
||One or two doses can provide lifetime immunity
May not be safe for those with weakened immune systems
||Typically requires primary series and booster doses
Can be administered to those with weakened immune systems
||May need booster doses
||May need booster doses
Can reduce side effects because it only contains essential antigens
Four Distinct FDA Approaches of Making Drugs/Vaccines Available as Quickly as Possible
||Accelerate the development of prospective drugs/vaccines
||Expedite the development and review of drugs/vaccines for serious conditions that may display major improvement over available therapy
||Allow faster approval of drugs/vaccines for serious conditions by using a surrogate or intermediate clinical endpoint
||Move up the target time by which the FDA aims to act upon the application (within 6 months vs standard 10 months)
|Questions to consider
||Will the drug/vaccine fill an unmet need for a serious condition?
||Does preliminary clinical evidence show that the drug/vaccine may have substantial improvement on a clinically significant endpoint over available therapy?
What is the magnitude of the treatment effect and clinical result?
||Will the drug/vaccine fill an unmet need for a serious condition?
Is there sufficient scientific support for the proposed surrogate or intermediate endpoint?
||Will the drug/vaccine substantially improve the safety or effectiveness of the prevention, diagnosis, or treatment of a serious condition?
||Drug/vaccine may be eligible for:
Rolling review (BLA can be submitted in sections at a time for FDA review)
Faster drug/vaccine approval and earlier access for the public
||Drug/vaccine is eligible for:
All features of the Fast Track designation
Intensive FDA guidance on efficient drug development program
Organizational commitment to involve senior management
||Faster drug/vaccine approval to meet the needs of those suffering from the condition
||Faster review time for drug/vaccine
Overall attention and resources are directed to evaluating priority applications over standard applications
|Information to note
||Can be requested at any time during the development process
Will likely require more frequent communications with the FDA to discuss development
||Should be requested before end of Phase II meetings
||FDA will accept or reject the clinical endpoint based on its scientific support
Phase IV confirmatory trials must be conducted to verify clinical benefit
||Although applicants can specifically request Priority Review, the FDA decides between Standard and Priority Review designation for each application