Biologics License Application Research Articles

Staying Out of Trouble: FDA Regulation of Orthobiologics and the Shoulder Surgeon

Food and Drug Administration (FDA) regulation of Orthobiologics can be challenging to interpret for the non-regulatory scientist. However, understanding how regulations apply to clinical use of these orthobiologic products is critical, as there are both ethical and legal ramifications to using orthobiologics in conflict with regulations. Recent FDA guidances have attempted to clarify these issues, although questions still remain regarding nuances in regulatory applications. FDA guidances, industry blogs, and relevant publications were searched for citations regarding recent orthobiologics and regulations. These sources were compiled into a current assessment of FDA regulations regarding the use of orthobiologics in the shoulder. Key to understanding these regulations is the FDA differentiation of human cellular and tissue based products (HCTPs) into 361 and 351 category products. While some controversy still exists, FDA has attempted to clarify these issues with several recent guidances. Of equal importance, FDA has ended enforcement discretion for many biologic products in June of 2021, creating a previously tolerated class of orthobiologics that now requires an Investigational New Drug (IND) application and subsequent Biologic License Application to legally market these orthobiologics. The Same Surgical Procedure Exception was further clarified in 2017 to exempt facilities from regulatory controls when specific guidelines are met. This article attempts to clarify the current thinking on FDA regulations and will allow the shoulder and elbow surgeon to stay within the current bounds of ethical and legal use of these products.

From bench to clinic: the development of VLA1553/IXCHIQ, a live-attenuated chikungunya vaccine.

Over the past 20 years, over 5 million cases of chikungunya, a mosquito-transmitted viral disease, have been reported in over 110 countries. Until recently, preventative strategies for chikungunya were largely ineffective, relying on vector control and individual avoidance of mosquito bites. This review outlines the preclinical and clinical efficacy and safety data that led to the approval of VLA1553 (IXCHIQ®), a live-attenuated vaccine against chikungunya disease. It also describes the innovative development pathway of VLA1553, based on an immunological surrogate of protection, and discusses ongoing and future post-licensure studies. In mice and non-human primate models, VLA1553 elicited high titres of neutralizing antibodies, conferred protection against wild-type chikungunya virus challenge and raised no safety concerns. A Phase 1 clinical trial of VLA1553 demonstrated 100% seroconversion among 120 healthy participants, with sustained neutralizing antibody titres after 12 months. These results and determination of a surrogate marker of protection led to advancement of VLA1553 directly into Phase 3 clinical development, as agreed with the US Food and Drug Administration (FDA) and the European Medicines Agency. The pivotal Phase 3 trial met its primary immunogenicity endpoint, achieving seroprotective levels based on immuno-bridging in baseline seronegative participants 28 days post-vaccination. These findings enabled submission of a Biologics License Application to the FDA for accelerated approval of VLA1553 in the US for adults aged ≥18 years. Ongoing and planned studies will confirm the clinical efficacy/effectiveness and safety of VLA1553 in adults and younger individuals, and will generate data in chikungunya endemic countries that have the highest unmet need. VLA1553 is the first vaccine approved for the prevention of chikungunya disease in adults, following accelerated development based on a serological surrogate marker of protection. VLA1553 adds to strategies to reduce the spread and burden of chikungunya in endemic populations and travellers.

HPR127 Examine the Use of Real-World Evidence To Support FDA Decision-Making for New Drug Applications and Biologics License Applications From 2021 to 2022

HPR127 Examine the Use of Real-World Evidence To Support FDA Decision-Making for New Drug Applications and Biologics License Applications From 2021 to 2022

Clinical pharmacology considerations for first-in-human clinical trials for enzyme replacement therapy.

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023. We surveyed study design elements across these FIH protocols including study population, dosage form, dose selection, treatment duration, immunogenicity, biomarkers, and study follow-up. A total of 18 FIH trials from 20 BLAs were identified and of those, 72% (13/18) used single ascending dose (SAD) and/or multiple ascending dose (MAD) study design, 83% (15/18) had a primary objective of assessing the safety and tolerability, 72% (13/18) included clinical endpoint assessments, and 94% (17/18) included biomarker assessments as secondary or exploratory endpoints. Notably, the majority of ERT products tested the approved route of administration and the approved dose was tested in 83% (15/18) of FIH trials. At last, we offer considerations for the design of FIH studies.

Development and validation of bioanalytical methods to support clinical study of disitamab vedotin.

Disitamab vedotin (RC48), a humanized anti-HER2 antibody conjugated with monomethyl auristatin E (MMAE), is the first antibody-drug conjugate in China with an approved biological license application. A bioanalytical method was established for three analytes (total antibody, conjugate antibody and free payload) to help characterize their pharmacokinetic behavior in clinical settings. The bioanalytical methods were validated according to M10 guidance. Electrochemiluminescence assaymethods were used for thequantitative measurement of total antibody and conjugated antibody in human serum. A LC-MS/MSmethod was used to quantify the concentration of MMAE in human serum. The method had high specificity and sensitivity with a quantitative range of 19.531-1250.000ng/ml (total antibody), 39.063-5000.000ng/ml (conjugated antibody)and 0.04-10.0ng/ml (MMAE), respectively.

Underrepresentation of Older Adults in Clinical Trials of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hematologic Malignancies: An FDA Analysis

Background: As the population ages, the prevalence of hematologic malignancies in older adults will continue to increase. Older adults, especially older than 75 years, are routinely underrepresented in clinical trials evaluating hematologic malignancies, largely due to access and logistics, comorbidities, toxicity concerns, and eligibility restrictions. Given the recent approvals of multiple CAR T-cell therapies for patients with hematologic malignancies, we evaluated the rates of enrollment of older adults (age ≥ 65 years) in registrational trials of CAR T-cell therapies submitted to the U.S. Food and Drug Administration (FDA). Methods: We conducted a pooled analysis of the registrational trials submitted to the FDA between 2017 and 2021 that supported approvals of autologous CAR T-cell therapies in patients with hematologic malignancies. Datasets submitted with the biologic license applications were pooled and analyzed descriptively for demographics, disease characteristics, and efficacy outcomes. Patients between the ages of 65 and 74 and age 75 and above were analyzed separately. Results: Thirteen registrational trials evaluating six CAR T-cell products in 1,319 patients with hematologic malignancies were submitted to FDA. The median age at enrollment was 60 years (range: 3 to 86). In total, 7% (88) of patients were 75 years and older, 28% (366) were between the ages of 65 and 74 years, and 66% (865) were under the age of 65 years. The hematologic malignancies included large B-cell lymphoma (59%), multiple myeloma (15%), follicular lymphoma (13%), B-cell acute lymphoblastic leukemia (9%), and mantle cell lymphoma (5%). Response rates by age group and histology are shown in Table 1 and Table 2. Conclusions: Older adults, particularly those aged 75 years or older, were underrepresented in the trials supporting FDA approval of CAR T-cell therapies considering the predominant hematologic malignancies included in this pooled analysis and the median age of diagnosis of these diseases in the U.S. population. Although clinically meaningful efficacy was achieved across age groups and diseases, more data are needed to determine the impact of age on efficacy outcomes in specific malignancies. In this analysis, data were limited among patients 75 years and older in all histologies except large B cell lymphoma. Work to evaluate the impact of age on safety and tolerability outcomes is ongoing. To improve accrual, greater efforts to understand and reduce barriers to clinical trial enrollment for older adults are needed, especially given the expanding use of CAR T-cell therapies and their toxicity profiles.

Rare oncology therapeutics: review of clinical pharmacology package of drug approvals (2019-2023) by US FDA, best practices and recommendations.

There are many challenges with rare diseases drug development and rare oncology indications are not different. To understand the regulatory landscape as it relates to application of clinical pharmacology principles in rare oncology product development, we reviewed publicly available information of 39 approvals by US FDA between January 2019 and March 2023. The objective was to understand the expected clinical pharmacology studies and knowledge base in such approvals. Model informed drug development (MIDD) applications were also reviewed, as such approaches are expected to play a critical role in filling clinical pharmacology gaps in rare oncology, where number of clinical trials and size of these trials will perhaps continue to be small. The findings highlighted how clinical pharmacology contributed to the evidence of effectiveness, dose optimization and elucidation of intrinsic and extrinsic factors affecting drug's behavior. Clinical pharmacology studies were often integrated with modeling in many of the NDAs/BLAs. Of the post marketing requirements (PMR) received, 18% were for dose optimization, 49% for DDI, 8% for QTc, 49% for specific population, and 5% for food effect. Two post marketing commitments (PMC) were issued for immunogenicity of the 11 biologics submissions. 15% (6 of 39) of the submissions used maximum tolerated dose (MTD) to advance their molecule into Phase 2 studies. Of them 3 approvals received PMR for dose optimization. 3 + 3 was the most prevalent Phase 1 design with use in 74% of the New Drug Applications (NDA)/Biologic License Applications (BLA) reviewed. Rest used innovative approaches such as BLRM, BOIN or mTPi, with BLRM being the most common. Seamless clinical pharmacology and MIDD approaches are paramount for rare oncology drug development.

The Use of Mass Spectrometry in Therapeutic Protein Biologics License Applications: A Retrospective Review Revisited.

Biologic license applications (BLAs) for 93 therapeutic proteins approved between 2016 and 2020 were analyzed for use of mass spectrometry (MS) as a follow up to a previous study that assessed MS use in BLAs from 2000 to 2015. Thirty percent of these BLAs were biosimilars, while only one biosimilar BLA was approved prior to 2016. This analysis evaluated the use of a variety of MS techniques and instrumentation. Results were further interpreted based on the relationship of MS use over time, between drug types, and between new drugs and biosimilars. MS data were included in 93 BLAs examined. The top eight quality attributes most assessed by MS in rank order were amino acid sequence, molecular mass, oxidation, disulfide bonds, deamidation, glycosylation, N-terminal sequence variants, and C-terminal sequence variants. These attributes were the same top attributes seen previously from BLAs approved between 2000 and 2015, and the use of MS to analyze them generally continued to increase across the new time frame. The average number of attributes analyzed by MS per BLA also continued to increase over the extended time frame of 21 years. High-resolution, accurate mass instrumentation such as the Orbitrap and time-of-flight (TOF) usage increased over time for all assessed attributes, while matrix-assisted laser desorption/ionization (MALDI)-TOF/(TOF) usage decreased. From highest to lowest rank, the top 11 attributes were antibody drug conjugate (ADC) characterization (i.e., drug load distribution/drug to antibody ratio (DAR), ADC and linkage site, and synthetic linker), isomerization, folding/higher-order structure (HOS), truncation, host cell proteins (HCPs), sequence variants (amino acid substitutions), succinimidation, glycation, PEGylation, charge variants, and oxidation.

Evaluation of Truncated AUC as an Alternative Measure to Assess Pharmacokinetic Comparability in Bridging Biologic-Device Using Prefilled Syringes and Autoinjectors.

Pharmacokinetic (PK) comparisons between therapeutic biologics have largely been based on the total area under the concentration-time curve (AUC) and the maximum concentration (Cmax ). For biologics with a long half-life, a PK comparability study may be long in duration and costly to conduct. The goal of this study was to evaluate whether a truncated AUC (tAUC) can be used to assess PK comparability when bridging prefilled syringe (PFS) and autoinjector (AI) treatment options for biologics with a long half-life. Fifteen biologics license applications (BLAs) were included to determine the concordance and geometric percent coefficient of variation (%CV) between tAUCs evaluated on days7, 14, 21, and 28 and AUC evaluated to infinity (AUC0-inf ). Concordance is established if the tAUCs are comparable with AUC0-inf . Trial simulation was performed to examine the effect of the absorption rate constant (ka ) and sample size on the concordance of tAUCs. The tAUCs evaluated on day14, 21, and 28 had 100% concordance with AUC0-inf for all 15 BLAs. The concordance of tAUC evaluated at day7 was 87.5%. Based on the trial simulation, tAUC evaluated to day28 post-dose can achieve high concordance (≥85%) for biologics exhibiting linear or nonlinear elimination with a ka of ≥0.1/day and with a sample size of 70 subjects per arm. tAUC appears to be a promising alternative PK measure, relative to AUC0-inf , for PK comparability assessments.

Use of Real-World Evidence in Neuroscience-Related New Drug and Biologics License Applications for Novel Therapeutics.

The US Food and Drug Administration (FDA) is evaluating the potential use of real-world evidence (RWE) in regulatory decision making. Some groups have evaluated the use of RWE in regulatory submissions in the United States and abroad, reporting that reliance on RWE to support new product approvals is relatively common. Confusion regarding the use of RWE in drug-approval decisions may arise, however, based on different application of the terms real-world data (RWD) and RWE. We evaluated RWE in new drug applications (NDAs) and biologics license applications (BLAs) from January 2019 to June 2021 for novel drugs and biologics approved by the FDA with indications related to psychiatry, neurology, pain, or sedation (here, termed neuroscience-related). We sought to determine whether the submissions included RWE and to describe the types of data and study designs used. Thirty neuroscience-related NDAs or BLAs were identified for novel drugs and biologics approved during the time-period of interest. Among these approvals, three applications (10%) were adjudicated as containing RWE, one of which included RWE as primary evidence of effectiveness. Our findings highlight how different operational definitions of the terms RWD and RWE can result in demonstrably different reporting of the use of RWE in regulatory decision making for neuroscience-related novel drugs and biologics. A better understanding of this topic, along with awareness of regulatory definitions of RWE, are important factors to promote accurate tracking and reporting of regulatory submissions involving RWE. These factors can also improve awareness among the stakeholder community regarding the role of RWD and RWE in regulatory decision making.

Bringing function to the forefront of cell therapy: how do we demonstrate potency?

Unlike conventional pharmaceuticals, biologics and Advanced Therapy Medicinal Products (ATMPs) are required to meet a standard of "potency" as part of the final release criteria at completion of manufacture. During early phase clinical trials, most regulatory agencies have been willing to accept very immature potency assays with an expectation that these will be improved, qualified and validated during the clinical development of the drug to Marketing Authorisation Application (MAA) or Biologics License Application (BLA) submission.This model of continuous development of potency assay in parallel with drug development has already led to at least two notable problem cases; namely Iovance and Mesoblast. Both companies completed successful phase III clinical trials but, in both cases, the initial BLA was rejected on the basis that their potency assay for drug product release was inadequate. Fortunately these issues appear to have been overcome in March of this year, with Mesoblast receiving acceptance of their BLA for Remestemcel and Iovance obtaining a rolling BLA approval for Lifileucel.

Benefit-risk assessment of Covid-19 vaccine, MRNA (MRNA-1273) for males age 18–64 years

Since the authorization of the Moderna mRNA COVID-19 vaccine, real-world evidence has indicated its effectiveness in preventing COVID-19 cases. However, increased cases of mRNA vaccine-associated myocarditis/pericarditis have been reported, predominantly in young adults and adolescents. The Food and Drug Administration conducted a benefit-risk assessment to inform the review of the Biologics License Application for use of the Moderna vaccine among individuals ages 18 and older. We modeled the benefit-risk per million individuals who receive two complete doses of the vaccine. Benefit endpoints were vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, and deaths. The risk endpoints were vaccine-related myocarditis/pericarditis cases, hospitalizations, ICU admissions, and deaths. The analysis was conducted on the age-stratified male population due to data signals and previous work showing males to be the main risk group. We constructed six scenarios to evaluate the impact of uncertainty associated with pandemic dynamics, vaccine effectiveness (VE) against novel variants, and rates of vaccine-associated myocarditis/pericarditis cases on the model results. For our most likely scenario, we assumed the US COVID-19 incidence was for the week of December 25, 2021, with a VE of 30% against cases and 72% against hospitalization with the Omicron-dominant strain. Our source for estimating vaccine-attributable myocarditis/pericarditis rates was FDA’s CBER Biologics Effectiveness and Safety (BEST) System databases. Overall, our results supported the conclusion that the benefits of the vaccine outweigh its risks. Remarkably, we predicted vaccinating one million 18–25 year-old males would prevent 82,484 cases, 4,766 hospitalizations, 1,144 ICU admissions, and 51 deaths due to COVID-19, comparing to 128 vaccine-attributable myocarditis/pericarditis cases, 110 hospitalizations, zero ICU admissions, and zero deaths. Uncertainties in the pandemic trajectory, effectiveness of vaccine against novel variants, and vaccine-attributable myocarditis/pericarditis rate are important limitations of our analysis. Also, the model does not evaluate potential long-term adverse effects due to either COVID-19 or vaccine-attributable myocarditis/pericarditis.

HPR111 A Systematic Review of Real-World Evidence (RWE) Supportive of New Drug and Biologic License Application Approvals in Rare Diseases

Real-world evidence (RWE) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This study aimed to evaluate the use of RWE generated for RD therapies to support regulatory application packages to the US Food and Drug Administration (FDA).

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

Regulatory approval pathway for COVID-19 vaccine in USA, Europe and India.

The coronavirus disease-2019 (COVID-19) outbreak has confused everyone, including healthcare experts, physicians and frontline workers. Monoclonal antibodies, anticoagulants and immunomodulatory therapy were initially used to treat COVID-19. However, they can only inhibit the virus from replicating, which is not enough to provide a lasting cure. As each month passes, a growing number of companies are working on vaccinations that will aid in the development of resistance against the corona virus. As a result, all regulatory bodies have stated that if a vaccine has high efficacy and low risk of adverse events, it will be approved through an emergency use application. However, there is one major hindrance: After completing phase II clinical trials with an emergency use application, the product can be released to the market. However, the firm should conduct phase III and phase IV trials at the same time, with peer review occurring after each cycle of clinical trials and also market data to be presented simultaneously to track adverse events. In this article, the author has compared the standard approval process (i.e. Standard Biological License application) with the emergency use application to describe how the COVID-19 vaccine was approved by the different regulatory bodies.

What Can Be Achieved with the Estimand Framework?

The ICH E9(R1) guidance on estimands is a key tool for the creation and review of protocol design and analysis planning, for both industry and regulatory statisticians. The framework has been described as useful for improving study design, intercurrent event handling, data collection, analysis, and interpretation to align the estimand with the primary clinical question to add clarity and precision to support regulatory decision-making. In this article, we describe our experience as regulatory statisticians in review of Investigational New Drug protocols and statistical analysis plans, with an emphasis on trials used to support substantial evidence of effectiveness in New Drug Applications and Biologic License Applications. Our intent is to describe our experience with this powerful and effective framework tool, to align the clinical trial’s primary objective with its analysis outcomes and interpretation.

Regulatory approval pathway for COVID-19 vaccine in USA, Europe and India

The coronavirus disease-2019 (COVID-19) outbreak has confused everyone, including healthcare experts, physicians and frontline workers. Monoclonal antibodies, anticoagulants and immunomodulatory therapy were initially used to treat COVID-19. However, they can only inhibit the virus from replicating, which is not enough to provide a lasting cure. As each month passes, a growing number of companies are working on vaccinations that will aid in the development of resistance against the corona virus. As a result, all regulatory bodies have stated that if a vaccine has high efficacy and low risk of adverse events, it will be approved through an emergency use application. However, there is one major hindrance: After completing phase II clinical trials with an emergency use application, the product can be released to the market. However, the firm should conduct phase III and phase IV trials at the same time, with peer review occurring after each cycle of clinical trials and also market data to be presented simultaneously to track adverse events. In this article, the author has compared the standard approval process (i.e. Standard Biological License application) with the emergency use application to describe how the COVID-19 vaccine was approved by the different regulatory bodies.

Paving the Road for Chimeric Antigen Receptor T Cells: American Society for Transplantation and Cellular Therapy 80/20 Task Force Consensus on Challenges and Solutions to Improving Efficiency of Clinical Center Certification and Maintenance of Operations for Commercially Approved Immune Effector Cell Therapies

As the number and type of regulatory authority-approved cellular therapies grow, clinical treatment centers face a heavy burden of duplicative documentation around initial qualification, ongoing auditing, and reporting, with overlapping requirements from each manufacturer to ensure safe use of their specific product, which in the United States are stipulated under individual Food and Drug Administration (FDA) Biologic License Applications. The American Society for Transplantation and Cellular Therapy (ASTCT) convened the 80/20 Task Force to consider challenges and potential solutions to these issues. The Task Force proposed that 80% of manufacturers' requirements for onboarding and ongoing operations of commercially available products could be standardized and streamlined. Task Force members interviewed dozens of stakeholders, including clinicians at large academic medical centers already using commercial and investigational immune effector cell (IEC) products, regulators, members of accrediting bodies and professional cellular therapy societies, and manufacturers of IEC therapies for oncologic indications. In November 2021, the Task Force organized and led virtual discussions in a public forum and at a private ASTCT 80/20 Workshop at the online AcCELLerate Forum, a cellular-therapy stakeholders' meeting organized by the ASTCT, National Marrow Donor Program (NMDP), and Center for International Blood and Marrow Transplant Research (CIBMTR). At the workshop, approximately 60 stakeholders worked to identify and prioritize common challenges in onboarding and maintenance of operations at clinical sites for commercial FDA-approved and future IEC therapies and ways to streamline the process. It was agreed that standardization would improve efficiency of onboarding, allowing more cost-effective, sustainable growth of approved IEC therapies at treatment centers, and facilitate wider access while maintaining safety and clinical success. This early but extensive survey of stakeholders resulted in 5 overarching suggestions for both established and emerging treatment centers: (1) eliminate duplication in accreditation and auditing of clinical sites; (2) define expectations for the education about and management of CAR-T therapy toxicities to potentially replace product-specific REMS programs; (3) streamline current REMS education, testing, and data reporting; (4) standardize information technology (IT) platforms supporting enrollment, clinical site-manufacturer communication, and logistics of maintaining chain of identity/chain of custody across multiple transportation steps; and (5) encourage the use of universal nomenclature by cell therapy manufacturers. Future discussions need to engage a broader range of stakeholders, including administrators, pharmacists, nurses, data coordinators, surgeons, pathologists, and those developing promising cellular therapies for solid tumors, as well as teams from smaller academic or community cancer center settings. Continued collaboration with stakeholders outside of clinical sites will include accrediting bodies/auditors, established and emerging cell therapy companies, software developers, professional societies, and the patients who receive these therapies. Active dialog with government regulators remains essential. Such joint efforts are critical as the number of IEC therapies for myriad oncologic and nononcologic indications grows.

Advanced Processes for Clinical Pharmacology Evaluation in Board Exams

As a medical educator for over 30 years, and a member of the National Board of Osteopathic Medical Examiners (NBOME) for 20 of this time, I am concerned about the burden placed on those taking boards. In the USA, an increase in Biologic License Applications (BLAs) plus New Molecular Entities (NMEs) over these past two decades is extensive. Considering that there was not an equivalent number of agents withdrawn from the market leaves a large net amount of new medicines to be learned in additional to what we are already teaching. In my opinion, this is an overload and one of the causes contributing to increased burnout among young physicians-to-be. As recently concluded, “Advances in medicine and technology mean that medical students are expected to learn significantly more information than their predecessors in the same amount of time1.” Other contributory factors cited in this article include participation in extracurricular, research and leadership activities, all designed to improve chances for admission into targeted residencies.

Effectiveness of Pfizer-BioNTech COVID-19 vaccine as evidence for policy action: A rapid systematic review and meta-analysis of non-randomized studies.

In December 2020, an interim recommendation for the use of Pfizer-BioNTech COVID-19 vaccine in persons aged ≥16 years was made under Food and Drug Administration's Emergency Use Authorization. In preparation for Biologics License Application approval, we conducted a systematic review and meta-analysis to inform the U.S. Centers for Disease Control and Prevention's Advisory Committee for Immunization Practice's (ACIP) decision-making for a standard recommendation. We conducted a rapid systematic review and meta-analysis of Pfizer-BioNTech vaccine effectiveness (VE) against symptomatic COVID-19, hospitalization due to COVID-19, death due to COVID-19, and asymptomatic SARS-CoV-2 infection. We identified studies through August 20, 2021 from an ongoing systematic review conducted by the International Vaccine Access Center and the World Health Organization. We evaluated each study for risk of bias using the Newcastle-Ottawa Scale. Pooled estimates were calculated using meta-analysis. The body of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We identified 80 articles, selected 35 for full-text review, and included 26. The pooled VE of Pfizer-BioNTech COVID-19 vaccine was 92.4% (95% CI: 87.5%-95.3%) against symptomatic COVID-19 with moderate evidence certainty (eight studies), 94.3% (95% CI: 87.9%-97.3%) against hospitalization due to COVID-19 with moderate certainty (eight studies), 96.1% (95% CI: 91.5%-98.2%) against death due to COVID-19 with moderate certainty (four studies), and 89.3% (88.4%-90.1%) against asymptomatic SARS-CoV-2 infection with very low certainty (two studies). The Pfizer-BioNTech COVID-19 vaccine demonstrated high effectiveness in all pre-specified outcomes and extended knowledge of the vaccine's benefits to outcomes and populations not informed by the RCTs. Use of an existing systematic review facilitated a rapid meta-analysis to inform an ACIP policy decision. This approach can be utilized as additional COVID-19 vaccines are considered for standard recommendations by ACIP.