Prelicensure Clinical Trials Research Articles

Prophylaxis of respiratory syncytial virus infection: current status and prospects for vaccine development

INTRODUCTION. Respiratory syncytial virus (RSV) is one of the most widespread pathogens that typically cause acute upper and lower respiratory tract infections in children and adults. Monoclonal antibody products have long been used for passive immunoprophylaxis in premature infants with bronchopulmonary dysplasia. However, vaccines have recently been licensed for the prophylactic immunisation of older adults with various risk factors for severe RSV infection (primarily, chronic cardiovascular and respiratory diseases and diabetes mellitus).AIM. This study aimed to review the current status of the development of vaccines for active immunisation against RSV infection, including the epidemiological rationale for their development, clinical trial results for licensed vaccines, recommendations for vaccination, and promising pipeline vaccines for RSV prevention.DISCUSSION. Initially hindered by the unique immunopathogenesis of RSV infection and the genetic hypervariability of RSV for a long time, attempts to develop an RSV vaccine succeeded when international researchers managed to identify a conservative neutralising antibody target capable of inducing specific immunity against RSV. This target, the RSV capsid protein stabilised in its prefusion (pre-F) conformation, can mediate viral entry into the cell following a conformational change. Several subunit vaccines based on recombinant pre-F proteins have successfully passed clinical trials and have been approved for the immunisation of older adults. In addition, one of these vaccines has been recommended for use during pregnancy to prevent RSV infection in newborns and infants. Currently, programmes are being implemented to develop novel RSV vaccines based on messenger RNA (mRNA) and non-replicating attenuated influenza vectors. This article examines and summarises the efficacy and safety parameters of two RSV vaccines approved in multiple countries around the world. Both vaccines have satisfactory safety profiles and comparable prophylactic efficacy parameters.CONCLUSIONS. Prelicensure clinical trials of novel RSV vaccines, including those being developed in the Russian Federation, should include prophylactic efficacy assessments in target patient populations. For vaccines approved by leading international regulators, clinical trials required for approval in the Russian Federation will be limited to bridging studies confirming the immunogenicity and safety of the vaccines.

A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Adverse events from HPV vaccination in Taiwan

The safety of human papillomavirus (HPV) vaccines has been evaluated continuously in pre-licensure clinical trials, post-marketing surveillance systems, and observational studies. Most studies have found no significant association between serious adverse events and HPV vaccination. However, these studies have focused on Western populations; similar studies focusing on Asian populations are insufficient. Our retrospective cohort study used the HPV-vaccination records of junior high-school adolescent girls aged 12–15 years between 2013 and 2018 in Taiwan’s National Immunization Information System and linked them to a registry for beneficiaries in Taiwan’s National Health Insurance Database (NHID) to establish the vaccinated group. We selected 19 serious diseases as serious adverse events. We compared the incidence rates of these serious adverse events between the vaccinated group and girls in the same age group population, and we calculated the standardized incidence ratio (SIR) to evaluate the risk of serious adverse events after HPV vaccination. Because of the onset of different types of diseases, we set three periods after the subjects received HPV vaccination: within 3 months, within 1 year, and during the study period (2013–2018). The results showed the incidence rates and the SIRs of 19 selected adverse events. Among the 19 selected serious adverse events, the disease with the highest incidence rate during the study period was fibromyalgia (73.23 cases per million population), and the disease with the lowest incidence rate during the study period was Crohn’s disease (0.15 cases per million population). The results showed no statistically significant increases in the risk of 19 selected serious adverse events and indicated no association between HPV vaccination and serious adverse events. Given the benefits and safety of HPV vaccination, our research can reduce concerns about vaccine side effects, inform health policies and improve public and clinician’s acceptance of HPV vaccine policy.

Considerations of hybrid immunity and the future of adolescent COVID-19 vaccination.

Pre-licensure clinical trials for the BNT162b2 COVID-19 vaccine showed high efficacy among adolescents.1 Similarly, post-licensure studies in this population found high mRNA vaccine effectiveness against both SARS-CoV-2 infection and hospitalisation during the pre-omicron period.2,3 However, emergence of the omicron variant in November, 2021, as well as later omicron subvariants, resulted in decreased COVID-19 vaccine effectiveness and more rapid waning of protection, particularly against infection.

A narrative review of vaccine pharmacovigilance during mass vaccination campaigns: Focus on myocarditis and pericarditis after COVID-19 mRNA vaccination.

Vaccines have had a tremendous impact on reducing the burden of infectious diseases; however, they have the potential to cause adverse events following immunization (AEFIs). Prelicensure clinical trials are limited in their ability to detect rare AEFIs that may occur in less than one per thousand individuals. While postmarketing surveillance systems have shown COVID-19 mRNA vaccines to be safe, they led to the identification of rare cases of myocarditis and pericarditis after COVID-19 vaccination that were not initially detected in clinical trials. In this narrative review, we highlight concepts of vaccine pharmacovigilance during mass vaccination campaigns and compare the approaches used in the context of myocarditis and pericarditis following COVID-19 vaccination to historical examples. We describe mechanisms of passive and active surveillance, their strengths and limitations, and how they interacted to identify and characterize the safety signal of myocarditis and pericarditis after COVID-19 mRNA vaccination. Articles were synthesized from a PubMed search using relevant keywords for articles published on vaccine surveillance systems and myocarditis and pericarditis after COVID-19 vaccination, as well asthe authors' collections of relevant publications and grey literature reports. The global experience around the identification and monitoring of myocarditis and pericarditis after COVID-19 mRNA vaccination has provided important lessons for vaccine safety surveillance and highlighted its importance in maintaining public trust in mass vaccination programmes in a pandemic context.

Prevention of Herpes Zoster: A Focus on the Effectiveness and Safety of Herpes Zoster Vaccines.

Infection with varicella zoster virus typically occurs in children and it can cause primary varicella infection or "chickenpox", or it can reactivate later in life and cause herpes zoster or "shingles". Herpes zoster mainly occurs in older adults, causing a reduction in activities of daily living, impacting quality of life, and may lead to serious complications, including chronic pain. Two vaccines are marketed to prevent herpes zoster: the live zoster vaccine and the non-live, recombinant zoster vaccine. The pre-licensure clinical trials show the efficacy of the live zoster vaccine to be between 50 and 70% and for the recombinant vaccine to be higher at 90 to 97%. Real-world effectiveness studies, with a follow-up of approximately 10 years, were reviewed in this article. These data corroborated the efficacy studies, with vaccine effectiveness being 46% and 85% for the live and recombinant vaccines, respectively. Safety data from the effectiveness studies show similar results to the clinical trials with mostly local injection-site reactions and mild systemic reactions seen with both vaccines, although in larger proportions with the recombinant vaccine. Rare adverse events, occurring less than 1% of the time, have been seen with both vaccine types and include disseminated herpes zoster with the live zoster vaccine and Guillain-Barré syndrome with the recombinant vaccine. The wider use of preventative measures with vaccines will reduce the herpes zoster burden of illness seen in older adults.

Non-clinical considerations for supporting accelerated inclusion of pregnant women in pre-licensure clinical trials with anti-HIV agents.

IntroductionTo allow the continued participation of women enrolled in pre‐licensure clinical trials who become pregnant, and to potentially enrol pregnant women in clinical trials, non‐clinical developmental and reproductive toxicology studies (DART) are essential. Generally during pharmaceutical development, DART studies are conducted late during clinical development, leading to the exclusion of pregnant women from enrolment and withdrawal of women becoming pregnant during pre‐licensure trials.DiscussionCompleting all DART studies prior to or early during the conduct of phase 3 trials (i.e. earlier than current common practice) can accelerate and facilitate the inclusion of women who become pregnant during pre‐licensure trials to remain on study drug and to potentially enrol pregnant women more rapidly. Promoting complementary strategies, such as alternative combinations of DART study designs and physiologically based pharmacokinetic modelling, could better inform drug dosing and safety in pregnancy at an earlier stage in drug development. The interpretation of the results of non‐clinical DART studies is often complex. Institutional review boards/ethics committees should have access to relevant expertise for interpretation and application of results of non‐clinical developmental and reproductive toxicity studies. Clear communication and thorough understanding of non‐clinical findings and the overall benefit–risk profile of the product are critical to review protocols and determine if women who become pregnant during a clinical trial could continue on study drug and/or to enrol pregnant women in the trial. The informed consent document should be well written so that participants can make an informed decision to stay on study drug or participate in a trial during pregnancy. Ultimately, the decision to allow women who become pregnant during pre‐licensure trials to remain on study will depend on the totality of the evidence and benefit–risk considerations.ConclusionsWe propose that industry completes non‐clinical reproductive toxicity studies prior to or early during the conduct of phase 3 trials in HIV drug development, especially for priority agents, and potentially uses alternative DART study design strategies to achieve this goal.

Safety and immunogenicity of HepB-CpG in women with documented pregnancies post-vaccination: A retrospective chart review

BackgroundThere are currently no published data on the use of HepB-CpG (HEPLISAV-B®) during pregnancy or in women with documented pregnancies in the post-vaccination period. We aimed to evaluate data from the clinical development program of HepB-CpG in women who became pregnant during study participation and follow up. MethodsWe identified all study participants in the HepB-CpG pivotal pre-licensure clinical trials that had documented pregnancies during study follow up. We measured immunogenicity among study participants in the HepB-CpG (Heplisav-B®) arm compared to the HepB-alum (Engerix-B®) arm of the studies by comparing seroprotection rates (SPRs; anti-HBs ≥ 10 mIU/mL) and geometric mean concentrations (GMCs) of anti-HBs, obtained with FDA approved anti-HBsAg antibody assays at prespecified time points up to 28 weeks of follow up. Pregnancy outcomes were ascertained by chart review of extracted medical records of study participants. ResultsWe identified 40 documented pregnancies in the HepB-CpG arm and 19 documented pregnancies in the HepB-alum arm. Among subjects with documentation of seroprotection rates, 97.2% (95% CI 85.5–99.9) were seroprotected in the HepB-CpG arm and 66.7% (95% CI 41.0–86.7) were seroprotected in the HepB-alum arm. In the HepB-CpG arm, thirty-six study participants from the pivotal trials had reported pregnancy outcomes, the majority, 21/36 (58%) had a healthy term delivery, with 3/36 (8%) with spontaneous abortions, 1/36 (3%) congenital anomaly, and 2/36 (6%) had preterm birth. In the HepB-alum arm, 10/17 (59%) had healthy term deliveries, with 2/17 (12%) had spontaneous abortions and 1/17 (6%) had congenital anomaly. ConclusionsThese limited data suggest that HepB-CpG is immunogenic in women who become pregnant after vaccination, and pregnancy outcomes appear to be similar to women who received HepB-alum prior to pregnancy. These results need to be further verified with larger prospective studies with HBV vaccine administration during pregnancy.

Risk of Guillain-Barré syndrome after vaccination against human papillomavirus: a systematic review and meta-analysis, 1 January 2000 to 4 April 2020.

BackgroundGuillain–Barré syndrome (GBS) is a rare autoimmune disease that can follow viral infections and has in a few cases been linked to vaccinations. Pre-licensure clinical trials did not observe an association between human papillomavirus (HPV) vaccination and GBS, a post-marketing study from 2017 reported an increased relative risk.AimWe assessed the risk of GBS after HPV vaccination through a systematic literature review and meta-analysis.MethodsWe searched Embase, MEDLINE and Cochrane for studies reporting on the risk of GBS after HPV vaccination in individuals aged ≥ 9 years, published between 1 January 2000 and 4 April 2020, excluding studies without a comparator group. Seven studies reporting relative effect sizes were pooled using random-effects meta-analysis. We assessed quality of evidence using the GRADE approach. Study protocol was registered (PROSPERO No. #CRD42019123533).ResultsOf 602 identified records, we included 25 studies. Based on over 10 million reports, cases of GBS were rare. In 22 studies no increased risk was observed, while in three studies a signal of increased risk of GBS after HPV vaccination was identified. Meta-analysis yielded a pooled random-effects ratio of 1.21 (95% CI: 0.60–2.43); I2 = 72% (95% CI: 36–88). This translates to a number needed to harm of one million to be vaccinated to generate one GBS case. Quality of evidence was very low.ConclusionsThe absolute and relative risk of GBS after HPV vaccination is very low and lacks statistical significance. This is reassuring for the already implemented vaccination programmes and should be used in respective communication activities.

Adverse events reported to the U.S. Food and Drug Administration Adverse Event Reporting System for tisagenlecleucel.

The U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell therapy, tisagenlecleucel, in August 2017. We sought to describe adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS) for tisagenlecleucel in the post-marketing period. We searched FAERS reports to identify U.S. patients treated with tisagenlecleucel between August 30, 2017-August 31, 2019. We reviewed individual reports, calculated AE frequencies and reporting rates (RRs), and used Empirical Bayesian Geometric Mean methods to identify disproportionate reporting. We identified 646 de-duplicated reports with a median age at AE of 18 (interquartile range: 11-56) years. The overall RR was 81.0%, and more than 95% of reports described a serious outcome. Cytokine release syndrome (CRS) was the most frequently reported AE (51.1%) with a RR of 41.4%; neurotoxicity was reported less frequently (21.2%), with a RR of 17.2%. Most disproportionately reported AEs were listed on the package insert or confounded by indication. We identified 13 subsequent neoplasms (SPN), the majority occurring within 6 months of tisagenlecleucel administration, and none reporting evidence of insertional mutagenesis. A total of 165 reports (26%) described a death outcome; most deaths occurred >30 days after treatment. The majority of deaths (64%) were due to progression of the underlying lymphoid neoplasm, and few (<5%) were attributed to CRS or neurotoxicity. We did not identify new safety concerns reported for tisagenlecleucel in the post-marketing period. Reporting rates for CRS and neurotoxicity were lower than identified in the prelicensure clinical trials.

Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example

Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.

Cross-neutralization Capacity of Immune Serum from Different Dosage of Sabin Inactivated Poliovirus Vaccine Immunization against Multiple Individual Polioviruses

ABSTRACT Introduction: Sabin strain inactivated poliovirus vaccine (sIPV) developed by Sinovac Biotech Co., Ltd., has shown good safety and immunogenicity against parental strains among infants in several finished pre-licensure clinical trials. Areas covered: To further study the neutralizing capacity of investigational sIPV immune serum against Sabin, Salk and recently circulating poliovirus strains, neutralization assay against ten individual strains was performed on backup serum collected from 250 infant participants of the finished phase II clinical trial. Expert commentary:: The sIPV can generate good immunogenicity against Sabin, Salk and recently circulating poliovirus strains. Taking into account its lower containment requirements and financial costs compared with the conventional Salk strain inactivated poliovirus vaccine, sIPV is an affordable and practical option for polio eradication.

Effectiveness of HPV vaccine by age at vaccination and number of doses: protocol for a population-based matched case–control study

IntroductionIn 2006, the first human papillomavirus (HPV) vaccine was approved by the Food and Drug Administration in the USA based on pre-licensure clinical trials that found it to be highly...

How to ensure we can track and trace global use of COVID-19 vaccines?

In response to the devastating SARS-Cov-2 pandemic, an unprecedented surge in vaccine development has occurred. More than 250 vaccines are being developed, at least 50 of which are in clinical trials [1]. Several companies have already started vaccine production ahead of the results of the pivotal Phase III trials. In anticipation of rapid availability of COVID-19 vaccines, shortcuts in the development and regulatory approval processes have been suggested and warned against to combat vaccine hesitancy [2]. Many COVID-19 vaccines are using novel technology platforms little or never used in clinical care previously [1]. Combined with the inherent limited sample size, duration, and population heterogeneity of pre-licensure clinical trials, there is a critical need to monitor safety and effectiveness of the COVID-19 vaccines post-introduction [3]. Several COVID-19 vaccines should be available to meet the global need, mostly via COVAX, a new alliance to ensure equitable access [4]. In addition, national mass vaccination programs will be aimed mostly at adults, not children -- whom vaccinations traditionally target. Moreover, these programs will likely be conducted in a highly dispersed manner in healthcare institutions, nursing homes, workplaces, schools, etc… [5] Sophisticated systems are needed therefore to track and trace on a global scale who was immunized with which COVID-19 vaccine product, where and when. This “exposure” data is vital for any post-introduction study.

Review of the initial post-marketing safety surveillance for the recombinant zoster vaccine

BackgroundThe adjuvanted recombinant zoster vaccine (RZV) received its first marketing authorization in October 2017, for prevention of herpes zoster in individuals aged ≥50 years. MethodsWe summarized safety information, following RZV administration, received by GSK via spontaneous adverse event (AE) reports submitted by healthcare providers, vaccine recipients and other reporters. Observed-to-expected (O/E) analyses were performed for selected outcomes: reports of death, Guillain–Barré syndrome and Bell’s palsy. Standard case definitions were used to assess individual case reports. Data mining, using proportional reporting ratio and time-to-onset signal detection methods, was employed to identify RZV-AE pairs with disproportionate reporting or unexpected time-to-onset distribution. ResultsBetween October 13, 2017 and February 10, 2019, an estimated 9.3 million doses were distributed and GSK received 15,638 spontaneous AE reports involving RZV. Most reports were classified as non-serious (95.3%) and originated from the United States (81.7%), where the majority of doses were distributed. Among reports with age or sex reported, individuals were mainly 50–69-year-olds (62.1%) and female (66.7%). Of all reports, 3,579 (22.9%) described vaccination errors, of which 82.7% were without associated symptoms. Of all vaccination error reports, most described errors of vaccine preparation and reconstitution (29.7%), inappropriate schedule or incomplete course of administration (26.7%), incorrect route of administration (16.4%), and storage errors (12.9%). The most commonly reported symptoms were consistent with the known RZV reactogenicity profile observed in clinical trials, including injection site reactions, pyrexia, chills, fatigue, headache. O/E analyses for selected outcomes and data mining analyses for all reported AEs did not identify any unexpected patterns. ConclusionsReview of the initial data from the post-marketing safety surveillance showed that the safety profile of RZV is consistent with that previously observed in pre-licensure clinical trials. Other studies are ongoing and planned, to continue generating real-world safety data and further characterize RZV.

Impact of Precision Medicine on Efficiencies of Novel Drug Development in Cancer.

Precision medicine (PM) offers opportunities for reducing the costs, burdens, and time associated with drug development. We examined time, number of trials, indications tested, and patient burden needed to achieve first U.S. Food and Drug Administration license for all five novel anticancer PM drugs and all 10 novel non-PM drugs receiving U.S. Food and Drug Administration approval during 2010-2014. The 15 drug portfolios encompassed 242 trials: 87 for PM drugs and 155 for non-PM drugs. Embase and MEDLINE databases were searched for all prelicensure clinical trials, and data on time, patient numbers, indications tested, and total treatment-emergent grade 3-5 adverse events were measured from the first trial of each drug. We did not find patterns suggesting greater efficiencies in PM compared with non-PM. Gains in efficiency for PM drug development may be offset by challenges with recruitment.

Post Marketing Surveillance Study of 2nd Dose Quadrivalent Human Papilloma Virus Vaccine in Elementary School Children in Jakarta, Indonesia: Safety Result and Implementation of School-Based HPV Immunization Program

Objective:Quadrivalent human papillomavirus (QHPV) vaccine has been advised for routine vaccination of pre-adolescent girls globally, and a two-dose QHPV vaccination schedule has been introduced in Indonesia to vaccinate 5th and 6th grade elementary school female students. This post-marketing surveillance study evaluated the possible adverse events following immunization with the two-dose QHPV vaccine in Indonesia.Methods:Girls studying in grade 6 of five designated elementary schools in Jakarta, receiving their 2nd dose of QHPV vaccine and provided informed consent (represented by their parents), were included in the study. Students who had received other immunizations either simultaneously or <1 month ago were excluded. Local and systemic reactions noted at 30 min, and 72 h to 28th day, after the immunization were recorded using a Children Symptom Dairy Card/Kartu Harian Anak Sekolah (KHAS/Student Daily Card).Results:A total of 500 students from 20 schools were included. No serious adverse events were reported during the study period. Fever (systemic reaction) of mild intensity was noted in 1.6 % (n=8) of participants, which subsided after day 6. Local reactions such as pain, redness and swelling were noted in 59.6% (n=295), 23.6% (n=118), and 17.2% (n=86) of participants, respectively. These resolved without any intervention in majority of the cases after day 5.Conclusion:These results along with the safety data from the pre-licensure clinical trials confirm the favorable safety profile of QHPV vaccine in pre-adolescent girls. The school-based two-dose QHPV immunization program in Indonesia is a safe and effective strategy for optimizing HPV vaccine coverage among pre-adolescent girls.

Postlicensure Safety Surveillance of Recombinant Zoster Vaccine (Shingrix) - United States, October 2017-June 2018.

Recombinant zoster vaccine (RZV; Shingrix), an adjuvanted glycoprotein vaccine, was licensed by the Food and Drug Administration (FDA) and recommended by the Advisory Committee on Immunization Practices for adults aged ≥50 years in October 2017 (1). The previously licensed live-attenuated zoster vaccine (ZVL; Zostavax) is recommended for adults aged ≥60 years. RZV is administered intramuscularly as a 2-dose series, with an interval of 2-6 months between doses. In prelicensure clinical trials, 85% of 6,773 vaccinated study participants reported local or systemic reactions after receiving RZV, with approximately 17% experiencing a grade 3 reaction (erythema or induration >3.5 inches or systemic symptoms that interfere with normal activity). However, rates of serious adverse events (i.e., hospitalization, prolongation of existing hospitalization, life-threatening illness, permanent disability, congenital anomaly or birth defect, or death) were similar in the RZV and placebo groups (2). After licensure, CDC and FDA began safety monitoring of RZV in the Vaccine Adverse Event Reporting System (VAERS) (3). During the first 8 months of use, when approximately 3.2 million RZV doses were distributed (GlaxoSmithKline, personal communication, 2018), VAERS received a total of 4,381 reports of adverse events, 130 (3.0%) of which were classified as serious. Commonly reported signs and symptoms included pyrexia (fever) (1,034; 23.6%), injection site pain (985; 22.5%), and injection site erythema (880; 20.1%). No unexpected patterns were detected in reports of adverse events or serious adverse events. Findings from early monitoring of RZV are consistent with the safety profile observed in prelicensure clinical trials.

Post-licensure safety surveillance of zoster vaccine live (Zostavax®) in the United States, Vaccine Adverse Event Reporting System (VAERS), 2006–2015

ABSTRACTBackground: Herpes zoster (HZ), or shingles, is caused by reactivation of varicella-zoster virus in latently infected individuals. Live-attenuated HZ vaccine (zoster vaccine live, ZVL) is approved in the United States for persons aged ≥50 years and recommended by the CDC for persons ≥60 years. Methods: We analyzed U.S. reports of adverse events (AEs) following ZVL submitted to the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting system to monitor vaccine safety, for persons vaccinated May 1, 2006, through January 31, 2015. We conducted descriptive analysis, clinical reviews of reports with selected pre-specified conditions, and empirical Bayesian data mining. Results: VAERS received 23,092 reports following ZVL, of which 22,120 (96%) were classified as non-serious. Of reports where age was documented (n = 18,817), 83% were in persons aged ≥60 years. Reporting rates of AEs were 106 and 4.4 per 100,000 ZVL doses distributed for all reports and serious reports, respectively. When ZVL was administered alone among persons aged ≥50 years, injection site erythema (27%), HZ (17%), injection site swelling (17%), and rash (14%) were the most commonly reported symptoms among non-serious reports; HZ (29%), pain (18%), and rash (16%) were the most commonly reported symptoms among serious reports. Six reports included laboratory evidence of vaccine-strain varicella-zoster virus (Oka/Merck strain) infection; AEs included HZ, HZ- or varicella-like illness, and local reaction with vesicles. In our review of reports of death with sufficient information to determine cause (n = 46, median age 75 years), the most common causes were heart disease (n = 28), sepsis (n = 4), and stroke (n = 3). Empirical Bayesian data mining did not detect new or unexpected safety signals. Conclusions: Findings from our safety review of ZVL are consistent with those from pre-licensure clinical trials and other post-licensure assessments. Transient injection-site reactions, HZ, and rashes were most frequently reported to VAERS following ZVL. Overall, our results are reassuring regarding the safety of ZVL.

Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review.

Failure in cancer drug development exacts heavy burdens on patients and research systems. To investigate inefficiencies and burdens in targeted drug development in cancer, we conducted a systematic review of all prelicensure trials for the anticancer drug, sorafenib (Bayer/Onyx Pharmaceuticals). We searched Embase and MEDLINE databases on October 14, 2014, for prelicensure clinical trials testing sorafenib against cancers. We measured risk by serious adverse event rates, benefit by objective response rates and survival, and trial success by prespecified primary endpoint attainment with acceptable toxicity. The first two clinically useful applications of sorafenib were discovered in the first 2 efficacy trials, after five drug-related deaths (4.6% of 108 total) and 93 total patient-years of involvement (2.4% of 3,928 total). Thereafter, sorafenib was tested in 26 indications and 67 drug combinations, leading to one additional licensure. Drug developers tested 5 indications in over 5 trials each, comprising 56 drug-related deaths (51.8% of 108 total) and 1,155 patient-years (29.4% of 3,928 total) of burden in unsuccessful attempts to discover utility against these malignancies. Overall, 32 Phase II trials (26% of Phase II activity) were duplicative, lacked appropriate follow-up, or were uninformative because of accrual failure, constituting 1,773 patients (15.6% of 11,355 total) participating in prelicensure sorafenib trials. The clinical utility of sorafenib was established early in development, with low burden on patients and resources. However, these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens, leading to excess patient burden. Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development.