Post-approval Studies Research Articles

Recent Advances in Sickle-Cell Disease Therapies: A Review of Voxelotor, Crizanlizumab, and L-glutamine.

Sickle-cell disease (SCD) is an inherited hemoglobinopathy, causing lifelong complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, chronic anemia, and end-organ damage, with negative effects on quality of life and life expectancy. Within the last five years, three new treatments have been approved: L-glutamine in 2017 and crizanlizumab and voxelotor in 2019. We conducted a literature search of these three medications, and of the 31 articles meeting inclusion criteria, 6 studied L-glutamine, 9 crizanlizumab, and 16 voxelotor. Treatment with L-glutamine was associated with decrease in pain crises, hospitalizations, and time to first and second crises, with a decrease in RBC transfusion rate. Barriers to filling and taking L-glutamine included insurance denial, high deductible, and intolerability, especially abdominal pain. Crizanlizumab was associated with a reduction in pain crises and time to first crisis, with reduction in need for opioid use. Adverse effects of crizanlizumab include headache, nausea, insurance difficulty, and infusion reactions. Voxelotor was associated with increased hemoglobin and decreased markers of hemolysis. Barriers for voxelotor use included insurance denial and side effects such as headache, rash, and diarrhea. These three medications represent exciting new therapies and are generally well-tolerated though price and insurance approval remain potential barriers to access. Other studies are ongoing, particularly in the pediatric population, and more real-world studies are needed. The objective of this article is to evaluate post-approval studies of crizanlizumab, voxelotor, and L-glutamine in SCD, with a focus on real-world efficacy, side effects, and prescribing data.

Estimated Cost of Developing a Therapeutic Complex Medical Device in the US

The US medical device market is the world's largest, but estimates of the cost to bring a medical device to market are not available to help inform policy making and regulatory efforts to enhance device safety and innovation. To estimate the mean expected capitalized cost of developing a novel therapeutic complex medical device. In this economic evaluation, an analytical model of novel therapeutic complex medical device development using data from public and proprietary sources with coverage from 2000 through 2018 was used to estimate the cost, duration, and phase transition success probability associated with each stage of development. Data analysis was completed in September 2021. Conduct of nonclinical and clinical studies; payment of FDA user fees for novel therapeutic complex medical devices. Mean development cost (in 2018 US dollars) incurred by developers for an FDA-approved novel therapeutic complex medical device, accounting for failures and cost of capital. In this economic analysis, the mean development cost for a novel therapeutic complex medical device was $54 million (95% CI, $25 million-$200 million) excluding any postapproval studies that might be required. After accounting for the cost of failed studies and cost of capital, the mean capitalized cost of bringing a novel therapeutic complex medical device to the US market was $522 million (95% CI, $205 million-$3382 million). The key factors associated with this cost were the phase transition probabilities: 46.9% for nonclinical to feasibility study, 48.0% for feasibility to pivotal study, 75.7% pivotal study to FDA premarket approval submission, and 80.5% for FDA premarket approval submission to approval. The nonclinical development stage constituted the largest portion of overall cost at 85.0% with the FDA review stage with the highest phase transition probability accounting for only a small fraction at 0.5%. In this economic evaluation study, the cost of therapeutic complex medical device development from proof of concept through postapproval stages was assessed accounting for the cost of failures and the cost of capital. Existing estimates did not account for all stages of development, capitalization, or failure costs, which this study suggests were substantial.

Medicaid and Accelerated Approval: Spending on Drugs with and without Proven Clinical Benefits.

Many state Medicaid officials are concerned about rising prescription drug spending, particularly drugs approved through the Food and Drug Administration's (FDA) accelerated approval pathway. The authors examined how much of Medicaid programs' accelerated approval spending is attributable to products that have demonstrated clinical benefits versus those that have not. Their findings provide support for states' concerns that pharmaceutical companies often fail to complete their required postapproval confirmatory studies within the FDA's requested timeline. But the findings also highlight one issue that policy stakeholders have not yet devoted substantial attention to: the use of surrogate endpoints involved in the postapproval confirmatory studies for most of the products in this study's sample. The granularity of the study's results enabled an analysis of the impact of different policy recommendations on both the accelerated approval pathway and Medicaid programs. These findings inform the current policy debate, suggesting that policy stakeholders might focus attention on products converting their approval on the basis of surrogate outcomes rather than on clinical outcomes.

The role of systemic therapy in melanoma brain metastases: a narrative review.

Melanoma is a disease notorious for the development of brain metastases, with consequently poor outcomes for patients who develop melanoma brain metastases (MBM). The treatment options for patients with MBM were limited to radiotherapy and surgery. MBM patients, particularly those with symptomatic disease, were excluded from clinical trials of immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors. Recent post-approval studies have, demonstrated important roles for existing systemic ICIs and BRAF/MEK inhibitors in untreated MBM, dramatically altering the landscape of melanoma patients in general and MBM in particular. These trials have also identified key areas for which more effective strategies are needed including: symptomatic MBM, and leptomeningeal disease (LMD). PubMed, Scopus and Embase databases were systematically queried to obtain records pertaining to the etiology of and treatment for MBM. Clinical trial databases were reviewed to obtain details regarding MBM clinical trials. We discuss the etiopathogenesis of MBM and the novel immune, molecular and metabolic features of MBM that make this disease a unique therapeutic challenge. We review advances in systemic therapy with ICIs and BRAF/MEK inhibitors in untreated MBM, along with novel combinations. Finally, we debate challenging situations such as LMD, and delineate novel treatments and new paradigms for therapeutic interventions. The historically poor outcomes for MBM patients have been transformed with the advent of effective systemic therapies including ICIs and BRAF/MEK inhibitors. An improved understanding of the molecular and immunogenomic characterization of MBMs has provided new targets that are being exploited in the clinic.

Abstract 78: Cardiovascular Implantable Electronic Device Lead Safety: Harnessing Real-world Remote Monitoring Data For Medical Device Evaluation

Background: Current important regulatory resources and methods to identify cardiac implantable electronic devices (CIED) lead failure include post-approval studies, which may be limited in scope, participant numbers, and by attrition; studies relying on administrative codes, which lack specificity in multi-chamber systems; and voluntary adverse event reporting, which cannot determine incidence or attribution to the lead. We determined whether adjudicated remote monitoring (RM) data can help to address these limitations and augment lead safety evaluation. Methods: We evaluated 48,148 patients from the Veterans Affairs National Cardiac Device Surveillance Program (VANCDSP), 4/1/19-4/1/21. We identified RM transmissions signifying incident lead abnormalities (possible lead failure, failure to capture, impedance out of range). We queried VA electronic health record (EHR) and Medicare fee-for-service claims data to determine if patients had administrative codes for lead failure. We verified structural lead failure through manual EHR review. Among patients with EHR-confirmed lead failure, we categorized subsequent clinical actions by cardiac chamber. Results: Of 48,148 actively monitored patients with CIEDs, 1174 (2.4%) had incident lead abnormalities detected on RM; 356 (30.3%) with administrative codes for lead failure and 818 (69.7%) without. Of the 356 patients, 220 (62%) had lead failure verified through chart review (positive predictive value [PPV], 62%). Among 276 patients randomly selected from 818 without administrative codes, 58 (26%) had EHR-confirmed lead failure (PPV, 21%). Patients with isolated right atrial or left ventricular lead failure were less likely to have claims and lead replacement procedures than those with right ventricular high-energy lead failure (Table). Conclusion: Remote monitoring may strengthen accurate real-world assessment of lead failure, particularly for leads where patients do not undergo replacement.

A Landscape Analysis of Post-Marketing Studies Registered in the EU PAS Register and ClinicalTrials.gov Focusing on Pregnancy Outcomes or Breastfeeding Effects: A Contribution from the ConcePTION Project.

IntroductionA large proportion of medicine product labels lack information on safety in pregnancy and breastfeeding. To address this gap, pharmaceutical companies are requested to develop post-approval studies regarding the use of drugs by pregnant and breastfeeding women.ObjectiveOur study aims to review key features of observational studies in pregnancy and breastfeeding and their impact on the respective medicine product labels.MethodsObservational studies focusing on the safety evaluation of medicines used during pregnancy and breastfeeding were selected from the European Union Register of Post-Authorization Studies (EU PAS register) and ClinicalTrials.gov. We extracted information on the variables of interest and performed an impact assessment on the respective label.ResultsA total of 141 observational studies were eligible. Of these, 63 studies (45%) were based on primary data collection and 55 studies (39%) on secondary use of health data. A small number of studies (8%) aimed to evaluate drug safety during breastfeeding. Studies using secondary data collection lasted around 2.9 years as opposed to 7.5 years’ duration for studies using primary data collection. Only two product labels were updated based on the study results.ConclusionThe duration is significantly longer for studies based on primary data collection, and these are also smaller in size (less power), whereas outcomes of interest are similar. For completed studies, the impact on the label was very low. Given the gap in adequate pregnancy information on product labels, the current process of generating evidence in pregnancy and breastfeeding seems neither efficient nor impactful. To support evidence-based decision making by prescribers, this current process might be redesigned.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-022-01154-7.

Evaluation of cardiovascular implantable electronic device leads post implant: ElectroPhysiology Predictable And SuStainable Implementation Of National Registries (EP PASSION).

Post-market evaluation is important to ensure the ongoing safety and effectiveness of cardiovascular implantable electronic device (CIED) leads. The Twenty-First Century Cures Act and subsequent Food and Drug Administrative (FDA) Guidance provide an opportunity to leverage real-world data sources for this purpose. The past 4years have seen the development of EP PASSION: a multi-stakeholder, collaborative effort between the FDA, CIED manufacturers, Heart Rhythm Society, and academics. Using real-world data, EP PASSION enables longitudinal evaluation of the long-term safety of CIED leads, addressing limitations of current approaches to generate evidence that informs regulatory, clinical, and manufacturer decision-making. This state of the art article describes the impetus for and launch of EP PASSION, the lessons learned, its current state, the current analytic approach, and the strengths and limitations of leveraging extant data sources for post-market lead evaluation. We also compare EP PASSION to traditional post-approval studies and describe possible future directions.

Testing the Fit of Regression Models Estimated with Extremely Small Samples: Application in Pharmaceutical Stability Studies

Pharmaceutical stability studies are conducted to estimate the shelf life, i.e. the period during which the drug product maintains its identity and stability. In the evaluation of process, regression curve is fitted on the data obtained during the study and the shelf life is determined using the fitted curve. The evaluation process suggested by ICH considers only the case of the true relationship between the measured attribute and time being linear. However, no method is suggested for the practitioner to decide if the linear model is appropriate for their dataset. This is a major problem, as a falsely selected model may distort the estimated shelf life to a great extent, resulting in unreliable quality control. The difficulty of model misspecification detection in stability studies is that very few observations are available. The conventional methods applied for model verification might not be appropriate or efficient due to the small sample size. In this paper, this problem is addressed and some developed methods are proposed to detect model misspecification. The methods can be applied for any process where the regression estimation is performed on independent small samples. Besides stability studies, frequently performed construction of single calibration curves for an analytical measurement is another case where the methods may be applied. It is shown that our methods are statistically appropriate and some of them have high efficiency in the detection of model misspecification when applied in simulated situations which resemble pre-approval and post-approval stability studies.

Raising Medicaid Rebates For Drugs With Accelerated Approval.

Through the Accelerated Approval Program, the Food and Drug Administration (FDA) may approve drugs that treat severe or life-threatening conditions on the basis of preliminary evidence of efficacy. Many of these drugs are made available at extremely high prices. In April 2021 the Medicaid and CHIP Payment and Access Commission endorsed a policy that would require manufacturers of drugs receiving accelerated approval to pay higher rebates to Medicaid until their drug's efficacy is demonstrated in confirmatory postapproval studies. We examined the impact of this policy by studying Medicaid spending on eighty-nine accelerated approval drugs during 2015-20. Medicaid spent an estimated $6.7billion on these drugs after estimated rebates under existing rules. Raising base rebates from 23.1percent to 30-80percent could have saved Medicaid $0.6-$5.2billion during this six-year period; raising inflationary rebates by two to four times would have had a smaller impact, creating savings of up to $0.9billion. Accelerated approval drugs represent a small but growing percentage of Medicaid's total prescription drug spending. The policy evaluated in this study can offer important savings, but implementation must account for the fact that many of these drugs have additional indications with regular FDA approval.

Real-world experience on the safety and effectiveness of Micra TPS in patients with pre-existing in situ CIEDs

Abstract Background The Micra pre-market study showed that the Micra transcatheter pacing system could be safely implanted in patients with pacing indications. Patients with pre-existing cardiac implantable electronic devices (CIED) were excluded from this clinical trial; however, this group of patients might benefit from a leadless pacemaker especially when a lead fails or after incidence of system-related infections. Objective To determine the outcome of patients with a pre-existing CIED or lead that remains in situ at the time of Micra implant attempt. Methods Patients who had a pre-existing CIED and/or lead at the time of Micra implantation attempt were identified from the Micra Post-Approval Registry and Micra Acute Performance studies. Baseline characteristics were summarized, and a Fine-Gray competing risk model was used to compare risk for major complication through 24 months for patients with and without a pre-existing CIED. Results Of the 2323 patients included in the analysis, 111 patients had a pre-existing CIED or lead at the time of Micra implantation attempt that remained in situ. Types of pre-existing devices included 81 pacemakers (45 single chamber, 32 dual chamber, 4 of unknown type), 10 ICDs (2 single chamber, 2 dual chamber, 6 unknown type), 10 CRT devices (6 CRT-P, 4 CRT-D), 3 generators of unknown type, and 7 patients had only leads remaining. Patients with pre-existing devices were younger and less likely to have a pacing indication of bradyarrhythmia with atrial fibrillation compared to patients without pre-existing devices (p<0.001 for both). Patients with prior devices were more likely to have a condition precluding implant of a transvenous pacemaker (67.6% vs. 21.3%, p<0.001). The presence of a pre-existing CIED did not impact the outcome of the Micra TPS implant procedure: implant success was >99% for both cohorts. Mean follow-up duration was 21.2±14.3 months (range 0–56) for pre-existing devices patients and 23.3±15.8 months (range 0–62) for other patients. The rate of major complications through 24 months was 1.8% for patients with and 3.8% for patients without prior devices (p=0.36). There were no major complications related to device malfunction or device-device interaction. There were 6 system revisions in 4 patients with preexisting devices and 52 revisions in 51 patients without preexisting devices. Pacing thresholds for patients with and without prior devices were similar at implant (0.72 and 0.63, respectively; p=0.31) and remained stable through 12 months. Conclusion Micra can be safely and successfully implanted in patients with a pre-existing CIED remaining in situ. It should be considered a treatment option for patients in whom CIED extraction may be deemed high risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Medtronic, Inc. Risk of major complications

Contribution of post marketing studies to define treatment strategies

Over the past two decades, an ever-expanding range of disease-modifying therapies (DMTs) has become available for multiple sclerosis (MS) on the basis of their efficacy in randomized controlled trials (RCTs). At the same time, the growing number of new DMTs has made treatment decisions more complicated in clinical practice. Major questions remain concerning long-term risks and benefits of therapies, risk stratification, treatment sequencing, benefits of different dosing and routes of administration and outcome definition. Post-marketing studies based on real-world (RW) data has gained attention as a good strategy for capturing important additional information to complement data from RCTs in order to address issues around the uncertainty of the evidence base. In the last years, the increasing amount of RW data collected in MS registries, administrative databases and health electronic records, the evolution in information technology infrastructure and the corresponding ability to store and process these data through new and more sophisticated statistical methods, drove an exponential growth of high quality post-marketing studies of MS treatments. These studies are providing insights into predictors of safety, tolerability and effectiveness of DMTs and the long-term comparative effectiveness between different DMTs that are proving to be critical in directing and improving MS intervention strategies in daily practice. Moreover post-marketing research, has become an integral part of the drug evaluation process for a wide range of agents. Regulatory bodies and pharma companies have stated their ambition for greater use of RWD for treatment decision making, post-approval surveillance studies and pricing and reimbursement decisions.

New antibiotics for the treatment of nonfermenting Gram-negative bacteria.

To discuss the current literature on novel agents for the treatment of carbapenem-resistant nonfermenting Gram-negative bacteria (NF-GNB) infections. Some novel agents have recently become available that are expected to replace classical polymyxins as the first-line options for the treatment of carbapenem-resistant NF-GNB infections. In this narrative review, we provide a brief overview of the differential activity of various recently approved agents against NF-GNB most encountered in the daily clinical practice, as well as the results from phase-3 randomized clinical trials and large postapproval observational studies, with special focus on NF-GNB. Since resistance to novel agents has already been reported, the use of novel agents needs to be optimized, based on their differential activity (not only in terms of targeted bacteria, but also of resistance determinants), the local microbiological epidemiology, and the most updated pharmacokinetic/pharmacodynamic data. Large real-life experiences remain of crucial importance for further refining the optimal treatment of NF-GNB infections in the daily clinical practice.

Characteristics of Preapproval and Postapproval Studies of Vaccines Granted Accelerated Approval by the US Food and Drug Administration.

Characteristics of Preapproval and Postapproval Studies of Vaccines Granted Accelerated Approval by the US Food and Drug Administration.

Impact of renal function in high bleeding risk patients undergoing percutaneous coronary intervention: a patient-level stratified analysis from four post-approval studies.

Data on ischemic and bleeding outcomes after percutaneous coronary intervention (PCI) in high bleeding risk (HBR) patients with chronic kidney disease (CKD) are scarce. We aimed to evaluate the association between CKD and ischemic and bleeding outcomes in HBR patients who underwent PCI. Among 10,502 patients in the four post-approval registries evaluating patients undergoing PCI, 2,300 patients presented with at least one major or two minor ARC-HBR criteria. CKD was defined as eGFR < 60mL/min/1.73m2. These HBR patients were divided into 3 groups: eGFR < 30mL/min/1.73m2 defined as severe CKD (N = 221), eGFR 30- < 60mL/min/1.73m2 defined as moderate CKD (N = 970), eGFR ≥ 60mL/min/1.73m2 defined as no CKD (N = 1,109). The primary endpoint was the composite of cardiac death, myocardial infarction, or stent thrombosis, and the safety endpoint was major bleeding up to 4-year follow-up. HBR patients with CKD were more often female and had higher rates of comorbidities compared to those without CKD. Reduced renal function was associated with higher rates of the primary endpoint (severe CKD vs. moderate CKD vs. no CKD: 30.2% vs. 12.5% vs. 9.1%, P < 0.01) as well as major bleeding (10.3% vs. 8.9% vs. 6.4%, P = 0.03). After adjustment, severe CKD and moderate CKD in HBR patients remained independent predictors for the primary endpoint (HR [95%CI] 2.84 [1.94-4.16], P < 0.01, 1.48 [1.10-2.00], P < 0.01) compared to those with no CKD. However, decreased renal function was no longer significantly associated with major bleeding after adjustment. In conclusions, in HBR patients undergoing PCI, CKD has an important impact on major ischemic events after PCI.

Does study subject diversity influence cardiology research site performance?: Insights from 2 U.S. National Coronary Stent Registries

Minorities and women are underrepresented in cardiovascular research. Whether their higher enrollment can be predicted or influences research site performance is unclear. We evaluated 104 sites that enrolled 4,184 patients in the U.S. Platinum Diversity (PD) and Promus Element Plus (PE Plus) studies (2012 to 2016). Research sites were ranked from lowest to highest minority and female enrollment, respectively. United States Census Bureau division and core-based statistical area (CBSA) populations were determined for each site and the following study performance metrics compared across quartiles of minority and female enrollment, respectively: (1) study subject enrollment rate (SER), (2) time to first patient enrolled, (3) rate of follow-up visits not done, (4) rate of follow-up visits out of window, and (5) protocol deviation rate (PDR). Multivariable regression was used to predict SER and PDR. Minority enrollment varied by region (P = .025) and population (P = .024) with highest recruitment noted in the Pacific, West South Central, South Atlantic, Mid-Atlantic and East North Central divisions. Female enrollment bore no relationship to region (P = .67) or population (P = .40). Median SER was similar in sites withi the highest vs lowest quartile of minority enrollment (SER of 4 vs 5 patients per month, respectively, P =0.78) and highest vs. lowest female enrollment (SER of 4 vs 4, respectively, P = .21). Median PDR was lower in sites within the highest vs lowest minority enrollment (0.23 vs 0.50 PDs per patient per month, respectively, P = .01) and highest vs. lowest female enrollment (0.28 vs. 0.37 PDs per patient per month, respectively, P = .04). However, this relationship did not persist after multivariable adjustment. All other site performance metrics were comparable across quartiles of minority and female enrollment. Minority, but not female enrollment, correlated with research site geographic region and surrounding population. High enrollment of minorities and women did not influence study performance metrics. These findings help inform future strategies aimed at increasing clinical trial diversity. The PD and PE Plus studies are registered at www.clinicaltrials.gov under identifiers NCT02240810 and NCT01589978, respectively. Question: Does the enrollment of more Blacks, Hispanics and women in US cardiovascular research studies influence the overall rate of study subject enrollment and/or other key study site performance metrics and can diverse enrollment be predicted? In this pooled analysis of 104 sites that enrolled 4,184 patients in the Platinum Diversity and Promus Element Plus Post-Approval Studies, we found that the enrollment of higher proportions of underrepresented minorities and women was univariately associated with lower protocol deviation rates while having no effect on other site performance metrics. A site's geographic location and surrounding population predicted minority, but not female enrollment. Meaning: These findings suggest that cardiovascular research subject diversity may be predicted from site characteristics and enhanced without compromising key study performance metrics. These insights help inform future strategies aimed at improving clinical trial diversity.

P042 RECOVER - the Real World Clinical Outcomes with Novel Modulator therapy combinations in people with cystic fibrosis

Background: Real-world, post-approval studies contribute significantly to the evidence surrounding the impact of new treatments, including CFTR modulators, but can be complex undertakings. Elexacaftor-tezacaftor-ivacaftor (ETI) was approved by EMA sooner than expected in August 2020 during a global pandemic. Method: RECOVER, a multi-centre, post-approval study examining the impact of ETI, and conducted in 8 clinical sites in Ireland and the UK over 2 years, examines important outcomes in children and adults prescribed ETI. The study will be conducted in 2 phases in line with ETI approval: 12+ and 6–11. In addition to routine data collected as part of normal care, key RECOVER endpoints include lung clearance index (LCI), spirometry-controlled CT, treatment adherence, GI symptoms, inflammation, liver disease markers, nasal inflammation and nitric oxide metabolism. Results: To date, 96 participants (56% female) out of a target of 137 in people with CFaged 12 and above, have been recruited (predominantly 12–18yrs to date). Recruitment and sample collection has been impacted by the effect of COVID-19 on CF care and CF centre attendance. Key challenges have included: Sputum collection (risks of induction and non-sputum producing participants) and coordination of study activities with limited clinic attendance. Despite this, key baseline data, prior to commencing treatment, has been successfully collected on the majority of participants to date. For subjects recruited to date, 56% have F508del/F508del and 44% F508del/minimum function mutations, mean age is 16.1 years, mean FEV1 83.6% (23–111%), mean LCI 12.2 (6.9–24.3). Recruitment and data collection is ongoing. Conclusion: Despite the impact of accelerated approval and COVID-19, we have been able to proceed with study initiation, recruitment and sample collection. Data from RECOVER and other international post-approval studies is likely to add significantly to our understanding of the impact of ETI on people with CF.

Post-implant care pathway: lessons learned and recommendations after 5 years of clinical implementation of hypoglossal nerve stimulation therapy.

Hypoglossal nerve stimulation (HNS) therapy is now an established and widely-available obstructive sleep apnea (OSA) treatment alternative for continuous positive airway pressure (CPAP)-intolerant patients. Additionally, the HNS body of literature is robust with strong data on safety, efficacy, and durability-from the 5-year STAR Trial outcomes, to post-approval studies of independent institutions, to the multicenter ADHERE registry which recently reported outcomes on over 1,000 patients and is poised to enroll 5,000 HNS patients total. Nevertheless, now with thousands of implanted patients across hundreds of certified centers, and that number growing rapidly, the post-implant management of the HNS patient represents the next critical frontier. Post-implant patient management (therapy titration, troubleshooting, adjustments, and adherence monitoring) across a longitudinal care model is key to ensuring long-term therapy success and optimizing patient outcomes and health benefits. As with CPAP, patient education and close clinical monitoring are often essential to successful long-term management. Although many HNS patients are clear responders with excellent comfort and adherence as well as effective improvement in symptomatic and objective outcome measures, and even a smaller subset is clear non-responders, there is a growing body of patients somewhere in the middle: good outcomes but not great; partial but incomplete response. These are the patients in whom a standardized best-practice approach to treatment monitoring and targeted therapy modifications is likely critical to optimizing long-term outcomes.

The Importance of Clinical Research in Pregnant Women to Inform Prescription Drug Labeling.

Pregnant women have historically been an understudied population and have been excluded from clinical trials. Recent efforts by stakeholders have raised awareness of the importance of clinical research in pregnant women to inform prescribing decisions. The Food and Drug Administration continues working to improve the format and content of prescription drug labeling for pregnant and lactating women, as demonstrated with the Pregnancy and Lactation Labeling Rule (PLLR), effective in 2015. The pregnancy labeling subsection now includes a subheading dedicated to the inclusion of pharmacokinetic (PK) data that inform the need for dose adjustments during pregnancy and the postpartum period. In addition, the PLLR also requires prescription drug labeling to be updated when important pregnancy information becomes available. Although PLLR improved the presentation of pregnancy-related information in labeling, there is a need to increase the quality and quantity of human data on the use of prescription drugs during pregnancy. PK studies in pregnant women should be incorporated into drug development programs and prioritized to obtain important information about safe and appropriate doses of a drug when used during pregnancy. In addition, opportunistic PK studies, postapproval pregnancy safety studies, ex vivo studies, and in silico modeling can be leveraged to better inform the risks and benefits of using a drug during pregnancy to inform study design and to further understand various mechanisms impacting pharmacokinetic/pharmacodynamic of drugs during pregnancy. It is important to address the significant existing data gaps and better inform the safety and dosing of prescription drugs for pregnant women.

Abstract 17056: Food and Drug Administration Mandated Post-Market Studies for High Risk Cardiovascular Devices Approved 2015-2019

Introduction: The Food and Drug Administration (FDA) emphasizes a “life-cycle approach” to medical device regulation, in which the pre-approval process is expedited and more emphasis is placed on post-approval data in order to shorten patient access to new devices. The FDA can mandate post approval studies (PASs) for high-risk devices to augment pre-approval data. This study describes the characteristics of FDA-mandated PASs. Methods: We searched the FDA database for all PASs required for original high-risk cardiovascular devices approved from January 1, 2015 and December 31, 2019. Data elements abstracted for each PAS included: study type, presence of controls, blinding, total number of patients enrolled, study duration, and whether primary outcomes were surrogate or composite measures. We also checked the FDA website for any available interim data prior to study completion. Results: The FDA approved 71 high-risk cardiovascular devices and ordered a total of 68 PASs for 49 (69%) devices. Most PASs were prospective cohorts (n=47, 69.1%). The median study size was 250 patients (IQR 151-563) and median study duration was 5 years (IQR 3-5). Only 19 studies (28%) included active or historic controls, 12 studies (17.7%) were randomized, 5 studies (7.3%) were single-blinded, and none were double-blinded (Table). Twenty-two (32.4%) studies provided data before completion of study. Conclusion: Most PAS are not randomized, lack controls, contain small numbers of patients, and have composite or surrogate primary outcomes that may not be clinically relevant, despite their importance for generating long-term clinical data for high-risk cardiovascular devices. Interim data are often not available. Increased quality and availability of evidence related to PASs would better establish device safety, effectiveness, and appropriate use. Lastly, PAS data should be readily accessible to help clinicians and patients make well-informed decisions.

The Role of Regulator-Imposed Post-Approval Studies in Health Technology Assessments for Conditionally Approved Drugs.

Background: The European Medicines Agency (EMA) aims to resolve uncertainties associated with conditionally approved drugs by imposing post-approval studies. Results from these studies may be relevant for health technology assessment (HTA) organizations. This study investigated the role of regulator-imposed post-approval studies within HTA. Methods: For all conditionally approved drugs up to December 2018, regulator-imposed post-approval studies were identified from EMA’s public assessment reports. The availability for and inclusion of study results in relative effectiveness (re)assessments were analyzed for 4 European HTA organizations: NICE (National Institute for Health and Care Excellence, England/Wales), HAS (Haute Autorité de Santé, France), ZIN (Zorginstituut Nederland, the Netherlands) and the European Network for Health Technology Assessment (EUnetHTA, Europe). When study results became available between an HTA organization’s initial assessment and reassessment, it was evaluated whether and how they affected the assessment and its outcome. Results: For 36 conditionally approved drugs, 98 post-approval studies were imposed. In total, 81 initial relative effectiveness assessments (REAs) and 13 reassessments were available, with numbers of drugs (re)assessed varying greatly between jurisdictions. Study results were available for 16 initial REAs (20%) and included in 14 (88%), and available for 10 reassessments (77%) and included in all (100%). Five reassessments had an outcome different from the initial REA, with 4 (2 positive and 2 negative changes) relating directly to the new study results. Reassessments often cited the inability of post-approval studies to resolve the concerns reported in the initial REA. Conclusion: Results from regulator-imposed post-approval studies for conditionally approved drugs were not often used in REAs by HTA organizations, because they were often not yet available at the time of initial assessment and because reassessments were scarce. When available, results from post-approval studies were almost always used within HTA, and they have led to changes in conclusions about drugs’ relative effectiveness. Post-approval studies can be relevant within HTA but the current lack of alignment between regulators and HTA organizations limits their potential.