An empirical analysis of overall survival in drug approvals by the US FDA (2006-2023).

BACKGROUND: The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. METHODS: We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. RESULTS: We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. CONCLUSION: About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

From target discovery to clinical drug development with human genetics.

The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.

An estimate of rate of deviation from NCCN guideline recommendations for central nervous system imaging in trials forming basis for drug approval in first line advanced non-small cell lung cancer (NSCLC).

IMPORTANCE: It is unknown whether and to what degree trials submitted to the US FDA to support drug approval adhere to NCCN guideline-recommended care in their baseline and surveillance CNS imaging protocols. OBJECTIVE: We sought to characterize the frequency with which the trials cited in US FDA drug approvals for first line advanced NSCLC between 2015 and 2020 deviated from NCCN guideline-recommended care for baseline and surveillance CNS imaging. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational analysis using publicly available data of (1) list of trials cited by the FDA in drug approvals for first line advanced NSCLC from 2015 to 2020 (2) individual trial protocols (3) published trial data and supplementary appendices (4) archived versions of the NCCN guidelines for NSCLC from 2009 to 2018 (the years during which the trials were enrolling). MAIN OUTCOMES AND MEASURES: Estimated percentage of trials for first line advanced NSCLC leading to FDA approval which deviated from NCCN guideline-recommended care with regards to CNS baseline and surveillance imaging. RESULTS: A total of 14 studies that had been cited in FDA drug approvals for first line advanced NSCLC met our inclusion criteria between January 1, 2015 and September 30, 2020. Of these trials, 8 (57.1%) deviated from NCCN guidelines in their baseline CNS imaging requirement. The frequency of re-assessment of CNS disease was variable amongst trials as well, with 9 (64.3%) deviating from NCCN recommendations. CONCLUSIONS AND RELEVANCE: The trials supporting US FDA drug approvals in first line advanced NSCLC often have CNS imaging requirements that do not adhere to NCCN guidelines. Many trials permit alternative, substandard methods and the proportion of patients undergoing each modality is uniformly not reported. Nonstandard CNS surveillance protocols are common. To best serve patients with advanced NSCLC in the US, drug approvals by the FDA must be based on trials that mirror clinical practice and have imaging requirements consistent with current US standard of care.

Use of Real-World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019.

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018-2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making.

Reforms of regulatory pathways for approval of new antineoplastic drugs in Japan from 2004 to 2019 and accompanying changes in pivotal clinical trial designs.

Background The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was established in 2004. Since then, various pieces of legislation, notices, and guidelines have been issued, and the regulatory approval pathways for domestic drugs have been diversified. However, the effects of these measures have not been fully examined. We examined the impact of these measures on the approval of antineoplastic drugs and the design of pivotal clinical trials for efficacy assessment by the PMDA. Methods We collected data on the antineoplastic drugs approved by the PMDA in fiscal years 2004-2019. We extracted the approval review pathways and the pivotal clinical trial designs from the PMDA review reports, and analyzed them to identify patterns. Results In total, 387 indications in oncology were approved by the PMDA in fiscal years 2004-2019, or 365 indications excluding multiple regulatory pathways. The number of approved indications generally increased year on year (p < 0.001). The largest number of approved indications was under the Orphan Drug Designation (31%, 114/365) and this continues to increase (p < 0.001). In the 288 indications for which clinical trial data were submitted for review, the pivotal clinical trial designs changed significantly (p < 0.001) after the guideline on clinical evaluation for antineoplastic drugs was revised in 2006. Conclusion The number of indications in oncology approved by the PMDA has been increasing over the past 16 years, alongside changes in regulatory pathways. The 2006 guideline on clinical evaluation had a particular impact on pivotal clinical trial designs.

Understanding Use of Real-World Data and Real-World Evidence to Support Regulatory Decisions on Medical Product Effectiveness.

RWE has potential to provide efficient and relevant information on the effectiveness of medical products, complementing the data generated in clinical trials; however, how RWE can support regulatory decision-making is unclear, potentially limiting its use. The objective of this study was to identify and characterize instances where RWE was included in the evidence package to support the effectiveness of a medical product regulated by U.S. Food and Drug Administration. A retrospective landscape analysis was conducted to identify instances where RWE was submitted to support effectiveness through targeted review of white and gray literature and publicly available FDA reviews of medical products. Trained evaluators examined FDA reviews to determine if and how RWE contributed to regulatory decision-making regarding effectiveness. Evaluators identified 34 instances of RWE submitted between 1954 and 2020, where 26% of instances were for oncology, 18% for hematology, and 12% for neurology. Over 50% of the products were indicated for use in rare disease or pediatric populations. 82% of products where RWE was submitted received an orphan designation. RWE was included in the product label in 59% of instances. Stated reasons indicating why submitted RWE did not significantly contribute to regulatory decision-making included lack of pre-specification of study design and analysis as well as data reliability and relevancy concerns. While there is historical use of RWE to support medical product effectiveness for oncology and rare diseases, potential exists to leverage the strengths of RWE to support other therapeutic areas and capture outcomes that are most relevant to patients.

Racial representation in clinical trials for dermatological new molecular entities.

Under-representation of ethnic minorities in clinical research has major implications for equality of access to current treatments in the field of dermatology. To determine whether there has been equitable representation of black individuals in the clinical trials for dermatological new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA) since 2015, we analysed data from the FDA Drug Trials Snapshots programme from January 2015 to the present. During this period, there was significant under-representation of black participants in clinical trials for NMEs treating acne vulgaris, plaque psoriasis, actinic keratosis and squamous cell carcinoma. These findings highlight the need to prioritize representation of ethnic minorities in clinical trials to enhance clinical practice in the field of dermatology and to improve the care and health of minorities.

Anticancer Drugs Approved by the US Food and Drug Administration From 2009 to 2020 According to Their Mechanism of Action.

Importance: Both novel and next-in-class cancer drugs have a role in oncology, but the relative development of each is understudied. Objective: To characterize the mechanisms of action of anticancer drugs approved by the US Food and Drug Administration (FDA) between 2009 and 2020, noting how many approvals were based on a new mechanism of action vs next-in-class approvals. Design, Study, and Participants: This cross-sectional study included all anticancer drugs approved by the FDA from January 2009 to December 2020. The mechanism of action of each drug was extracted from FDA labels. Supportive-care treatments were excluded. Exposures: Name of drug approved, date of approval, indication, tumor type, mechanism of action, broad pharmaceutical class, and biological target. Approvals considering all tumor types and each tumor type separately were classified in 3 nonoverlapping categories: new mechanism of action, next in class, or subsequent approval. Main Outcomes and Measures: The number of all approvals each year; the number of approvals based on a new mechanism of action, either by drug (considering all tumor types) or by indication (considering tumor types separately); and the frequency of these numbers over time. Results: Overall, 332 approvals were included. Between 2009 and 2020, there was an increase in the total number of approvals from 8 to 57. We found that 209 approvals (63%) were for a next-in-class indication in a new tumor type (84 [25%]) or a subsequent indication of the same drug in the same tumor type (195 [59%]). When considering each tumor type separately, 123 approvals (37%) were based on a new mechanism of action. Conclusions and Relevance: In this study, approvals based on a new mechanism of action represented a minority of all approvals. Further consideration of incentives for drug development are needed to prioritize novel or highly innovative and transformative anticancer drugs.

New Indications and Approvals for Anticancer Drugs.

Several anticancer drugs have received new indications; new drug approvals; or regular approvals to replace previous accelerated, conditional approvals.

Characteristics of Cost-effectiveness Studies for Oncology Drugs Approved in the United States From 2015-2020.

Importance: Increasingly, cost-effectiveness analyses are being done to determine the value of rapidly increasing oncology drugs; however, this assumes that these analyses are unbiased. Objective: To analyze the characteristics of cost-effectiveness studies and to determine characteristics associated with whether an oncology drug is found to be cost-effective. Design, Setting, and Participants: This retrospective cross-sectional study included 254 cost-effectiveness analyses for 116 oncology drugs that were approved by the US Food and Drug Administration from 2015 to 2020. Exposures: Each drug was analyzed for the incremental cost-effectiveness ratio per quality-adjusted life year, the funding of the study, the authors' conflict of interest, the threshold of willingness-to-pay, from what country's perspective the analysis was done, and whether a National Institute for Health and Care Excellence cost-effectiveness analysis had been done. Main Outcomes and Measures: The main outcome was the odds of a study concluding that a drug was cost-effective. Results: There were 116 drug approvals with 254 studies and country perspectives. Of the country perspectives, 132 (52%) were from the US. Forty-seven of 78 drugs with cost-effective studies had been shown to improve overall survival, whereas 15 of 38 of drugs without a cost-effectiveness study had been shown to improve overall survival. Having a study funded by a pharmaceutical company was associated with higher odds of a study concluding that a drug was cost-effective than studies without funding (odds ratio, 41.36; 95% CI, 11.86-262.23). Conclusions and Relevance: In this cross-sectional study, pharmaceutical funding was associated with greater odds that an oncology drug would be found to be cost-effective. These findings suggest that simply disclosing potential conflict of interest is inadequate. We encourage cost-effectiveness analyses by independent groups.

Real-world Use of and Spending on New Oral Targeted Cancer Drugs in the US, 2011-2018.

Importance: Launch prices of new cancer drugs in the US have substantially increased in recent years despite growing concerns about the quantity and quality of evidence supporting their approval by the US Food and Drug Administration (FDA). Objective: To assess the use of and spending on new oral targeted cancer drugs among US residents with employer-sponsored insurance between 2011 and 2018, stratified by the strength of available evidence of benefit. Design, Setting, and Participants: In this cross-sectional study, dispensing claims for oral targeted cancer drugs first approved by the FDA between January 1, 2011, and December 31, 2018, were analyzed. The number of patients with drugs dispensed and the total payment for all claims were aggregated by calendar year, and these outcomes were arrayed according to evidence underlying FDA approvals, including pivotal study design (availability of randomized clinical trials) and overall survival (OS) benefit, as documented in drug labels. This study was conducted from July 17, 2019, to July 23, 2021. Main Outcomes and Measures: Annual and cumulative numbers of patients who had dispensing events, and annual and cumulative sums of payment for eligible drugs. Results: Of 37 348 patients who had at least 1 of the 44 new oral targeted drugs dispensed between 2011 and 2018, 21 324 were men (57.1%); mean (SD) age was 64.1 (13.1) years. Most individuals (36 246 [97.0%]) received drugs for which evidence from randomized clinical trials existed; however, a growing share of patients received drugs without documented OS benefit during the study period: from 12.7% in 2011 to 58.8% in 2018. Cumulative spending on all sample drugs totaled $3.5 billion by the end of 2018, of which 96.8% was spent on drugs that were approved based on a pivotal randomized clinical trial. Cumulative spending on drugs without documented OS benefit ($1.8 billion [51.6%]) surpassed that on drugs with documented OS benefit ($1.7 billion [48.4%]) by the end of 2018. Conclusions and Relevance: The findings of this cross-sectional study suggest that drugs used for treatment of cancer without documented OS benefits are adopted in the health system and account for substantial spending.

Feasibility of Randomized Controlled Trials for Cancer Drugs Approved by the Food and Drug Administration Based on Single-Arm Studies.

Background: The US Food and Drug Administration (FDA) introduced an Accelerated Approval (AA) pathway to expedite patient access to new drugs. AA accepts less rigorous trial designs, including single-arm studies (SAS), owing to perceived lack of feasibility of timely randomized controlled trials (RCTs). Methods: We designed hypothetical RCTs with endpoints of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) for FDA approvals based on SAS for solid tumors during 2010-2019. Existing standards of care served as controls. RCTs were designed to detect a difference with power of 0.80, α-error of 5% (2-sided), and 1:1 randomization. Accrual duration was estimated based on participation by less than 5% of eligible patients derived from cancer-specific incidence and mortality rates in the United States. Results: Of 172 (18.0%) approvals during the study period, 31 (18.0%) were based on SAS. Median sample size was 104 (range = 23-411), and 77.4% were AA. All studies reported ORR, 55% reported duration of response, 19.4% reported PFS, and 22.5% reported OS. Median sample sizes needed to conduct RCTs with endpoints of ORR, PFS, and OS were 206, 130, and 396, respectively. It would have been theoretically possible to conduct RCTs within duration comparable with that required by SAS for 84.6%, 94.1%, and 80.0% of approvals with endpoints of ORR, PFS, and OS, respectively. Conclusion: An overwhelming majority of FDA approvals based on SAS should be feasible as RCTs within a reasonable time frame. Given the collateral harms to patients and to scientific rigor, drug approval based on SAS should only be permitted under exceptional circumstances.

Characteristics of drugs approved in Japan without conducting confirmatory clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. METHODS: Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. RESULTS AND DISCUSSION: Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. WHAT IS NEW AND CONCLUSION: The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally.

Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations.

BACKGROUND: It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice. METHODS: We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI. RESULTS: The median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >FI. CONCLUSION: The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm.

Patient Participation in Clinical Trials of Oncology Drugs and Biologics Preceding Approval by the US Food and Drug Administration.

Importance: Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. Objective: To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. Design, Setting, and Participants: This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. Main Outcomes and Measure: The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. Results: A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). Conclusions and Relevance: The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics.

Immune checkpoint inhibitors (ICIs) are considered a new standard-of-care across many cancer indications. This review provides an update on ICIs approved by the Food and Drug Administration (FDA), with focus on monoclonal antibodies that target the programmed cell death 1 (PD-1) or its ligand, PD-1 ligand 1 (PD-L1), including information on their clinical indications and associated companion diagnostics. The information is further discussed with strategies for identifying predictive biomarkers to guide the clinical use of PD-1/PD-L1-targeted therapies.

Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP, OATP1B1, and OAT3 transporters.

Tolvaptan (TLV) was US Food and Drug Administration (FDA)-approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM-4013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5 mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90 mg TLV or 48 h following 7 days of once daily 300 mg TLV (i.e., in the presence of DM-4103). In trial 2, 40 mg furosemide (OAT3 substrate) was administered alone and in presence of DM-4103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (Cmax ) were 1.54 (90% CI 1.26-1.88) and for area under the concentration-time curve from time 0 to the time of the last measurable concentration (AUCt ) were 1.69 (90% CI 1.34-2.14), indicating no clinically significant interaction. DM-4103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250 ml; TLV has solubility of ~0.01 g/250 ml. For OATP1B1/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM-4103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.