Administrative Aspects of Molecular Diagnostics-Oversight, Regulatory Approval Process, Clinical and Operational Workflows, and Payment Models.

e18501 Background: Cancer clinical trials based in the United States (US) have lacked adequate representation of racial and ethnic minorities, the elderly, and women. Pivotal clinical trials leading to United States Food and Drug Administration (FDA) approval are often multi-national trials and may also lack generalizability to underrepresented populations in the United States. We determined the racial, ethnic, age, and sex enrollment in pivotal trials relative to the US cancer population. Methods: We reviewed the FDA’s Drug Approvals and Databases for novel and new use drug approvals for breast, colorectal, lung, and prostate cancer indications from 2008 through 2020. Drugs@FDA was searched for drug approval summaries and FDA labels to identify clinical trials used to justify clinical efficacy that led to FDA approval. For eligible trials, enrollment data were obtained from FDA approval summaries, FDA labels, ClinicalTrials.gov, and corresponding journal manuscripts. Enrollment Fraction (EF) was calculated as enrollment in identified clinical trials divided by 2017 SEER cancer prevalence. All data sources were publicly available. Results: From 2008 through 2020, 60 drugs received novel or new use drug approval for breast, colorectal, lung, or prostate cancer indications based on 66 clinical trials with a total enrollment of 36,830. North America accounted for 9,259 (31%) enrollees of the 73% of trials reporting location of enrollment. Racial demographics were reported in 78% of manuscripts, 66% of ClinicalTrials.gov pages, and 98% of FDA labels or approval summaries. Compared with a 0.4% enrollment fraction among White patients, lower enrollment fractions were noted in Hispanic (0.2%, odds ratio [OR] vs White, 0.46; 95% confidence interval [CI], 0.43 to 0.49, P< 0.001) and Black (0.1%, OR 0.29; 95% CI 0.28 to 0.31, P< 0.001) patients. Elderly patients (age ≥ 65 years) were less likely than younger patients to be enrollees (EF 0.3% vs 0.9%, OR 0.27; 95% CI 0.26 to 0.27, P< 0.001) despite accounting for 61.3% of cancer prevalence. For colorectal and lung cancer trials, females were less likely than males (EF 0.7% vs 1.1%, OR 0.66; 95% CI 0.63 to 0.68, P< 0.001) to be enrolled. Conclusions: Black, Hispanic, elderly, and female patients were less likely to enroll in cancer clinical trials leading to FDA approvals from 2008 to 2020. Race and geographic enrollment data were inconsistently reported in journal manuscripts and ClinicalTrials.gov. The lack of appropriate representation of specific patient populations in these key clinical trials limits their generalizability. Future efforts must be made to ensure equitable access, representation, and reporting of enrollees that adequately represent the US population of patients with cancer.

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

should decrease pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), without affecting systemic arterial pressure (SAP), and potentially improve oxygenation by redistributing pulmonary blood flow to ventilated areas of lung. INO (INO Therapeutics Inc., Clinton NJ) possesses these properties and has gained approval from the Food and Drug Administration (FDA) for the care of neonates with acute lung injury and pulmonary hypertension (PH), and widespread clinical acceptance (but not FDA approval) for adults with PH with or without lung injury. Delivered as a gas, INO is preferentially distributed to the ventilated areas of the lung, where it produces relaxation of pulmonary vascular smooth muscle via activation of guanylate cyclase and the conversion of guanosine-5-triphosphate to cyclic guanosine monophosphate. 1 Absorbed INO is rapidly inactivated by hemoglobin, thereby preventing systemic effects and confining its vasodilator properties to the pulmonary circulation. 1 The search for inhaled selective pulmonary vasodilators was an active area of research, particularly in Europe and Australia, before the widespread publicity and testing of INO in the early 1990s. However, research on this subject appears to have declined inversely with the growing acceptance and use of INO. Until FDA approval had been granted, INO had been supplied free of charge in the United States on an investigational-drug basis. However, after FDA approval, the cost of treatment with INO became very expensive. This prompted a search at our institution for alternative agents to INO. The purpose of this article is to review the published experience concerning alternative inhaled vasodilators and, when possible, compare their reported efficacy with that of INO.

The use of molecular tests as an adjunct to FNA diagnosis of thyroid nodules has been increasing. However, the true impact of these tests on surgical practice has not been demonstrated. This study examines the usefulness of molecular testing on surgical management decisions in patients referred for thyroid surgery at a tertiary care center. Clinical information was collected from patients who presented to Johns Hopkins Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between August 2009 and March 2013. Tests included an RNA-based gene expression classifier, a DNA-based somatic mutation panel, BRAF, NRAS, and/or RET/PTC translocation. A surgical management algorithm was created by consensus of four thyroid surgeons. Postsurgical pathology analysis in each case was then used to judge the appropriateness of the surgical decision-making and the usefulness of preoperative molecular testing, in guiding surgical planning. Of 114 patients assessed by preoperative molecular testing, 87 (72%) underwent surgery. Surgical management was altered in nine (10%) patients on the basis of molecular testing. Of these, surgical management change was appropriate, relative to the postoperative pathology analysis, for three patients and inappropriate for six patients. In this study, molecular testing of thyroid nodule did not alter the surgical management of the majority of patients with thyroid nodules. These results indicate that molecular testing may be overused in patients for whom the results would not change surgical management. Furthermore, our data question the usefulness of the molecular tests examined in guiding preoperative surgical decision-making.

In the United States, drugs and medical devices are regulated by different divisions of the U.S. Food and Drug Administration (FDA). While defined similarly, drugs and medical devices differ in their modes of action. Both are products that are labeled, promoted, or used in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease. A device, however, does not achieve its intended purpose through a chemical action within or on the body or by being metabolized by the body. 1 Although both drugs and medical devices must comply with federal regulations regarding labeling, advertising, production, and postmarketing surveillance, there are differences in the FDA premarket review and approval processes. FDA clearance and prescription status of a device do not necessarily mean that safety and efficacy have been shown for the product or that clinical trials have been conducted. We conducted a literature review to (a) examine the historical legislation and approval processes for drugs, medical devices, and combination products and (b) discuss implications of the differences in FDA review processes for clinicians and payers. ■■ Methods

Approved by the US Food and Drug Administration (FDA) in 2010, sipuleucel-T (Provenge(®)) was the first 'personalized' cancer vaccine for the treatment of prostate cancer in a metastatic, non-symptomatic population of 30,000 men in the USA. Sipuleucel-T is prepared individually for each patient and infused in three sessions over a period of 1 month. However, in 2015, Dendreon, the owner of sipuleucel-T, filed for bankruptcy. This opinion paper reviews the probable reasons this innovative product failed to achieve commercial success. PubMed and internet searches were performed focused on pricing, reimbursement, and market access. We found that sipuleucel-T's FDA approval was delayed by 3 years, reportedly because of the vaccine's new mechanism of action. Sipuleucel-T was cleared by the European Medicines Agency 2 years later, but other national agencies were not approached. It was priced at $US93,000 for a course of treatment, and this high price combined with the company's late securement of reimbursement for the vaccine by the US Centers for Medicare and Medicaid Services (CMS) resulted in another year's delay in accessing the market. Despite a positive recommendation by the National Comprehensive Cancer Network, sipuleucel-T's complex administration, high price, and uncertainty about the reimbursement status deterred doctors from prescribing the product. Furthermore, the vaccine's supply was limited during the first year of launch due to limited manufacturing capacity. In addition, two oral metastatic prostate cancer drugs with similar survival benefits reached the US market 1 and 2 years after sipuleucel-T. Also, even though Dendreon's market capitalization topped $US7.5 billion following the FDA's approval of sipuleucel-T, this value degraded gradually until the firm's bankruptcy 5 years later. We conclude that the bankruptcy of Dendreon was largely due to the delay in securing FDA approval and CMS coverage, as well as the high cost that had to be incurred by providers up-front. Licensing sipuleucel-T to a pharmaceutical company more experienced in the market access pathway may have saved the company and the product.

e18202 Background: Patient-reported outcomes (PROs) are increasingly valued as a key tool in patient-focused treatment decisions. However, a lack of standardization leads to significant variability in PRO collection and reporting in ground-breaking clinical trials of novel agents. We sought to characterize the mechanisms of assessment and variability by which PROs are reported for newly approved anti-cancer therapies. Methods: We reviewed the U.S. Food and Drug Administration (FDA) approvals between 2011 and 2017 for anti-cancer new molecular entities (NMEs) and new biologic approvals (BLAs). For each therapy, the pivotal clinical trial leading to FDA approval was identified using the national clinical trial (NCT) number and assessed for inclusion of PROs. A separate PubMed search was conducted to evaluate for PRO publication distinct from the original trial based on national clinical trial registry number. Results: From 2011 to 2017, the FDA approved 66 NMEs/BLAs based on 74 clinical trials for cancer treatment. Of the 74 clinical trial publications, 21 (28%) of the trials published PRO data in their original clinical publication, 18 (24%) published a separate PRO analysis, and 35 (47%) did not publish PRO data in either format. Among the 32 clinical trials (43%) that listed PROs as pre-specified outcomes, 72% published PROs (23/32). The separate PRO analyses (N = 18) were published considerably later following FDA approval (mean 605 days) than the original clinical trials (mean 20 days, N = 74, P < 0.001). Conclusions: As cancer treatment options expand, therapy decisions become increasingly nuanced. PROs assist decision-making by providing detailed information on important aspects of quality of life and tolerability. Our research has identified a significant lag in the publication of companion studies of PRO data associated with pivotal clinical trials, representing a meaningful gap in information critical to patients and oncologists in the process of making informed decisions.

e20550 Background: Soon after the publication of the PACIFIC trial, the Food and Drug Administration (FDA) approved durvalumab following definitive chemoradiation in patients with unresectable stage III non-small cell lung cancer (NSCLC). However, patterns of durvalumab adoption within the United States are currently unknown. We investigated the pace of uptake of durvalumab as well as patient and tumor characteristics associated with receipt of durvalumab following FDA approval. Methods: This study used the nationwide Flatiron Health database, a longitudinal electronic health record-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). From this de-identified database, we selected patients with stage IIIB-C NSCLC who completed at least two cycles of first-line (1L) platinum doublet chemotherapy between February 16, 2018 (FDA approval date for durvalumab) and August 16, 2019, and did not develop disease progression over a follow-up period of at least 120 days after 1L chemotherapy. In the absence of radiation therapy and surgery details in the database, these criteria served as a proxy for selecting patients who were most likely to be eligible for consolidative durvalumab. We evaluated temporal trends in the uptake of durvalumab after completion of 1L chemotherapy using the Cochran-Armitage test, clustering the time periods in 3-month intervals. We also characterized patient and tumor characteristics associated with durvalumab receipt using the chi-square test and multivariable logistic regression. Results: A total of 424 patients were included in our study sample, among whom 282 (66.5%) patients had documentation of having received durvalumab after 1L chemotherapy. Within the first 3 months after FDA approval, 60.4% of potentially eligible patients received durvalumab, while in the final 3 months of the study period, this proportion rose modestly to 68.3% (p = 0.19). On univariable and multivariable analysis, patient characteristics like age, sex, race, insurance, smoking status, performance status, and comorbidity score, as well as tumor characteristics like histology, EGFR status, and PD-L1 status, were not significantly associated with receipt of durvalumab. However, there was significant geographic variability in receipt of durvalumab, ranging from 65.7% in the South to 85.3% in the Midwest (chi-square p = 0.04). Conclusions: Early adoption of durvalumab upon completion of 1L chemotherapy for stage IIIB-C lung cancer was rapid across the United States, starting at over 60% in the first three months after FDA approval. Regional variation appears to be a more powerful driver than patient characteristics in discrepancies of durvalumab dissemination. Further exploration into these regional variations may help improve guideline-concordant care.

Introduction

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. 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. 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. The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. 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). 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.

e13655 Background: Over the past decades, US congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. It remains unclear whether multiple designations per indication are redundant. This study analyzes cancer drugs with multiple special designations regarding their FDA approval timelines, evidence, benefit, epidemiology and price. Methods: All anti-cancer drugs and their supplemental indication approvals were identified in the Drugs@FDA database from 2000 to 2022. For each indication, clinical trial characteristics, epidemiologic, and price data were collected from FDA labels, the Global Burden of Disease Study, and Medicare & Medicaid Part B and D, respectively. The association between overall survival (OS) and progression-free survival (PFS) hazard ratios (HR) and drug indications’ number of special designations were compared in meta-analyses and meta-regressions. Results: We identified 170 anti-cancer drugs with FDA approval in 455 indications. The median time to first FDA approval was 13.8 years for drugs with zero, 7.3 years with one, 7.1 years with two, 7.8 with three, 5.8 with four, and 5.3 with five special designations (HR per additional designation: 1.27, 95%CI: 1.09-1.48, p=.002). Drug indications with more special designations were more frequently granted to rare diseases with fewer treatment options supported by smaller and shorter open-label phase 1/2 trials. OS HRs were 0.79 for indications with zero, 0.74 with one, 0.73 with two, 0.69 with three, 0.59 with four, and 0.52 with five special designations (p=.024). On average, each additional special designation was associated with lower HRs for OS (ß=-0.03, p=.002) and PFS (ß=-0.07, p<.001). Each additional special designation was associated with a 19.05% (95%CI: 4.56-35.55, p=.013) higher drug price. Conclusions: The FDA’s special designations are non-redundant. Multiple special designations are associated with faster approval times and a greater efficacy for patients with high unmet needs, while multiple special designations are associated with less robust trial evidence and higher drug prices. This study supports the strategy of special FDA designations for unmet clinical needs.

BackgroundOver the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.ObjectivesThis study reviews the FDA’s five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price.MethodsWe conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview.ResultsExpedited approval reduces new drugs’ time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as “breakthroughs”, are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US.ConclusionSpecial FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

The US Food and Drug Administration (FDA) approved 5-aminolevulinic acid (5-ALA; Gleolan®; photonamic GmbH and Co. KG) for use as an intraoperative optical imaging agent in patients with suspected high-grade gliomas (HGGs) in 2017. This was the first ever optical imaging agent approved as an adjunct for the visualization of malignant tissue during surgery for brain tumors. The approval occurred a decade after European approval and a multicenter, phase III randomized trial which confirmed that surgeons using 5-ALA fluorescence-guided surgery as a surgical adjunct could achieve more complete resections of tumors in HGG patients and better patient outcomes than with conventional microsurgery. Much of the delay in the US FDA approval of 5-ALA stemmed from its conceptualization as a therapeutic and not as an intraoperative imaging tool. We chronicle the challenges encountered during the US FDA approval process to highlight a new standard for approval of intraoperative optical imaging agents in brain tumors.

BackgroundThe U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product’s actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication.MethodsWe searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials.ResultsBetween 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01–2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15–0.16).ConclusionsMany postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers.

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