Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020.

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

Price changes and within-class competition of cancer drugs in the USA and Europe: a comparative analysis.

BACKGROUND: Cancer drugs are a major component of pharmaceutical spending in the USA and Europe. The number of approved cancer drugs continues to increase. More new drugs with overlapping mechanisms of action and similar approved indications might be expected to decrease prices within drug classes. We compared patterns of price changes for cancer drugs within the same class in the USA and in two European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. METHODS: For this comparative analysis, we identified cancer drugs approved for the treatment of solid cancers in the USA and Europe (Germany and Switzerland) between Jan 1, 2009, and Dec 31, 2020, using the US Food and Drug Administration's Drugs@FDA database and the European Medicines Agency's publicly available database. We considered cancer drugs as within-class competitors if they were approved for the same indication and had the same biological mechanism. We calculated monthly treatment prices for each drug, median price changes at launch and over time, and differences within and across drug classes. European price data were converted to US dollars by applying the exchange rates on Dec 1, 2020, and prices were adjusted for inflation. Median changes in the drugs' monthly treatment prices at 2 and 4 years after market entry across and within drug classes were also assessed. For the USA, correlations in relative price changes between all pairs of drugs within and across drug classes were calculated with Spearman's rank correlation. FINDINGS: Our study cohort comprised 12 drug classes covering nine indications. With the exception of one drug, increasing prices were observed within and across all drug classes in the USA (median 6·07% [range -3·60 to 33·83] 2 years after market entry, and 15·31% [-4·15 to 54·64] 4 years after market entry). By contrast, in Europe, prices generally decreased over time or did not increase more than inflation (2 years after market entry: -21·01% [range -50·72 to 12·71] in Germany and -1·48% [-26·81 to 1·69] in Switzerland; 4 years after market entry: -25·54% [-51·81 to 11·63] in Germany and -13·02% [-43·83 to 18·31] in Switzerland). In the USA, most prices changes within and across drug classes occurred at the end and beginning of the year (ie, from Dec 1 to Jan 31). In the USA, correlation for price changes was r=0·29 (SD 0·36) for within-class drugs and r=0·28 (0·36) for drugs across drug classes. INTERPRETATION: Competition within classes of cancer drugs generally did not constrain rising prices in the USA. Price negotiations, as practised in Germany or Switzerland, could help address the high prices of cancer drugs in the USA. FUNDING: Swiss Cancer Research Foundation (Krebsforschung Schweiz), Swiss National Science Foundation, and Arnold Ventures.

Coverage of New Drugs in Medicare Part D.

Policy Points Only a small minority of new drugs in "nonprotected" classes are widely covered by Part D plans nationwide in the year after US Food and Drug Administration (FDA) approval. Part D plans frequently apply utilization management restrictions such as prior authorizations to newly approved drugs in both protected and nonprotected classes. Drug price influences both formulary inclusion (in nonprotected classes) and coverage restrictions (in both protected and nonprotected classes), while other drug characteristics such as therapeutic benefits are not consistently associated with formulary design. Plans do not seem to favor the minority of drugs that are determined to offer added therapeutic benefit over existing alternatives. CONTEXT: Medicare Part D is an outpatient prescription drug benefit for older Americans covering more than 46 million beneficiaries. Except for mandatory coverage for essentially all drugs in six protected classes, plans have substantial flexibility in how they design their formularies: which drugs are covered, which drugs are subject to restrictions, and what factors determine formulary placement. Our objective in this paper was to document the extent to which Part D plans limit coverage of newly approved drugs. METHODS: We examined the formulary design of 4,582 Part D plans from 2014 through 2018 and measured (1) the decision to cover newly approved drugs in nonprotected classes, (2) use of utilization management tools in protected and nonprotected classes, and (3) the association between plan design and drug-level characteristics such as 30-day cost, therapeutic benefit, and the US Food and Drug Administration (FDA) expedited regulatory pathway. FINDINGS: The FDA approved 109 new drugs predominantly used in outpatient settings between 2013 and 2017. Of these, 75 fell outside of the six protected drug classes. One-fifth of drugs in nonprotected classes (15 out of 75) were covered by more than half of plans during the first year after approval. Coverage was often conditional on utilization management strategies in both protected and nonprotected classes: only seven drugs (6%) were covered without prior authorization requirements in more than half of plans. Higher 30-day drug costs were associated with more widespread coverage in nonprotected classes: drugs that cost less than $150 for a 30-day course were covered by fewer than 20% of plans while those that cost more than $30,000 per 30 days were covered by more than 50% of plans. Plans were also more likely to implement utilization management tools on high-cost drugs in both protected and nonprotected classes. A higher proportion of plans implemented utilization management strategies on covered drugs with first-in-class status than drugs that were not first in class. Other drug characteristics, including availability of added therapeutic benefit and inclusion in FDA expedited regulatory approval, were not consistently associated with plan coverage or formulary restrictions. CONCLUSIONS: Newly approved drugs are frequently subject to formulary exclusions and restrictions in Medicare Part D. Ensuring that formulary design in Part D is linked closely to the therapeutic value of newly approved drugs would improve patients' welfare.

Associations With Definitive Outcomes and Clinical Benefit of Cancer Drugs at the Time of Marketing Approval and in the Postmarketing Period.

BACKGROUND: Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. METHODS: Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. RESULTS: We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. CONCLUSIONS: Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.

Prices and clinical benefit of cancer drugs in the USA and Europe: a cost-benefit analysis.

BACKGROUND: Increasing cancer drug prices are a challenge for patients and health systems in the USA and Europe. By contrast with the USA, national authorities in European countries often directly negotiate drug prices with manufacturers. The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) developed frameworks to evaluate the clinical value of cancer therapies: the ASCO-Value Framework (ASCO-VF) and the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We aimed to assess the association between the clinical benefit of approved cancer drugs based on these frameworks and their drug prices in the USA and four European countries (England, Switzerland, Germany, and France). METHODS: For this cost-benefit analysis, we identified all new drugs with initial indications for adult cancers that were approved by the US Food and Drug Administration between Jan 1, 2009, and Dec 31, 2017, and by the European Medicines Agency up until Sept 1, 2019. For drugs indicated for solid tumours, we assessed clinical benefit using ASCO-VF and ESMO-MCBS. We compared monthly drug treatment costs between benefit levels using hierarchical linear regression models, and calculated Spearman's correlation coefficients between costs and benefit levels for individual countries. FINDINGS: Our cohort included 65 drugs: 47 (72%) drugs were approved for solid tumours and 18 (28%) were approved for haematological malignancies. The monthly drug treatment costs in the USA were a median of 2·31 times (IQR 1·79-3·17) as high as in the assessed European countries. There were no significant associations between monthly treatment costs for solid tumours and clinical benefit in all assessed countries, using the ESMO-MCBS (p=0·16 for the USA, p=0·98 for England, p=0·54 for Switzerland, p=0·52 for Germany, and p=0·40 for France), and for all assessed countries except France using ASCO-VF (p=0·56 for the USA, p=0·47 for England, p=0·26 for Switzerland, p=0·23 for Germany, and p=0·037 for France). INTERPRETATION: Cancer drugs with low or uncertain clinical benefit might be prioritised for price negotiations. Value frameworks could help identify therapies providing high clinical benefit that should be made rapidly available across countries. FUNDING: Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Clinical benefit and cost of breakthrough cancer drugs approved by the US Food and Drug Administration.

BACKGROUND: The clinical benefit and pricing of breakthrough-designated cancer drugs are uncertain. This study compares the magnitude of the clinical benefit and monthly price of new and supplemental breakthrough-designated and non-breakthrough-designated cancer drug approvals. METHODS: A cross-sectional cohort comprised approvals of cancer drugs for solid tumors from July 2012 to December 2017. For each indication, the clinical benefit from the pivotal trials was scored via validated frameworks: the American Society of Clinical Oncology Value Framework (ASCO-VF), the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks. A high clinical benefit was defined as scores ≥ 45 for the ASCO-VF, overall survival gains ≥ 2.5 months or progression-free survival gains ≥ 3 months for all cancer types for the ASCO-CRC criteria, a grade of A or B for trials of curative intent and a grade of 4 or 5 for trials of noncurative intent for the ESMO-MCBS, and scores of 4 and 5 and a combined score ≥ 16 for the NCCN Evidence Blocks. Monthly Medicare drug prices were calculated with Medicare prices and DrugAbacus. RESULTS: This study identified 106 trials supporting approval of 52 drugs for 96 indications. Forty percent of these indications received the breakthrough designation. Among the included trials, 33 (43%), 46 (73%), 35 (34%), and 67 (69%) met the thresholds established by the ASCO-VF, ASCO-CRC, ESMO-MCBS, and NCCN, respectively. In the metastatic setting, there were higher odds of clinically meaningful grades in trials supporting breakthrough drugs with the ASCO-VF (odds ratio [OR], 3.69; P = .022) and the NCCN Evidence Blocks (OR, 5.80; P = .003) but not with the ASCO-CRC (OR, 3.54; P = .11) or version 1.1 (v1.1) of the ESMO-MCBS (OR, 1.22; P = .70). The median costs of breakthrough therapy drugs were significantly higher than those of nonbreakthrough therapies (P = .001). CONCLUSIONS: In advanced solid cancers, drugs that received the breakthrough therapy designation were more likely than nonbreakthrough therapy drugs to be scored as providing a high clinical benefit with the ASCO-VF and the NCCN Evidence Blocks but not with the ESMO-MCBS v1.1 or the ASCO-CRC scale.

Association between progression-free survival and patients' quality of life in cancer clinical trials.

Quality of life outcomes provide essential information for patients and physicians in oncology care. However, the validity of progression-free survival (PFS) as a surrogate for quality of life, and the inclusion and reporting of quality of life endpoints in clinical trials, is unclear. We performed a retrospective study of phase III clinical trials of drugs for advanced or metastatic solid tumors published between 2010 and 2015. Correlation coefficient (r) and area under the ROC curve (AUC) for association between PFS and positive quality of life were evaluated. Of the 352 Phase 3 trials included, 190 (54%) included a quality of life endpoint, of which 23% did not report pre-specified quality of life outcomes; a total of 125,962 patients were enrolled in studies lacking, or not reporting, quality of life outcomes. Among the 147 trials that reported quality of life outcomes, 99 (67%) reported no effect, 38 (26%) reported a positive effect and 10 (7%) reported a negative effect of treatment on patients' global quality of life. The association between PFS and improvement in global quality of life was weak (r = 0.34; AUC = 0.72), as was the association between PFS and improvement in any domain of quality of life. In conclusion, PFS benefit was not strongly correlated with improvements in patients' quality of life, and, despite the palliative intent of treatments in the advanced/metastatic setting, the availability of quality of life data from clinical trials of cancer drugs was poor.

Delays in completion and results reporting of clinical trials under the Paediatric Regulation in the European Union: A cohort study.

BACKGROUND: Few medicines have been approved for children, leading to rates of off-label prescribing reported to be as high as 90%. In 2007, the European Union adopted the Paediatric Regulation, which mandates that pharmaceutical companies conduct paediatric studies for all new medicines, unless granted a waiver. We aimed to evaluate the availability of paediatric trial results from studies required under the Paediatric Regulation for new medicines authorised in the EU. METHODS AND FINDINGS: The European Medicines Agency (EMA) public database of paediatric investigation plans was searched for new medicines centrally authorised in the EU between 1 January 2010 and 31 December 2014 with at least 1 required paediatric study. For our study cohort of paediatric clinical trials required for these medicines, we used internal EMA databases and publicly available trial registries to determine changes to the planned completion date or study design, rates of trial completion, time to trial completion, and results reporting (peer-reviewed publication or posting on trial registry). Cox proportional hazards regression models were constructed to examine factors associated with study completion. A total of 326 paediatric clinical trials were required for 122 novel medicines authorised by the EMA between 2010 and 2014. In all, 76% (247/326) of paediatric studies were not planned to be completed until after the initial marketing authorisation. The planned completion dates for 50% (162/326) were further postponed by a median of 2.2 years. Overall, 38% (124/326) of paediatric studies were completed as of 30 November 2017. The rate of trial completion for paediatric studies planned to be completed after initial marketing authorisation was 23% (56/247), versus 86% (68/79) for trials planned to be completed before authorisation (adjusted hazard ratio 0.11; 95% CI 0.06-0.19). Among completed studies, the results were reported in a public registry or in the peer-reviewed literature for 85% (105/124) at a median of 1.1 years after study completion, and 60% (74/124) were published in a peer-reviewed journal. Limitations of this study include the potential lack of generalisability to medicines not authorised by the EMA and the possibility for more of these trials to be completed or published in the future. CONCLUSIONS: The completion of many paediatric studies required under the Paediatric Regulation has been delayed. Paediatric studies planned to be completed after marketing authorisation were associated with a lower likelihood of eventual completion, highlighting the need to examine the implementation of current policies in ensuring timely availability of important paediatric information.

Reforming the World Health Organization's Essential Medicines List: Essential but Unaffordable.

This Viewpoint proposes restructuring the WHO Essential Medicines List to remove consideration of cost and cost-effectiveness from the expert committee reviews of clinical effectiveness, safety, and public health value, and chartering a new framework for pooled global negotiation and procurement of costly medicines included in the list.

Leveraging Novel and Existing Pathways to Approve New Therapeutics to Treat Serious Drug-Resistant Infections.

Accelerating the development and approval of novel therapeutics has emerged as a key public health priority given the mortality, morbidity, and economic costs associated with infections caused by drug-resistant bacteria. However, there is limited empirical evidence to guide policymaking, such as the factors that may disadvantage antibiotics compared to other classes of drugs. In this Article, we empirically examine characteristics of the key clinical trials underpinning FDA's approval of antibiotics and other drugs over the past decade. Despite perceptions that antibiotic trials are larger and more difficult to conduct, we find that antibiotic trials are no larger than those conducted for drugs approved in other disease areas with high unmet medical needs, suggesting that policymakers may need to target other levers to meaningfully stimulate innovation. We discuss the risks and benefits of harnessing new and existing regulatory pathways to speed the approval of new drugs, particularly those intended to treat patients with serious and life-threatening infections, and we evaluate ways that proposals for new regulatory pathways could be improved to better prioritize and expedite the approval of therapies with the greatest potential for patient health benefits.