Balancing ethical norms and duties for the introduction of new medicines through conditional marketing authorization: a research agenda.

The European Medicines Agency's conditional marketing authorization (CMA) aims to expedite patient access to medicines for unmet medical needs by shifting a part of the drug development process post-authorization. We highlight ethical issues surrounding CMA, comprising (i) the complexity of defining unmet medical need; (ii) poor understanding of CMA and its impact on informed consent; (iii) hope versus unrealistic optimism; (iv) implications of prolonged post-authorization studies and potential patient harm; (v) rights and duties of patients surrounding participation in post-authorization studies; (vi) access to previously authorized CMA medicines; and (vii) the "benefit slippage" phenomenon, defined as the gradual shift of strict criteria to less strict criteria. We propose a comprehensive research agenda to address these ethical issues, and stress the need for multi-stakeholder engagement to ensure patient-centered use of CMA.

Surrogate Endpoints for Late Kidney Transplantation Failure.

In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.

Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: A comparison with standard approved cancer drugs.

AIMS: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. METHODS: We identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. RESULTS: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4). CONCLUSION: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.

A Decade of Marketing Authorization Applications of Anticancer Drugs in the European Union: An Analysis of Procedural Timelines.

BACKGROUND: Cancer is a serious global health problem and a major cause of death. The European Medicines Agency (EMA) has established several regulatory initiatives to expedite the development and authorization of drugs to ensure timely access of patients. In this study, we analyzed the procedural timelines of marketing authorization applications for anticancer drugs in the EU, with a specific focus to special regulatory programs, scientific advice and company size. METHODS: Anticancer drugs that received an opinion from the EMA between January 2010 and December 2019 were included in the study. Public assessment reports were used to obtain publicly available information of the drugs. RESULTS: We identified 96 applications for new anticancer drugs. 34 applications were granted access to at least one expedited program offered by the EMA. Total procedure time was reduced from average 370 to 200-215 days when accelerated assessment was granted. Granting of a conditional marketing authorization or an orphan designation, as well as having scientific advice, only mildly affected total procedure time. Average total procedure time of small companies was much longer compared with medium-sized and large companies (483 versus 356 days), which was caused by an increased clock stop time. CONCLUSION: Total procedure time for anticancer is mainly affected by the granting of accelerated assessment, which reduced the total procedure time, and company size, where total procedure time is much longer for small companies. Small companies are advised to have, and especially adhere to scientific advice to reduce procedure time and increase the chance of success.

Considerations on the chemistry, manufacture and control requirements for conditional marketing authorization drugs in China / 中国药科大学学报

@#Drug Administration Law revised in 2019 proposed for the first time conditional marketing authorization at the legal level, marking the formal implementation of the conditional marketing authorization in China. This paper compares the regulations and technical requirements of conditional marketing authorization drugs in China with those in Europe and the United States, in an attempt to learn from the experience of chemistry, manufacture and control review of these drugs in Europe and the United States, and to discuss the pharmaceutical technical requirements of conditional marketing authorization drugs in China.

Remdesivir emergency approvals: a comparison of the U.S., Japanese, and EU systems.

INTRODUCTION: There were no formal regulatory approvals for antivirals for the COVID-19 pandemic as of June 2020. AREAS COVERED: We compare the first regulatory approvals for remdesivir, through emergency pathways available to three of the main regulators in the world, the U.S., Japan, and the EU. We look at the data supporting the decisions and how authorities exchanged information and collaborated to speed up approvals. Based only on topline data available as of 29 April 2020, regulators granted approvals to remdesivir based on very limited but robust data and waiting for more safety and efficacy data. This included the Emergency Use Authorization in the U.S. on 1 May, the Special Approval for Emergency in Japan on 7 May, and Compassionate Use (3 April) followed by a Conditional Marketing Authorization in Europe (Opinion 25th June, Decision (3 July)). EXPERT OPINION: While the regulatory approvals were clearly based on evidence, regulators used agile methods to speed up approval, and make the first antiviral with reliable data available to patients in their constituencies in a very short time frame. More data and wider patient access are still necessary for this product, and more treatments are needed for patients affected by COVID-19.

Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

Differences in Health Technology Assessment Recommendations Among European Jurisdictions: The Role of Practice Variations.

BACKGROUND: Health technology assessment (HTA) plays an important role in reimbursement decision-making in many countries, but recommendations vary widely throughout jurisdictions, even for the same drug. This variation may be due to differences in the weighing of evidence or differences in the processes or procedures, which are known as HTA practices. OBJECTIVE: To provide insight into the effects of differences in practices on interpretation of intercountry differences in HTA recommendations for conditionally approved drugs. METHODS: HTA recommendations for conditionally approved drugs (N = 27) up until June 2017 from England/Wales, France, Germany, the Netherlands, and Scotland were included. Recommendations and practice characteristics were extracted from these five jurisdictions and this data was validated. The effect of nonsubmissions, resubmissions, and reassessments; cost-effectiveness assessments; and price negotiations on changes in the percentage of negative recommendations and the interpretation of intercountry differences in HTA outcomes were analyzed using Fisher exact tests. RESULTS: The inclusion of cost-effectiveness assessments led to significant increases in the proportion of negative recommendations in England/Wales (from 4% to 50%, P<.01) and Scotland (from 21% to 71%, P<.01). The subsequent inclusion of price negotiations led to significant reductions in the proportion of negative recommendations in England/Wales (from 50% to 14%, P<.01), France (from 31% to 3%, P=.012), and Germany (from 34% to 0%, P<.01). Results indicated that the inclusion of nonsubmissions and resubmissions might affect Scottish negative HTA recommendations (from 7% to 21%), but this effect was not significant. No significant effects were observed in the Netherlands, possibly owing to sample size. CONCLUSION: Variations in HTA practices between international jurisdictions can have a substantial and significant impact on conclusions about recommendations by HTA bodies, as exemplified in this cohort of conditionally approved products. Studies comparing international HTA recommendations should carefully consider possible practice variations between jurisdictions.