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.

Estimation of manufacturing development costs of cell-based therapies: a feasibility study.

BACKGROUND AIMS: Cell-based therapies (CBTs) provide opportunities to treat rare and high-burden diseases. Manufacturing development of these innovative products is said to be complex and costly. However, little research is available providing insight into resource use and cost drivers. Therefore, this study aimed to assess the feasibility of estimating the cost of manufacturing development of two cell-based therapy case studies using a CBT cost framework specifically designed for small-scale cell-based therapies. METHODS: A retrospective costing study was conducted in which the cost of developing an adoptive immunotherapy of Epstein-Barr virus-specific cytotoxic T lymphocytes (CTLs) and a pluripotent stem cell (PSC) master cell bank was estimated. Manufacturing development was defined as products advancing from technology readiness level 3 to 6. The study was conducted in a Scottish facility. Development steps were recreated via developer focus groups. Data were collected from facility administrative and financial records and developer interviews. RESULTS: Application of the manufacturing cost framework to retrospectively estimate the manufacturing design cost of two case studies in one Scottish facility appeared feasible. Manufacturing development cost was estimated at £1,201,016 for CTLs and £494,456 for PSCs. Most costs were accrued in the facility domain (56% and 51%), followed by personnel (20% and 32%), materials (19% and 15%) and equipment (4% and 2%). CONCLUSIONS: Based on this study, it seems feasible to retrospectively estimate resources consumed in manufacturing development of cell-based therapies. This fosters inclusion of cost in the formulation and dissemination of best practices to facilitate early and sustainable patient access and inform future cost-conscious manufacturing design decisions.

Regulatory Safety Learning Driven by the Mechanism of Action: The Case of TNF-α Inhibitors.

The summary of product characteristics (SmPCs) is an important information source that includes the adverse drug reactions (ADRs) associated with the drug. Drugs with the same mechanism of action are expected to have a similar ADR profile and thus a substantial overlap of the described ADRs in the SmPC. The objective of this study is to assess this overlap. We extracted all ADRs (excluding hypersensitivity and administration site reactions) that were described in the first and all subsequent versions of the SmPCs of all approved TNF-α inhibitors in the European Union. The Medical Dictionary for Regulatory Activities was used to characterize the ADRs. At the end of follow-up, 293 unique ADRs (at high level term level) were described in the SmPCs of the 5 TNF-α inhibitors. There was substantial variation in the number of ADRs described in the SmPC among the TNF-α inhibitors. Of the 293 ADRs, 133 (45%) were described in the SmPC of one TNF-α inhibitor and 39 (13%) in the SmPCs of all 5 TNF-α inhibitors. Serious ADRs and ADRs classified as important risks were described approximately four times more often in a second SmPC than ADRs not classified as such. In conclusion, the ADRs described in the SmPCs of the TNF-α inhibitors differ considerably in number and type. In order to adequately inform prescribers and patients, acquired knowledge of the safety profile of drugs with the same mechanism of action should increasingly be taken into account in the assessment of all drugs within the class.

Adverse Drug Reaction Reporting in Africa and a Comparison of Individual Case Safety Report Characteristics Between Africa and the Rest of the World: Analyses of Spontaneous Reports in VigiBase®.

INTRODUCTION: Following the start of the World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) by 10 member countries in 1968, it took another 24 years for the first two African countries to join in 1992, by which time the number of member countries in the PIDM had grown to 33. Whilst pharmacovigilance (PV), including the submission of individual case safety reports (ICSR) to VigiBase(®), the WHO global ICSR database, is growing in Africa, no data have been published on the growth of ICSR reporting from Africa and how the features of ICSRs from Africa compare with the rest of the world (RoW). OBJECTIVE: The objective of this paper was to provide an overview of the growth of national PV centres in Africa, the reporting of ICSRs by African countries, and the features of ICSRs from Africa, and to compare ICSRs from Africa with the RoW. METHODS: The search and analysis interface of VigiBase(®)--VigiLyze(®)--was used to characterise ICSRs submitted by African countries and the RoW. The distribution of ICSRs by African countries was listed and characterised by anatomic therapeutic chemical (ATC) code, Medical Dictionary for Regulatory Activities (MedDRA(®)) system organ class (SOC) classification, and patient age and sex. The case-defining features of ICSRs between Africa and the RoW were also compared. RESULTS: The number of African countries in the PIDM increased from 2 in 1992 to 35 at the end of September 2015, and African PIDM members have cumulatively submitted 103,499 ICSRs (0.88 % of global ICSRs) to VigiBase(®). The main class of products in African ICSRs are nucleoside and nucleotide reverse transcriptase inhibitors (14.04 %), non-nucleoside reverse transcriptase inhibitors (9.09 %), antivirals for the treatment of HIV infections (5.50 %), combinations of sulfonamides and trimethoprim (2.98 %) and angiotensin-converting enzyme (ACE) inhibitors (2.42 %). The main product classes implicated in ICSRs from the RoW are tumour necrosis factor-α (TNFα) inhibitors (5.29 %), topical nonsteroidal anti-inflammatory preparations (2.26 %), selective immunosuppressants (2.08 %), selective serotonin reuptake inhibitors (2.04 %) and HMG CoA reductase inhibitors (1.85 %). The main SOCs reported from Africa versus the RoW include skin and subcutaneous tissue disorders (31.14 % vs. 19.58 %), general disorders and administration site conditions (20.91 % vs. 30.49 %) and nervous system disorders (17.48 % vs. 19.13 %). The 18-44 years age group dominated ICSRs from Africa, while the 45-64 years age group dominated the RoW. Identical proportions of females (57 % Africa and the RoW) and males (37 % Africa and the RoW) were represented. CONCLUSIONS: As at the end of September 2015, 35 of 54 African countries were Full Member countries of the PIDM. Although the number of ICSRs from Africa has increased substantially, ICSRs from Africa still make up <1 % of the global total in VigiBase(®). The features of ICSRs from Africa differ to those from the RoW in relation to the classes of products as well as age group of patients affected. The gender of patients represented in these ICSRs are identical.