Histology independent drug development - Is this the future for cancer drugs?

The Cancer Drug Development Forum (CDDF)'s 'Histology independent drug development - is this the future for cancer drugs?' workshop was set up to explore the current landscape of histology independent drug development, review the current regulatory landscape and propose recommendations for improving the conduct of future trials. The first session considered lessons learnt from previous trials, including innovative solutions for reimbursement. The session explored why overall survival represents the most valuable endpoint, and the importance of duration of response, which can be captured with swimmer and spider plots. The second session on biomarker development and treatment optimisation considered current regulations for companion diagnostics, FDA guidance on histology independent drug development in oncology, and the need to establish cut-offs for the biomarker of tumour mutational burden to identify the patients most likely to benefit from PDL1 treatment. The third session reviewed novel trial designs, including basket, umbrella and platform trials, and statistical approaches of hierarchical modelling where homogeneity between study cohorts enables information to be borrowed between cohorts. The discussion highlighted the need to agree 'common assessment standards' to facilitate pooling of data across studies. In the fourth session, the sharing of data sets was recognised as a key step for improving equity of access to precision medicines across Europe. The session considered how the European Health Data Space (EHDS) could streamline access to medical records, emphasizing the importance of introducing greater accountability into the digital space. In conclusion the workshop proposed 11 recommendations to facilitate histology agnostic drug development.

Extension of Indication for Authorised Oncology Products in the European Union: A Joint Effort of Multiple Stakeholders.

After marketing authorisation, the development of a medicinal product often continues with studies investigating new therapeutic indications. Positive results can potentially lead to changes to the terms of the marketing authorisation, such as an extension of therapeutic indication(s). These studies can be initiated and sponsored by the marketing authorisation holder (MAH) or by others. When results from an investigator-initiated trial suggest that an authorised medicinal product is safe and effective for a new therapeutic indication, physicians may want to treat their patients with this medicinal product. In such a situation, it is desirable to extend the therapeutic indication(s) via the regulatory approval process, as this can facilitate patient access within the European Union. There may however be challenges when the MAH did not conduct the study and might not have access to the data. In this perspective, we focus on the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product based on results from investigator-initiated trials. We address: (1) the advantages of an extension of indication; (2) the regulatory requirements for a variation application; (3) investigator-initiated trials as a basis for regulatory approval; (4) the role of the MAH in extending the indication. With this article, we want to emphasize the importance of a collaborative approach and dialogue between stakeholders with the aim to facilitate access to effective medicinal products.

Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma.

On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value<0.0001). The median OS was not reached for the nivolumab + ipilimumab group and was 25.95 months for the sunitinib group. The OS rates were 89.5% and 86.2% at 6 months, and 80.1% and 72.1% at 12 months in the nivolumab +ipilimumab and the sunitinib groups, respectively. K-M curves separated after approximately 3 months, favouring nivolumab + ipilimumab. This was not mirrored in the favourable-risk patients where no statistically significant difference was observed between nivolumab + ipilimumab and sunitinib in favourable-risk patients (HR 1.45 (descriptive 99.8% CI 0.51 to 4.12), p =0.2715).

Regulatory and Evidence Requirements and the Changing Landscape in Regulation for Marketing Authorisation.

In this chapter, we describe the changing landscape of the EU pharmaceutical legislation concerning regulation and evidence requirements for marketing authorisation. First, we describe the legal requirements for marketing authorisation and the development of EU pharmaceutical legislation and the concept of risk-benefit balance. Second, we describe special types of authorisation, such as conditional approval and approval under exceptional circumstances, and special provisions such as incentives for orphan medicinal products and paediatric investigational plans. Lastly, we describe the available methodological guidelines focussing on choice of endpoints.

The European Medicines Agency review of pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphomas: summary of the scientific assessment of the committee for medicinal products for human use.

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m(2) administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician's best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

The European medicines agency review of eribulin for the treatment of patients with locally advanced or metastatic breast cancer: summary of the scientific assessment of the committee for medicinal products for human use.

The European Commission issued on March 17, 2011, a marketing authorization valid throughout the European Union (EU) for eribulin (Halaven; Eisai Limited). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a marketing authorization for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least 2 chemotherapeutic regimens for advanced disease. Eribulin mesylate is a structurally simplified synthetic analogue of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai (ATC code L01XX41). Eribulin is a nontaxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates leading to G(2)-M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. The recommended dose of eribulin is 1.23 mg/m(2) (equivalent to 1.4 mg/m(2) eribulin mesylate) to be administered intravenously over 2 to 5 min on days 1 and 8 of a 3-week cycle. In the pivotal trial, eribulin was associated with increased overall survival in patients with locally advanced or metastatic breast cancer who received at least 2 prior chemotherapy lines for advanced disease (median overall survival was 13.2 months in the eribulin arm vs. 10.6 months in the control arm; HR = 0.805; 95% confidence interval, 0.677-0.958; P = 0.014). The most common side effects are asthenia or fatigue and neutropenia. The objective of this article is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary report and product information, including product characteristics, are available on the European Medicines Agency website.

The European Medicines Agency review of cabazitaxel (Jevtana®) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use.

On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application, a 2.4-month longer median overall survival time and a 30% lower risk for death were observed for cabazitaxel, compared with mitoxantrone. The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).