Therapeutic innovation & regulatory science最新文献

Background: Safety analyses play a pivotal role in drug development, ensuring the protection of patients while advancing innovative pharmaceuticals to market. A single study generally does not have sufficient sample size to evaluate all important safety events with reasonable precision and may not cover the full target population for the investigational treatment. Integrated analyses (pooled or meta-analysis) over several studies may be helpful in that regard. But without a structured conscious workflow accompanied with appropriate statistical methods for the integrated analysis, this can easily take a route compromising the interpretation.

Methods: In this article we apply the ICH estimand framework to clinical trial integration and summarize respective critical statistical assumptions to ensure the integrated analyses are interpretable.

Results: The estimand framework is valuable for developing principles for a deeper understanding of the critical statistical aspects of planning an integrated safety analysis. Our principles address the clinical question of interest, estimand and estimation. Special focus was given to the criteria for inclusion and exclusion of the component studies in the integrated analysis, and to integration of estimates pertaining to signal detection.

Conclusion: Performing an integrated analysis and its preparatory steps calls for a good understanding of the clinical question of interest and its estimand, care and sound practice, to enable interpretation and avoid introducing unnecessary bias. It is valuable to use the estimand framework not only for efficacy evaluations, but also for safety evaluations in clinical trials and for integrated safety analyses.

Introduction: The European Medicines Agency Innovation Task Force (ITF) acts as early point of contact for medicine and technology developers to enable innovation during early drug development stages through ITF briefing meetings.

Aim: To reflect on the current pace of innovation and to assess the potential of ITF stakeholder interactions, a comprehensive analysis of the ITF briefing meetings held between 2021 and 2022 was conducted with a focus on individual questions raised by the developers and the related feedback provided by the European regulators.

Methods: Questions raised during ITF briefing meetings were extracted and categorised into main and sub-categories, revealing different themes across the whole medicine development process such as manufacturing technologies, pre-clinical developments, and clinically relevant questions.

Results: There was positive feedback from regulators who gave initial guidance in 85% of the answers, provided concrete examples in 20% of the answers and recommended to continue discussions through additional regulatory procedures in 22% of the answers.

Conclusion: This analysis frames the content and the type of topics discussed during ITF briefing meetings. Moreover, it describes the type of regulatory feedback provided to medicine developers and identified potential for improvement of these early interactions. Therefore, this analysis emphasises the role of ITF briefing meetings in fostering innovation in medicine.

The phenomenon of delta inflation, in which design treatment effects tend to exceed observed treatment effects, has been documented in several therapeutic areas. Delta inflation has often been attributed to investigators' optimism bias, or an unwarranted belief in the efficacy of new treatments. In contrast, we argue that delta inflation may be a natural consequence of clinical equipoise, that is, genuine uncertainty about the relative benefits of treatments before a trial is initiated. We review alternative methodologies that can offer more direct evidence about investigators' beliefs, including Bayesian priors and forecasting analysis. The available evidence for optimism bias appears to be mixed, and can be assessed only where uncertainty is expressed explicitly at the trial design stage.

Background: Digital therapeutics (DTx) have attracted attention as the substitutes or add-ons to conventional pharmacotherapy and the number of DTx products authorized with the regulatory reviews of the clinical evidence is increasing. Insomnia is one of the major targets of the DTx due to the benefit from cognitive behavioral interventions and several products have been launched in the market with regulatory reviews. However, common features of the products and the clinical evidence required by each regulatory agency have not been investigated.

Methods: In this study, we identified the DTx products with the primary indication of insomnia authorized with regulatory reviews of clinical evidence by literature and website searches, and investigated the common features of the products and of the study designs for the pivotal clinical trials.

Results: The total of 6 DTx products were identified. The components of cognitive behavioral therapy for insomnia (CBT-I) were identified as common features of the products. All the pivotal clinical trials were randomized, parallel-group, blind studies against insomnia patients. No products have been authorized in multiple countries regardless of the similarity of the features of the products and of the study designs for the pivotal clinical trials.

Conclusions: Our study revealed that the components of CBT-I and gold standard design in pivotal clinical trials were adopted in all the DTx products for insomnia authorized with reviews of clinical evidence. At the same time, our findings suggest the needs of internationally harmonized regulatory review and authorization system to facilitate the early patient access to the promising DTx products.

Contamination of drug products and substances containing impurities is a significant concern in the pharmaceutical industry because it may impact the quality and safety of medicinal products. Special attention is required when mutagenic impurities are present in pharmaceuticals, as they may pose a risk of carcinogenicity to humans. Therefore, controlling potential mutagenic impurities in active pharmaceutical ingredients to an acceptable safety limit is mandatory to ensure patient safety. As per the International Council for Harmonization (ICH) M7 (R2)³ Guideline, mutagenic impurities are those compounds or materials that induce point mutations. In 2018, the sartan class of drugs was recalled due to the presence of N-nitrosamine impurities, which are potential mutagens. In addition to the primary impurities being detected, this class of products, especially losartan, irbesartan and valsartan, have been identified as having organic azido contaminants, which are again highly reactive toward DNA, leading to an increased risk of cancer. These azido impurities form during the preparation of the tetrazole moiety via the reaction of a nitrile intermediate with sodium azide. Given that this is a newly raised issue in the pharmaceutical world, it should be noteworthy to review the related literature. Thus, this review article critically accounts for (i) the toxicity of azido impurities and the proposed mechanism of mutagenicity, (ii) the regulatory perspective, and (iii) the sources and control strategies used during the preparation of drug substances and (iv) future perspectives.

The expanding availability of real-world data (RWD) has led to an increase in both the interest and possibilities for using this information in postmarketing safety analyses and signal management. While there is enormous potential value from the safety insights generated through RWD, the analysis preparation, execution, and communication required to reliably deliver the evidence can be time consuming. Since the safety signal assessment process is a regulated and timebound process, any supporting RWD analyses require a rapid turnaround of well-designed and informative results. To address this challenge, a TransCelerate BioPharma working group was formed and developed a framework to help teams responsible for safety signal assessment overcome the challenges of working with RWD rapidly to deliver analyses within regulatory timelines. Here, a previously performed safety assessment was evaluated within the context of the developed framework to illustrate how the framework may be adopted in practice.

We analyzed factors shaping the choice of the lead indication (i.e., cancer type) in the first clinical development projects of new oncological drugs in the United States (US), and how the type of pharmaceutical company is related to this choice. We selected 576 new clinical development projects in the US since 2000 for analysis. These projects were characterized according to three potential perspectives detected by multiple correspondence analysis: the morbidity of the cancer type which corresponds to market size of each cancer type, the company's previous experience with the cancer type, and the company's attitude to development risks. Mega firms tend to choose cancer types with higher morbidity (and large-market), previously experienced cancer types, while diverse small firms choose both major and rare cancers and both high- and low-risk projects, indicating that different sizes of firms utilize different development entry patterns. Common tendencies concerning the choice of lead indication were found across all companies. Cancer types the company had developed and launched in the past were more likely to be chosen; cancer types with high five-year survival rates and those with high competition were less likely to be chosen. The study showed that pharmaceutical companies seem to enter clinical development from cancer types where they can demonstrate their strengths and advantages through experience, depending on each cancer type's different market sizes and development difficulties. The results could provide clues for considering what support measures and incentives are appropriate to balance the efficiency of industrial development and the fulfillment of society's unmet medical needs.

Objective: This paper aims to develop a biosimilar value framework with local stakeholders in Gulf Cooperation Council (GCC) countries.

Methods: A convenience sample of ten key opinion leaders from the United Arab Emirates, Kingdom of Saudi Arabia, Kuwait, Oman and Qatar participated in an expert panel meeting in November 2022 that examined factors positively influencing biosimilar adoption in these countries. The discussion was structured around a conceptual biosimilar value framework and an overview of biosimilar policies as derived from a targeted review of the peer-reviewed and grey literature.

Results: The expert panel agreed on a biosimilar value framework for the GCC countries that is founded on trust, cost savings and contextual considerations. They emphasized the importance of launching educational initiatives that build trust in and expand knowledge of all stakeholders about biosimilars. This also includes making stakeholders aware of the various value propositions of biosimilars as an instrument to produce, for example, cost savings. Finally, they stressed that biosimilar adoption is influenced by contextual factors such as incentives and implementation efforts.

Conclusion: Our proposed biosimilars value framekwork is the first set of recommendations in the Arab countries designed to help policymakers and decision-makers promote biosimilar adoption, both in high-income GCC countries and in low- and middle-income countries.

Background: The risk-based approach (RBA) of clinical trial was first introduced in 2011-2012. RBA necessitates implementing risk reduction activities that are proportionate to risk in order to reduce avoidable quality issues. However, there is no consistent methodology or research for identifying and evaluating risks and planning risk reduction activities. We aimed to evaluate risk reduction activities and their effects by using two risk identification and evaluation methods.

Methods: Among the risk identification and evaluation methods, we selected one method with the lowest number of categories for identifying risks [risk assessment form (RAF)] and one with the highest number [risk assessment tool (RAT)]. Each method was used to identify and evaluate risks in and plan risk reduction activities for the research on ponatinib blood concentration and treatment outcome in patients with chronic phase chronic myelogenous leukemia. RAF and RAT can identify risk using abstract questions and a list of concrete risks, respectively. The sites were randomized into two groups to implement planned risk reduction activities using RAF and RAT and to compare the mean of errors and protocol deviation per subject visit between the two groups.

Results: The mean of errors per subject visit and the mean of protocol deviation per subject visit were lower in the RAF group than in the RAT group.

Conclusions: Our study indicates that risk reductions can be successfully implemented by using a method to identify and evaluate risks in a small number of abstract categories that are critical to quality of clinical research.