The Assessment of the Innovativeness of a New Medicine in Italy

Objectives: Starting from April 2017, the Italian Medicine Agency (AIFA) has approved new criteria for defining any new medicinal product with an innovative indication. The purpose of the study is to analyze the activity of innovativeness evaluation according to the new approach, to estimate the weight of each criterion considered for innovativeness definition, and to evaluate how the new approach works in terms of consistency and reproducibility.Methods: A retrospective analysis was performed on the final reports evaluating the drug innovativeness assessment published on the AIFA's website between April 2017 and January 2021. Descriptive statistics, chi-square test, whether the conditions were respected, or Fisher's exact test was used to explore the association between characteristics of drugs and the innovativeness status and the association between the three criteria. Profiles of the decision process and their relationship with innovativeness response were described. In order to evaluate the weight of each criterion in predicting the innovativeness status, a Classification Tree (CT) algorithm was applied.Results: Overall, of the 109 published drugs reports, 37 (33.9%) were recognized as fully innovative, 29 (26.6%) were considered conditionally innovative, while for 43 (39.4%) reports innovativeness was not recognized. Considering the three criteria of the decision process, the added therapeutic value was the only criterion statistically associated with a drug's degree of innovation (p < 0.001). The therapeutic need and the quality of clinical evidence were statistically associated (p = 0.008) even if only a mild association was observed. The added therapeutic value was the most important variable in predicting the innovativeness status according to the classification tree (CT) model applied, achieving an accuracy of 89.4%. No difference was found between orphans and non-orphan drugs or oncological and non-oncological drugs.Discussion: The added therapeutic value is the most important criterion of the multidimensional approach for the innovativeness status definition of a new medical product. A mild association was found between the therapeutic need and the quality of evidence. Overall, similar decision profiles bring the same evaluation of innovativeness status, indicating a good consistency and reproducibility between decisions.

Broadening the reach of the FDA Sentinel system: A roadmap for integrating electronic health record data in a causal analysis framework

The Sentinel System is a major component of the United States Food and Drug Administration’s (FDA) approach to active medical product safety surveillance. While Sentinel has historically relied on large quantities of health insurance claims data, leveraging longitudinal electronic health records (EHRs) that contain more detailed clinical information, as structured and unstructured features, may address some of the current gaps in capabilities. We identify key challenges when using EHR data to investigate medical product safety in a scalable and accelerated way, outline potential solutions, and describe the Sentinel Innovation Center’s initiatives to put solutions into practice by expanding and strengthening the existing system with a query-ready, large-scale data infrastructure of linked EHR and claims data. We describe our initiatives in four strategic priority areas: (1) data infrastructure, (2) feature engineering, (3) causal inference, and (4) detection analytics, with the goal of incorporating emerging data science innovations to maximize the utility of EHR data for medical product safety surveillance.

Environmental risk of pharmaceuticals: let´s look at the whole package

Concern about potential deleterious effects of pharmaceuticals in the environment is growing fast. From wiping out vulture populations in Asia, to feminization of fish, pharmaceuticals have shown to provoke important consequences albeit at very low concentrations. A recent article addresses the environmental impact of metered-dose inhalers for asthma in the United Kingdom due to the greenhouse effects hydrofluorocarbons they contain. Since 2005, it is mandatory for all new drugs in Europe to be assessed for their environmental impact. Crucially, this regulation solely refers to the active pharmaceutical ingredient, not the “whole medicine” or finished medical product. This can sometimes lead to incongruences. For instance, it does not consider the environmental impact of the hydrofluorocarbons contained in MDIs. Another example is Adasuve®, an antipsychotic (loxapine) aimed at the rapid control of agitation in patients suffering from psychotic disorders. The device was developed as a rapid systemic delivery of loxapine by inhalation of a thermally generated aerosol for single use. Apart from the active substance it holds a medical-grade plastic housing and a lithium battery. Therefore, after every single use, a lithium battery waste is produced. We envision that we are on a brink of a new era in pharmacotherapy, in which environmental aspects of drugs are taken into account. In definitive, we agree with Wilkinson & Woodcock. When considering the environmental impact of pharmaceuticals, we need to take into account the whole package.

Mapping conflict of interests: scoping review

Objective To identify all known ties between the medical product industry and the healthcare ecosystem. Design Scoping review. Methods From initial literature searches and expert input, a map was created to show the network of medical product industry ties across parties and activities in the healthcare ecosystem. Through a scoping review, the ties were then verified, cataloged, and characterized, with data abstracted on types of industry ties (financial, non-financial), applicable policies for conflict of interests, and publicly available data sources. Main outcome measures Presence and types of medical product industry ties to activities and parties, presence of policies for conflict of interests, and publicly available data. Results A map derived through synthesis of 538 articles from 37 countries shows an extensive network of medical product industry ties to activities and parties in the healthcare ecosystem. Key activities include research, healthcare education, guideline development, formulary selection, and clinical care. Parties include non-profit entities, the healthcare profession, the market supply chain, and government. The medical product industry has direct ties to all parties and some activities through multiple pathways; direct ties extend through interrelationships among parties and activities. The most frequently identified parties were within the healthcare profession, with individual professionals described in 422 (78%) of the included studies. More than half (303, 56%) of the publications documented medical product industry ties to research, with clinical care (156, 29%), health professional education (145, 27%), guideline development (33, 6%), and formulary selection (8, 1%) appearing less often. Policies for conflict of interests exist for some financial and a few non-financial ties; publicly available data sources seldom describe or quantify these ties. Conclusions An extensive network of medical product industry ties to activities and parties exists in the healthcare ecosystem. Policies for conflict of interests and publicly available data are lacking, suggesting that enhanced oversight and transparency are needed to protect patient care from commercial influence and to ensure public trust.

The U.S. Food and Drug Administration’s Complex Innovative Trial Design Pilot Meeting Program: Progress to date

Background The Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration have been leaders in advancing science to protect and promote public health by ensuring that safe and effective drugs and biological products are available to those who need them. Recently, new therapeutic discoveries, increased understanding of disease mechanisms, the need for innovation to optimally use resources, and global public health crises have led to an evolving drug development landscape. As a result, the U.S. Food and Drug Administration and medical product developers are faced with unique challenges and opportunities. The U.S. Food and Drug Administration is proactively meeting the challenges of this evolving landscape through various efforts, including the Complex Innovative Trial Design Pilot Meeting Program. Our focus, here, will be on the pilot meeting program. Methods The U.S. Food and Drug Administration has defined a process to facilitate the implementation of the Complex Innovative Trial Design Pilot Meeting Program. The process is transparent and outlines the steps and timeline for submission, review, and meetings. Results Five submitted meeting requests have been selected for participation in the Complex Innovative Trial Design Pilot Meeting Program. Conclusion The pilot meeting program has been successful in further educating stakeholders on the potential uses of complex innovative designs in trials intended to provide substantial evidence of effectiveness. The selected submissions, thus far, have all utilized a Bayesian framework. The reasons for the use of Bayesian approaches may be due to the flexibility provided, the ability to incorporate multiple sources of evidence, and a desire to better understand the U.S. Food and Drug Administration perspective on such approaches. We are confident the pilot meeting program will have continued success and impact the collective goal of bringing safe and effective medical products to patients.

Small Molecule/HLA Complexes Alter the Cellular Proteomic Content

A medical product usually undergoes several clinical trials, including the testing of volunteers. Nevertheless, genomic variances in the patients cannot be considered comprehensively and adverse drug reactions (ADRs) are missed or misinterpreted during trials. Despite the relation between ADRs and human leukocyte antigen (HLA) molecules being known for several years, the fundamental molecular mechanisms leading to the development of such an ADR often remains only vaguely solved. The analysis of the peptidome can reveal changes in peptide presentation post-drug treatment and explain, for example, the severe cutaneous ADR in HLA-B*57:01-positive patients treated with the antiretroviral drug abacavir in anti-HIV therapy. However, as seen in the biophysical features of HLA-A*31:01-presented peptides, treatment with the anticonvulsant carbamazepine only induces minor changes. Since the binding of a drug to a certain HLA allelic variant is extremely distinct, the influence of the small molecule/protein complex on the proteomic content of a cell becomes clear. A sophisticated methodology elucidating the impact of drug treatment on cells is a full proteome analysis. The principal component analysis of abacavir, carbamazepine or carbamazepine-10,11-epoxid treated cells reveals clear clustering of the drug-treated and the untreated samples that express the respective HLA molecule. Following drug treatment, several proteins were shown to be significantly up- or downregulated. Proteomics and peptidomics are valuable tools to differential clinical outcomes of patients with the same HLA phenotype.

Health Software Product or Software as Medical Device

The number of software products in the field of health and medicine increases excessively. Self-tracking, fitness, health advice, dose calculation, and analysis of physiological data - apps are popular and commonly used. Some of the products are affected by the medical device regulation, consciously or unconsciously. For young entrepreneurs, it is difficult to recognize and understand the distinction between software as medical product and health software products. A product-related orientation guide could help start-ups to understand the difference and to find the right strategy for placing their product on the market. All relevant information were collected and analyzed. Input came from a systematic literature research, an evaluation of the CHARISMHA study and a consideration of the medical device regulation as well as the relevant standards (e.g. IEC 62304 and IEC 82304). The guide was adapted to the particular situation of start-ups and microenterprises, inter alia having regard to missing regulatory affairs competences. A product-related orientation guide for young entrepreneurs was developed, which helps to identify whether products are affected by the medical device regulation or not. The guide uses a few simple questions, and it allows the entrepreneurs to estimate the related effort. Furthermore, it provides an overview of relevant standards and needed competences for the chosen path. The guide brings certainty and can help young entrepreneurs to identify the upcoming workload at an early stage. Due to the decision tree concept, it is easy to adapt the product-related strategy and see the consequences. This might help entrepreneurs to find the right strategy for placing their product on the market. Nevertheless, field testing with the guide is necessary to validate its benefit.

Combination strategies to maximize the benefits of cancer immunotherapy

Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.