Accelerating regulation in response to COVID-19.

Regulators are finding ways to support the expedited development and distribution of novel coronavirus-related vaccines, tests and treatments. Gary Humphreys reports.

Translational hurdles with cannabis medicines.

PURPOSE: Internationally, there has been widespread medical use of cannabis medicines before rigorous evaluations in randomised controlled trials (RCTs). Some advocates of medicinal use of cannabis argue that real-world evidence (RWE) can be a substitute for or at least supplement evidence from RCTs. We explore the utility, limitations and impact of RWE in the translation of cannabis medicines research into clinical practice using the established literature. METHODS: A literature search was performed via Embase and Medline using a diverse range of cannabinoid and RWE search terms. The review provides a snapshot of cannabis medicine RWE initiatives from around the world. RESULTS: Diverse and novel sources of real-world data and RWE include international cannabis registries, surveys, post-marketing data collection and use of electronic or digital health records. The strengths and limitations of using RWE in translational research are highlighted, along with the identification of barriers to RCTs involving cannabis medicines. CONCLUSIONS: RWE promises to play a significant role in the evaluation of cannabis medicines around the world. When used appropriately RWE may complement RCT data by providing valuable insights into cannabis medicine safety and effectiveness. TAKE HOME MESSAGES: It is important that real-world evidence (RWE) is used to complement rather than replace randomised controlled trial (RCT) evidence on cannabis medicines. Technological advances have created the opportunity to explore diverse and novel sources of cannabis medicine RWE. Although RWE may be more reflective of real-world clinical practice, it cannot provide conclusive evidence of the safety and efficacy of cannabis medicines. While acknowledging its limitations, RWE may nonetheless provide some guidance on safety and adverse events of cannabis medicines. RWE has already had a significant impact on the regulation of cannabis medicines.

Proportion of Patients in Phase I Oncology Trials Receiving Treatments That Are Ultimately Approved.

BACKGROUND: Phase I oncology trials are often regarded as a therapeutic option for patients. However, such claims have relied on surrogate measures of benefit, such as objective response. METHODS: Using a systematic search of publications, we assessed the therapeutic value of phase I cancer trial participation by determining the probability that patients will receive active doses of treatments that eventually receive FDA approval or a National Comprehensive Cancer Network (NCCN) guideline recommendation for their indication. ClinicalTrials.gov, PubMed, American Society of Clinical Oncology reports, NCCN guidelines, and Drugs@FDA were searched between May 1, 2018, and July 31, 2018. All statistical tests were 2-sided. RESULTS: A total of 1000 phase I oncology trials initiated between 2005 and 2010 and enrolling 32 582 patients were randomly sampled from 3229 eligible trials on ClinicalTrials.gov. A total of 386 (1.2%) patients received a treatment that was approved by the US Food and Drug Administration for their malignancy at a dose delivered in the trial; including NCCN guideline recommendations, the number and proportion are 1168 (3.6%). Meta-regression showed a statistically significantly greater proportion of patients receiving a drug that was ultimately FDA approved in biomarker trials (rate ratio = 4.49, 95% confidence interval [CI] = 1.53 to 13.23; P = .006) and single-indication trials (rate ratio = 3.32, 95% CI = 1.21 to 9.15; P = .02); proportions were statistically significantly lower for combination vs monotherapy trials (rate ratio = 0.09, 95% CI = 0.01 to 0.68; P = .02). CONCLUSIONS: One in 83 patients in phase I cancer trials received a treatment that was approved for their indication at the doses received. Given published estimates of serious adverse event rates of 10%-19%, this represents low therapeutic value for phase I trial participation.

In Vitro-to-In Vivo Extrapolation of Transporter Inhibition Data for Drugs Approved by the US Food and Drug Administration in 2018.

A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (N = 42) was performed. In vitro-to-in vivo predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed in vitro inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P-gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti-infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated in vivo, 56% showed positive clinical interactions (area under the concentration-time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs < 2), seven of the nine interactions (involving five drugs) resulted in labeling recommendations. Interestingly, more than half of the drugs with predictions greater than the cutoffs had no further evaluations, highlighting that current basic models represent a useful, simple first step to evaluate the clinical relevance of in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically-based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters in vivo (AUCRs of 0.94-1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs < 2.

New Drug Reimbursement and Pricing Policy in Taiwan.

BACKGROUND: Taiwan has implemented a national health insurance system for more than 20 years now. The benefits of pharmaceutical products and new drug reimbursement scheme are determined by the Expert Advisory Meeting and the Pharmaceutical Benefit and Reimbursement Scheme (PBRS) Joint Committee in Taiwan. OBJECTIVES: To depict the pharmaceutical benefits and reimbursement scheme for new drugs and the role of health technology assessment (HTA) in drug policy in Taiwan. METHODS: All data were collected from the Expert Advisory Meeting and the PBRS meeting minutes; new drug applications with HTA reports were derived from the National Health Insurance Administration Web site. Descriptive statistics were used to analyze the timeline of a new drug from application submission to reimbursement effective, the distribution of approved price, and the approval rate for a new drug with/without local pharmacoeconomic study. RESULTS: After the second-generation national health insurance system, the timeline for a new drug from submission to reimbursement effective averages at 436 days, and that for an oncology drug reaches an average of 742 days. New drug approval rate is 67% and the effective rate (through the approval of the PBRS Joint Committee and the acceptance of the manufacturer) is 53%. The final approved price is 53.6% of the international median price and 70% of the proposed price by the manufacturer. Out of 95 HTA reports released during the period January 2011 to February 2017, 28 applications (30%) conducted an HTA with a local pharmacoeconomic study, and all (100%) received reimbursement approval. For the remaining 67 applications (70%) for which HTA was conducted without a local pharmacoeconomic analysis, 54 cases (81%) were reimbursed. CONCLUSIONS: New drug applications with local pharmacoeconomic studies are more likely to get reimbursement.

Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation.

BACKGROUND: There is considerable public and political interest in the use of cannabis products for medical purposes. METHODS: The task force of the European Pain Federation (EFIC) conducted a survey with its national chapters representatives on the status of approval of all types of cannabis-based medicines, the covering of costs and the availability of a position paper of a national medical association on the use of medical cannabis for chronic pain and for symptom control in palliative/supportive care. RESULTS: Thirty-one out of 37 contacted councillors responded. Plant-derived tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray is approved for spasticity in multiple sclerosis refractory to conventional treatment in 21 EFIC chapters. Plant-derived THC (dronabinol) is approved for some palliative care conditions in four EFIC chapters. Synthetic THC analogue (nabilone) is approved for chemotherapy-associated nausea and vomiting refractory to conventional treatment in four EFIC chapters'. Eight EFIC chapters' countries have an exceptional and six chapters an expanded access programme for medical cannabis. German and Israeli pain societies recommend the use of cannabis-based medicines as third-line drug therapies for chronic pain within a multicomponent approach. Conversely, the German medical association and a team of finish experts and officials do not recommend the prescription of medical cannabis due to the lack of high-quality evidence of efficacy and the potential harms. CONCLUSIONS: There are marked differences between the countries represented in EFIC in the approval and availability of cannabis-based products for medical use. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a common document on cannabis-based medicines. SIGNIFICANCE: There are striking differences between European countries in the availability of plant-derived and synthetic cannabinoids and of medical cannabis for pain management and for symptom control in palliative care and in the covering of costs by health insurance companies or state social security systems.

Evaluación positiva de medicamentos: marzo, abril y mayo 2017 / Possitive assessment of drugs: March, April and May 2017

Se reseñan los medicamentos evaluados y con dictamen positivo por comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento hechos públicos en marzo, abril y mayo 2017, y considerados de mayor interés para el profesional sanitario. Se trata de opiniones técnicas positivas que son previas a la autorización y puesta en el mercado del medicamento (AU)

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in March, April and May of 2017, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product (AU)

Lost interest for existing compounds: New boosts.

Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected.

Novel approaches are needed to develop tomorrow's antibacterial therapies.

Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up. Antibiotics are a public trust; every individual's use of antibiotics affects their efficacy for everyone else. As such, responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics. More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance emergence. Economic transformation will require new business models to support antibiotic development. Finally, regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant. Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.

Clinical trials update 2014: year in review.

This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that were ongoing at the end of 2014, according to data obtained from both the "ClinicalTrials.Gov" website and from corporate press releases and presentations.

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment.

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.

Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU.

PURPOSE: To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed. METHODS: Information about orphan drug designation, approval, refusal or withdrawal was obtained from the website of the European Medicines Agency and from the European Public Assessment Reports. RESULTS: From 2000 up to 2010, 80.9 % of the 845 candidate orphan drug designations received a positive opinion from the European Medicines Agency (EMA)'s Committee on Orphan Medicinal Products. Of the 108 OMP marketing authorizations applied for, 63 were granted. Randomised clinical trials were done for 38 OMPs and placebo was used as comparator for nearly half the licensed drugs. One third of the OMPs were tested in trials involving fewer than 100 patients and more than half in trials with 100-200 cases. The clinical trials lasted less than one year for 42.9 % of the approved OMPs. CONCLUSION: Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs' efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market.

Current regulatory perspectives on genotoxicity testing for botanical drug product development in the U.S.A.

Genotoxicity testing is an important part of preclinical safety assessment of new drugs and is required prior to Phase I/II clinical trials. It is designed to detect genetic damage such as gene mutations and chromosomal aberration, which may be reflected in tumorigenic or heritable mutation potential of the drug. Botanical new drugs in the U.S. are entitled to a waiver for preclinical pharmacology/toxicology studies, including genotoxicity testing, in support of an initial clinical trial under IND, contingent on previous human experience. Recently, ethical concerns have been raised over conducting Phase I/II clinical trials of new drugs with positive genotoxicity findings in healthy volunteers. Although the relevance of this issue to patients, as opposed to healthy volunteers, depends on the drug's indication, duration of treatment, and specific findings related to the assays, the regulatory view is to avoid exposing patients to genotoxic compounds unnecessarily in clinical trials. This philosophy may impact on herbal supplement marketing and botanical drug development, in that genotoxicity data are often lacking while consumers are exposed to the herbal supplement, or healthy volunteers are tested in an initial Phase I/II clinical trial on the botanical drug. This paper presents results of a survey conducted on genotoxicity data in botanical INDs submitted to the Agency and discusses the significance of this information. The information presented indicates that the sponsors of botanical INDs have increasingly recognized the importance of genotoxicity information and may have prioritized its acquisition in their strategic drug development programs.

Single technology appraisals by NICE: are they delivering faster guidance to the NHS?

BACKGROUND: In 2005, a new technology appraisal process (the Single Technology Appraisal [STA]) was implemented by the National Institute for Health and Clinical Excellence (NICE), an independent agency that provides guidance to the UK NHS on the use of technology. The objective of STAs was to provide faster guidance to the NHS in order to help overcome the problems of 'NICE blight'. METHODS: Publicly available data from the NICE website and date of first marketing authorization (MA) from the Electronic Medicines Compendium were used to determine if STAs for cancer technologies have in fact been able to provide faster guidance than multiple technology appraisals (MTAs) for cancer interventions. RESULTS: STAs in cancer have, on average, taken 12.8 months from the date that NICE lists in the project history to guidance date. This compares with 20.7 months for MTAs in cancer. However, the time between the date of first MA and guidance is longer for cancer-related STAs than MTAs (95.1 months vs 74.6 months). The reasons for this are not clear; however, the STA programme includes examples of using an older product to treat a new cancer site, which may account for some of the differential. It may also reflect the timing that products are referred to NICE. CONCLUSIONS: The overall results suggest that STAs may be faster once NICE looks at the specific product, but that there is a greater delay in the referral of STA products to NICE than for MTA products. However, the time taken for STAs is still short of the target of 9.75 months (or 39 weeks) [assuming no appeals].

The identification of benefit in medical intervention: an overview and suggestions for process.

Benefit and risk assessments are not only important to regulatory authorities but also important to the providers, patients, pharmaceutical industry, and payers. In order for patients and providers to continue to have access to new innovative medicines, which have some level of inherent risk, it is critical to have a systematic and balanced focus on understanding the safety risks and benefits to the patient during drug development, at the time of approval and postmarketing. There has been a significant amount of activity around efforts to improve the ability to assess risks in the postmarketing environment. However, there is no widely accepted, systematic approach or process for the ongoing evaluation of benefit. This article introduces 4 critical components in the process of identifying and assessing benefit with a goal of providing a framework that is transparent, comprehensive, applicable to various perspectives, and simple to communicate and implement. We propose the development of a catalog applied to a particular disease to identify the optimal data sources and methods to address the interests of a given perspective. Two key resources will need to be developed to support the catalog development: (1) a summary of benefit measures and preferences by disease and from various perspectives and (2) an investment in a simple visual communication mechanism with minimal statistical language. As the emphasis is on transparency, relevance, applicability, and communication, this approach to assessing benefit should maximize the impact of these data to all stakeholders and decision makers.