Comparative Expedited Regulatory Programs of U.S Food & Drug Administration and Project Orbis Partners.

Project Orbis was initiated in May 2019 by the Oncology Center of Excellence to facilitate faster patient access to innovative cancer therapies by providing a framework for concurrent submissions and review of oncology products among international partners. Since its inception, Australia's Therapeutic Goods Administration (TGA), Canada's Health Canada (HC), Singapore's Health Sciences Authority (HSA), Switzerland's Swissmedic (SMC), Brazil's National Health Surveillance Agency (ANVISA), United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), and most recently Israel's Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, have joined Project Orbis. While each country has its own expedited review pathways to bring promising therapies to patients, there are some similarities and differences in pathways and timelines. FDA's fast-track designation and MHRA's marketing authorization under exceptional circumstances (MAEC) allow non-clinical and limited clinical evidence to support approval under these programs. HC's Extraordinary Use New Drug (EUND) pathway allows granting exceptional use authorization with limited clinical evidence. ANVISA, HSA, MTIIR, and TGA do not have standard pathways that allow non-clinical evidence and limited clinical evidence. While there is no definite regulatory pathway for HSA, the current framework for approval does allow flexibility in the type of data (non-clinical or clinical) required to demonstrate the benefit-risk profile of a product. HSA may register a product if the agency is satisfied that the overall benefit outweighs the risk. All Project Orbis Partner (POP) countries have similar programs to the FDA accelerated approval program except ANVISA. Although HSA and MTIIR do not have defined pathways for accelerated approval programs, there are opportunities to request accelerated approval per these agencies. All POP countries have pathways like the FDA priority review except MHRA. Priority review timelines for new drugs range from 120 to 264 calendar days (cd). Standard review timelines for new drugs range from 180 to 365 cd.

A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme.

The safety and efficacy of a generic product are partly based on demonstrating bioequivalence to the innovator product; however, when the innovator product is no longer available as a comparator product, a survey conducted within the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP) indicated that the criteria for selecting an alternative comparator product varies. For most members of the BEWGG, an existing marketed generic that was approved based on a comparison with the locally registered innovator product can be used, contingent on criteria that ranges from allowing any generic to be used, to allowing only specific criteria-defined generics to be used. Notwithstanding the acceptability of a generic as an alternative comparator, it is not always the preferred comparator for several jurisdictions. Some jurisdictions require the use of a locally sourced alternative innovator comparator (e.g., the same medicinal ingredient manufactured by a different company) or a foreign innovator comparator. Unlike the other members of the BEWGG, the European Union (EU) has no such options available, rather mechanisms are in place to allow manufacturers to develop a new comparator. The criteria described herein regarding the use of an alternative comparator product can also be applied to scenarios where a specific strength of a series of strengths or an innovative fixed dose combination are discontinued. The results of the survey demonstrate that while criteria for selecting alternative comparator products are not harmonized among the BEWGG participants, the common concern for all jurisdictions is to select a comparator product that meets the safety and efficacy standards of the original innovator product.

Allergy-like immediate reactions with herbal medicines in children: A retrospective study using data from VigiBase®.

BACKGROUND: The use of herbal medicines in children and the general population is continually on the rise with an overall herbal lifetime and current use ranging between 0.8%-85.5% and 2.2%-8.9%, respectively. Although acute hypersensitivity reactions are generally considered to be rare, little knowledge exists on the frequency and type of these reactions especially in specific populations like children. OBJECTIVES: To assess the patterns of acute hypersensitivity reactions to herbal medicines reported to the WHO global individual case safety report (ICSR) database VigiBase® in children. STUDY DESIGN: From the original VigiBase® extract for the time between 1968 and 2014, we included all reports with adverse drug reactions (ADR) associated with herbal medicines in children where WHO-ART reaction terms were indicative of acute hypersensitivity reactions. RESULTS: VigiBase® contained 2646 ICSRs with 14 860 distinct adverse reactions reported in association with herbal medicine in children. Among those, 79 cases with 107 allergy-like reactions met our inclusion criteria. The most commonly reported WHO-ART terms were urticaria or rash/rash erythematous (59.8%), and allergic reaction (8.4%). The most frequently reported suspected herbal medicines were mixed herbal products (51.4%), Hedera helix (15.0%), and Echinacea purpurea (5.6%). Most frequent routes of administration were oral (75.9%), topical (8.9%), and rectal (3.8%). Over 30% of cases were reported in the age group from 7 to 12 years. The majority of reports were received from Germany (29.1%), Thailand (21.5%), and Australia (11.4%). CONCLUSION: VigiBase® contains a considerable number of acute hypersensitivity reactions in children associated with herbal medicines, including life-threatening reactions such as anaphylactic shock.

Allergy-Like Immediate Reactions with Herbal Medicines: A Retrospective Study Using Data from VigiBase®.

INTRODUCTION: Herbal medicines are used worldwide and with an increasing popularity in Western countries. Although often perceived as 'naturally safe', herbals may cause severe adverse drug reactions (ADRs), with immediate allergic reactions being particularly life threatening. OBJECTIVES: The aim of this study was to analyse immediate allergy-like ADRs to herbals documented in VigiBase®, the WHO international pharmacovigilance database. METHODS: The documentation of all suspected ADRs in association with herbal exposure reported to VigiBase® from 1969 to August 2014 was retrieved. Among all reports in which WHO-ART reaction terms were indicative of acute allergic reactions, those classified as 'suspect' with a documented causality assessment and latency time of ≤1 day were selected. For the most frequent specific herbal-ADR combinations, the information component (IC) as a measure of disproportionality based on Bayesian statistics was calculated. RESULTS: We identified 757 reports out of 1039 ADRs. Products with mixed herbals (36.0 %) as well as those administered orally (63.2 %) were predominant. The most frequent reactions were urticaria and rash (49.2 %). Anaphylactic reactions accounted for 9.5 %. Disproportionally frequent reporting of mouth edema (IC = 1.81) and anaphylactic reactions (IC = 1.24) to Phleum pretense were noted. CONCLUSION: Our findings indicate that herbal medicines for oral use carry a risk of causing immediate allergy-like ADRs. Studies using the Vigibase® database can identify specific combinations of particular herbs and adverse reactions. Healthcare professionals and patients should be aware of these risks and report any serious adverse experiences.