The new year saw the publication by EMA and FDA of the draft list of activities the two agencies planned to carry out in 2018. In Europe, the European Parliament expressed in favour of Amsterdam as the final location of the European Medicines Agency (EMA); the relocation project has entered the operative phase, centered on the availability of the temporary seat by 1° January 2019 and of the definitive Vivaldi building by mid November 2019, and it will be closely monitored by the new tracking tool available on EMA’s web site.
In the US, after President Trump announced one year ago his intention to deregulate the FDA and the pharmaceutical sector, FDA’s Commissioner Dr Scott Gottlieb has already put in place many new initiatives intended to speed up approval times of both drug products and medical devices, as well as to increment the number of generic and biosimilars available on the US’s market. “While we don’t have the authority to regulate prices, we do have the authority — and the responsibility — to ensure that the agency’s policies are not impeding competition that could ultimately be a check to rising drug prices and patient access. Our role as gatekeeper of cost-effective, high-quality generic drug products is a foundational part of fostering human and animal drug competition”, wrote Scott Gottlieb.

EMA’s workplans for 2018

The European Medicines Agency has published the “2018 Work Plan for the GMP/GDP Inspectors Working Group“, a document that might undergo modifications according to the needs established by the ongoing procedures to relocate the Agency to Amsterdam.
After the public consultation in October 2016, the publication of the final “Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container” is expected for Q2 2018. A six months open consultation on the “Guideline on the manufacture of the finished dosage form (V)” should be launched in Q1 2018, and the one on the “Guideline on quality of water for pharmaceutical use (H+V)” in Q3.
Two GMP draft guidelines are both expected to be released by Q4 2018: the final text of the “GMP Guide: Annex 21” regarding the importation of medicinal products should be sent to the European Commission for final approval, while the “GMP and Marketing Authorisation Holders” guideline should pass through the publication of a Reflection Paper on the relationship between GMP Compliance and the respective responsibilities and activities of marketing authorisation holders and manufacturing authorisation holders.
Other GMP guidelines are expected to undergo revision, namely EMA should provide the European Commission with a final text of the “GMP Guide: Introductions” in order to reflect recent changes to the legal basis for GMP affecting the overall structure of EU GMP guidance, including authorised products, IMPs, ATMPs and active substances. By the end of the year are also expected amendments or publication of Q&A for the following GMP Guides: Chapter 1 (Pharmaceutical Quality System), Chapter 4 (Documentation), Annex 1 (Manufacture of Sterile Medicinal Products) and Annex 11 (Computerised Systems).
Inspection activities will be focused on the development of procedures and co-ordination with respect to centrally authorised products and plasma master files for third-country blood establishments; a better use of resources should be reached through an improved sharing of information from international regulatory authority partners and the implementation of other risk-based approaches. Inspections of active substance manufacturers will be afforded on the base of the knowledge gained from the equivalency assessments involved in the listing of third countries by virtue of Article 111b of Directive 2001/83/EC. Joint audits will be also ensured within the frameworks of the PIC/S (Pharmaceutical Inspection Convention/Co-operation Scheme) and Mutual Recognition Agreement (MRA).
The IWG will be also involved in the revision of GMP provisions in the context of ‘disruptive innovation’ and in the preliminary activities necessary to support the Commission to prepare for EU enlargement. From the legislative point of view, a particular attention shall be paid to assess the impact of the Clinical Trials Regulation on GMP inspections and related activities, and on the development of new legislation for veterinary medicinal products.
According to the “COMP work plan 2018”, activities in the field of orphan medicines will focus on the implementation of Articles 3, 5 and 7 of Regulation (EC) No 141/2000, on improving the quality of initial orphan designation applications and in ensuring consistency, transparency, quality and detail of the COMP’s opinions on significant benefit at the time of marketing authorisation.
The COMP plans to implement OMARs (Orphan maintenance assessment reports) for all MAA procedures including the reassessments at extension of indication, checking for the utility and content of the new tool by end of Q2 2018 with external stakeholders. Other activities will be aimed to improve recommendations and guidance to sponsors, with regard to initial orphan designation, maintenance and type II variations. It will be also evaluated the possibility to create a new guidance to replace the “COMP recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation”. Other points of action include working on the prevalence methodology, analysis of non-clinical models, new online tools to handle procedures and a better understanding of similarities and differences between the concepts of significant benefit and added therapeutic value as used by HTAs.
Also the Safety Working Party (SWP) published its Work plan for 2018. Several draft guidelines should be object of public consultation (i.e. the ones on the non-clinical evaluation of radiopharmaceuticals, on the qualification of non-genotoxic impurities and a Reflection paper on non-clinical requirements for plasma-derived replacement therapies). A Q&A document on the implementation of risk based prevention of cross contamination in production and a Reflection paper providing an overview of the current regulatory testing requirements and opportunities for implementation of the 3Rs are expected to reach final release during the year. A detailed list of guidelines undergoing revision, many of which are ICH guidelines, is also provided.

The new American way

We also are modernizing how we work with innovators throughout the development process to bring products to patients more efficiently, using the best available science”, wrote Scott Gottlieb in an editorial published in January in the FDA’s blog. Among the main initiatives carried out by the Agency in 2017, the Commissioner remembered the approval of the first-ever gene therapy product and the field of individualized medicine, with new draft guidance for the development of treatments that address genetic mutations. “This collective progress reflects a fundamental shift in science that’s enabling us to attack more diseases with novel platforms”, wrote Scott Gottlieb. A shift that needs innovative regulatory approaches to regulate highly novel areas of science like gene therapy, targeted medicine, cell-based regenerative medicine, and digital health.
In the field of generic medicines, FDA granted also some tentative approvals, which do not allow the applicant to market the generic drug product and postpones the final approval until all patents/exclusivity issues have expired. Medical devices have gained an increased relevance as therapeutic tool (95 approval in 2017), and have benefited of the application of the “least burdensome standard” for generating critical information needed to evaluate the opportunity to conduct post-clinical studies to favour patients access to new, breakthrough devices.
The new policy framework established by FDA’s Commissioner also includes the possibility for certain diagnostic tests to undergo review by accredited third parties. A pilot program was also launched to evaluate how to regulate digital health devices.
The sharing of information between all stakeholders, including patients, is also central to FDA’s new policies: new searchable databases have been created to better inform patients and health care professionals of adverse events, and new programs for post-marketing surveillance have been set in place.
The FDA’s Unified Agenda (Fall 2017 edition) adds other new priorities of action for 2018, including advancing biosimilar policies, modernising the sector of over-the-counter products (OTC), and better informing women about health issues and risk factors. The detailed “Guidance Agenda”, providing the detailed list of new and revised draft guidances expected for 2018, has been published by the Center for Drug Evaluation and Research (CDER).
According to an earlier editorial by Scott Gottlieb, 2018 will see the FDA working to improve the quality of medicines, with a particular focus on the activities of outsourcing facilities. The Agency also plans to introduce new national standards for the licensing of prescription drug wholesale distributors and third-party logistics providers, as part of track-and-trace requirements.
Informed decisions by patients will be pursued by the proposal of a new type of patient medication document for prescription drugs and biologics. FDA is also planning to expand the scope of non-prescription drug products, for example through the use of self-selection questions on a mobile medical app prior to permitting access to the drug. “We will be proposing to allow certain innovative approaches for demonstrating that a drug product can be used safely and effectively in a nonprescription setting”, wrote Scott Gottlieb.
Another important area to be addressed by the FDA is the modernisation of standards in order to better reflect the latest science. Efforts towards the harmonisation of global standards and of the FDA’s requirements for accepting foreign clinical data for new medical devices have been announced by the Commissioner. Devices and veterinary drugs shall also benefit the possibility to use electronic submission procedures. Commissioner Gottlieb also announced the intention to remove an outdated inspection provisions for biologics and outdated drug sterilization requirements.

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