Review of Developments in GMP and the Regulation of Medicines July 2024
This month reported issues have come from the UK, EU, USA and WHO regulatory authorities.
The topics covered in this edition of the “Update” include:
UK MHRA
New pregnancy prevention measures introduced for topiramate.
EU
European Commission (EC)
Proposed amendments to the European Commission guidelines on variations categories and procedures
European Medicines Agency (EMA)
HMA-EMA joint Big Data Steering Group
Big Data Steering Group and industry stakeholders meeting
Two new advice pilots to improve clinical trials in Europe
Medicine shortages and availability issues: guidance for companies
Faster access to clinical trial information in Europe
Recommendations & actions to tackle shortages of GLP-1 receptor agonists
EMA-FDA parallel scientific advice (animal drug products)
Q&A on classification of veterinary medicinal products
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
New general chapter on Extractable elements in plastic materials for pharmaceutical use (2.4.35) adopted
Reference Standards
Ireland HPRA
Updated Q&A on the Windsor Framework
HPRA Medicinal Products Newsletter
USA
The US Food and Drug Administration (USFDA)
Report on the State of Pharmaceutical Quality
Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics
Facility Readiness: Goal Date Decisions Under GDUFA
FDA issues agency-initiated proposed order regarding OTC monograph drugs containing acetaminophen
What You Should Know about Eye Drops
Considerations in Demonstrating Interchangeability With a Reference Product: Update
International
PIC/S
Pharmaceutical Inspection Co-operation Scheme (PIC Scheme)
Zimbabwe applies for PIC/S pre-accession
Products
US FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors
FDA approves selpercatinib for RET fusion-positive thyroid cancer
First nasal adrenaline spray for emergency treatment against allergic reactions
Conferences
Joint HMA/EMA Big Data Steering Group workshop on RWE methods
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
Medicines and Healthcare products Regulatory Agency (MHRA)
New pregnancy prevention measures introduced for topiramate.
Migraine and antiseizure medication topiramate must no longer be prescribed to women and girls unless they fulfil the requirements of a Pregnancy Prevention Programme.
Following a major safety review triggered by a new study conducted in Europe, the UK MHRA is introducing new safety measures for topiramate, also known by the brand name Topamax
The Commission on Human Medicines (CHM) looked at findings from studies examining the risks associated with the use of topiramate during pregnancy, which showed that children born to mothers who take topiramate during pregnancy face a risk level approximately 2 to 3 times higher of intellectual disability, autism spectrum disorders and attention deficit hyperactivity disorder.
Europe
European Commission (EC)
Proposed amendments to the European Commission guidelines on variations categories and procedures
The European Commission is reviewing the rules governing the procedures for post-authorisation changes to the terms of a marketing authorisation for human medicines.
This concerns the Commission Regulation (EC) No 1234/2008 together with the variations guidelines within the existing legal framework of Regulation (EC) No 726/2004 and Directive 2001/83/EC.
In this context, EMA, the heads of Medicines Agencies (HMA) and the European Commission are inviting pharmaceutical industry representatives and other interested parties to comment on the proposed amendment. This refers specifically to the guidelines on the details of the different categories of variations and operation of the variations procedures.
Readers can find the documents with the proposed changes in the 'Stakeholder consultation' section on the web page indicated below (a clean version and one with track changes).
European Medicines Agency (EMA)
HMA-EMA joint Big Data Steering Group
The Final Minutes teleconference 22 April 2024 have been published.
Big Data Steering Group and industry stakeholders meeting
The 23 May 2024 summary report of this biannual meeting which was co-chaired by Jeppe Larsen (DKMA) and Peter Arlett (EMA), has now been published.
Two new advice pilots to improve clinical trials in Europe
The Accelerating Clinical Trials in the EU (ACT EU) initiative is launching two advice pilots aimed at improving the quality of applications for clinical trials.
The first pilot offers developers of medicinal products scientific advice on clinical trials and on requirements for marketing authorisation applications (MAA). In this pilot programme, the Scientific Advice Working Party (SAWP), coordinated by EMA, and the Clinical Trials Coordination Group (CTCG), managed by HMA, will be the bodies assessing incoming requests of a scientific nature. This pilot consolidates the views of these two groups to minimise avoidable divergences. It is the first time that both entities are providing joint scientific advice on clinical trials.
The second pilot is coordinated by the CTCG and provides technical and regulatory support on the dossier of a CTA prior to its submission through the Clinical Trials Information System. Developers of medicinal products who wish to receive advice on the requirements for a MAA or a CTA may apply to these pilots.
Medicine shortages and availability issues: guidance for companies
A 'Shortage prevention and mitigation plans' section was added to this guidance on 18 June 2024.
Medicine shortages are recognised as a growing issue across the EU and globally. They affect medicines of all classes and are increasingly affecting European countries. This may have a significant impact on patient care as they can lead to medicine rationing and delay of critical treatments and can require patients to use alternatives which may be less efficacious or may increase the risk of medication errors due to unfamiliarity with the new regimen.
The implementation of shortage prevention plans (SPP) will facilitate the MAH’s compliance of their obligations to ensure, within the limits of their responsibilities, an adequate and continuous supply to the market (article 81 Directive 2001/83).
MAHs should have in place a SPP for any medicinal product for human use they place on the market of the EU/EEA. The SPP should be part of the annual product quality review and updated accordingly on an annual basis or if relevant changes occur such as critical shortage occurrence or a variation of the supply chain. The degree of effort, formalization and documentation should be proportionate to the identified level of risk for each medicine.
It is highly recommended that the high-level hierarchy of the company (personnel with power and resources to solve the detected deficiencies in the supply chain) is involved in the development of the SPP. It is key that the company considers the SPPs not as an administrative document but as a useful tool that is beneficial, first and foremost for them to identify any potential risk and be prepared if shortages occur.
The SPP should be part of the company pharmaceutical quality system, and should be subject to continuous evaluation.
SPPs should be readily available for submission to the Competent Authorities concerned (Competent Authority of the Member State where the medicinal product has been placed on the market and, in addition, the EMA for a medicinal product covered by a centralised marketing authorisation) upon request.
SPPs can be subject to inspection during GMP and/or GDP inspections or inspections of MAHs, in accordance with national regulations.
[An important addition to the guidance which must not only be addressed at the highest levels of a company but must also be a part of the Pharmaceutical Quality System and is open to review during GMP inspections. Be Warned and be compliant! MBH]
Faster access to clinical trial information in Europe
Revised rules for Clinical Trials Information System (CTIS) became applicable on18 June 2024.
One of the key changes is earlier availability of information on authorised clinical trials. Importantly, the new rules eliminate the previously available deferral mechanism, which allowed clinical trial sponsors to delay publishing certain data and documents for up to seven years after a trial’s completion to protect commercially confidential information.
The updated rules strike a balance between transparency of information and protection of commercially confidential information. They benefit patients, because key clinical trial information, that patients flagged as being most relevant for them, is published early. They also benefit clinical trial sponsors because they introduce process simplifications. Finally, they benefit healthcare professionals because the resulting system is more user-friendly, facilitating access to information on clinical trials and enrolment in clinical trials, and also increasing awareness of possible treatment options.
Recommendations &actions to tackle shortages of GLP-1 receptor agonists
GLP-1 receptor agonists are authorised for the treatment of diabetes1 or for weight management under certain conditions or both.
Since 2022, a surge in demand for some of these medicines, coupled with other issues such as manufacturing capacity constraints, has led to shortages across the EU.
The use of GLP-1 receptor agonists for cosmetic weight loss in people without obesity or people with overweight who do not have weight-related health problems has been mentioned frequently in news outlets and social media and is worsening existing shortages.
The continued high demand for these medicines has also attracted criminal activity, increasing the risk of falsified products entering the market with serious consequences for public health.
EMA-FDA parallel scientific advice (animal drug products)
The EMA and the U.S. FDA, Center for Veterinary Medicine (CVM) of the U.S. Department of Health and Human Services have a program to provide parallel scientific advice (PSA) to applicants/sponsors. The goal of the PSA program is to provide a mechanism for EMA assessors and FDA reviewers to concurrently exchange with applicants/sponsors their views on scientific issues during the development phase of new veterinary medicinal products. Such interactions are expected to increase dialogue between the two agencies and applicants/sponsors in the early lifecycle stages of a new product, provide a deeper understanding of the bases of regulatory decisions, optimize product development, and avoid unnecessary testing replication or unnecessary diverse testing methodologies. The agencies conduct PSA procedures under the auspices of the confidentiality arrangement between the European Commission, the EMA, and FDA.
Q&A on classification of veterinary medicinal products
This Q&A document has been developed by CVMP and EMA to address uncertainties in terms of product classification by providing guidance and clarity to stakeholders from the viewpoint of 1) whether a VMP is a non-biological VMP, biological VMP other than immunological VMP, or immunological VMP and 2) whether a VMP is a novel therapy product. The guiding principle is to ensure that the dossier contains information that will allow for adequate assessment of the product. The classification is based first and foremost on the definitions provided by the Regulation (EU) 2019/6 and takes into account scientific (such as mode of action) and regulatory aspects (such as data requirements influenced by the use and properties of the product).
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
New general chapter on Extractable elements in plastic materials for pharmaceutical use (2.4.35) adopted
With the implementation of the ICH Q3D guideline on elemental impurities, the control of elemental impurities has undergone a shift in paradigm, moving away from pure substance-based testing towards a holistic control strategy at the medicinal product level.
The plastics used in the manufacture of containers for pharmaceutical use (Ph. Eur. 3.1. Materials used for the manufacture of containers and subsections) are not directly within the scope of ICH Q3D and as such, are not covered by general chapter 5.20. Nevertheless, their quality has an impact on the final quality of the manufactured container as they are used as the material of construction.
ICH Q3D states that when a review of the materials of construction demonstrates that the container closure system does not contain elemental impurities, no additional risk assessment needs to be performed.
For these reasons, the experts of Ph. Eur. Group 16 have developed and validated a new state-of-the-art procedure to assess extractable elements in different plastic materials available on the European market.
The resulting draft chapter, Extractable elements in plastic materials for pharmaceutical use (2.4.35), intended to provide a framework for the assessment of extractable elements in different plastic materials, was published in Pharmeuropa twice (issues 32.2. and 32.3). Careful consideration was given to the numerous comments received during the public consultations and the general approach ahead was also discussed, both by the European Pharmacopoeia Commission (EPC) at several sessions and by Group 16. As a result, the revised text now covers only the analytical procedure for testing of extractable elements in plastic materials for pharmaceutical use. The initially proposed mandatory limits for extractable elements have been omitted from the final version. These limits will be provided as a recommendation in a new general text to be included in section 5 of the Ph. Eur. (general text 5.42).
Reference Standards
5 new Ph. Eur. reference standard and 13 replacement batches released in May 2024
Ireland
The Health Products Regulatory Authority (HPRA)
Updated Q&A on the Windsor Framework
HPRA has published an updated Q&A based on questions it has received from companies, relating to the impact of the Windsor Framework on the regulation of human medicines.
The document includes updated information on:
· Joint labels between IE/UK
· Medicines moving from Northern Ireland to the Republic of Ireland
· The expiry of Brexit Derogations approved in Ireland
HPRA Medicinal Products Newsletter
Issue 77 has now been published.
United States of America
The US Food and Drug Administration (USFDA)
Report on the State of Pharmaceutical Quality
The annual report on the state of pharmaceutical quality is intended to help characterize the quality of the U.S. drug supply chain. It is updated each year to provide current and cumulative data about pharmaceutical manufacturers, their products, and postmarket quality defects. In addition, this report provides insights about import alert additions, recalls, and warning letters. The report also highlights emerging approaches to surveil, characterize, and advance pharmaceutical quality. FDA uses the Report on the State of Pharmaceutical Quality, in part, to inform regulatory decision making and quality surveillance activities.
Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics
This guidance provides recommendations to assist industry in the development of oligonucleotide therapeutics under section 505 of the Federal Food, Drug, and Cosmetic Act. Specifically, this guidance represents the FDA’s recommendations for certain evaluations during development of oligonucleotide therapeutics, including: (1) characterizing the potential for QTc interval prolongation, (2) performing immunogenicity risk assessment, (3) characterizing the impact of hepatic and renal impairment, and (4) assessing the potential for drug-drug interactions. This guidance provides recommendations on when to conduct these assessments and what types of assessments are suitable to address the topics listed above.
Facility Readiness: Goal Date Decisions Under GDUFA
This guidance provides information to applicants on how FDA intends to assign a goal date based on a facility’s readiness for inspection as certified on Form FDA 356h, submitted as part of an original abbreviated new drug application (ANDA) This guidance explains how FDA incorporates a program enhancement agreed upon by the Agency and industry as part of the negotiations
FDA issues agency-initiated proposed order regarding OTC monograph drugs containing acetaminophen
FDA issued a proposed administrive order, to address a safety issue related to over-the-counter (OTC) monograph drug products containing acetaminophen.
Based on a comprehensive scientific review of available data, FDA determined that acetaminophen continues to be associated with the risk of rare but serious skin reactions. This proposed, if finalized, would require drug companies to add a warning to the labeling.
FDA is seeking comments on this proposed order and instructions on how to submit comments are found below. After a review of comments, FDA will issue a final order. FDA has communicated about this safety issue in the past.
[This is paracetamol in the UK/EU and other markets. Might other regulators follow suit? MBH]
What You Should Know about Eye Drops
Ophthalmic drug products, such as eye drops, pose a heightened risk of harm to users because drugs applied to the eyes bypass some of the body’s natural defenses. Any drug used in the eyes must be sterile to reduce the risk of infection. There have been several recent safety recalls related to OTC eye drop products. These recalls resulted from various safety concerns, including reports of infections, partial loss of vision, and blindness. The recalls were due to product contamination risks.
Facilities manufacturing eye drops marketed in the U.S. are required to be registered with FDA. FDA actively monitors eye drops in the marketplace by conducting surveillance, including sampling and testing products on the market, and monitoring side effects.
FDA uses a risk-based approach to identify facilities for inspection. FDA may recommend voluntary recalls to remove products from the market.
Considerations in Demonstrating Interchangeability with a Reference Product: Update
Since publication of the Interchangeability Guidance, (May 2019) experience has shown that for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product. Accordingly, FDA’s scientific approach to when a switching study or studies may be needed to support a demonstration of interchangeability has evolved. As described in this draft guidance, applicants for proposed interchangeable products may choose to provide an assessment of why the comparative analytical and clinical data provided in the application or supplement support a showing that the switching standard set forth in section 351(k)(4)(B) of the PHS Act has been met.
International
Pharmaceutical Inspection Co-operation Scheme (PIC Scheme)
Zimbabwe applies for PIC/S pre-accession
On 20 October 2023, the Medicines Control Authority of Zimbabwe (MCAZ) applied for PIC/S pre-accession. The pre-accession application was considered complete on 6 December 2023. The Rapporteur is in the process of being appointed by written procedure.
Products
US FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors
On June 13, 2024, the Food and Drug Administration granted accelerated approval to repotrectinib (AUGTYRO, Bristol-Myers Squibb Company) for adult and pediatric patients 12 years and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed following treatment or have no satisfactory alternative therapy.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review, fast track designation, breakthrough therapy designation, and orphan drug designation.
FDA approves selpercatinib for RET fusion-positive thyroid cancer
FDA granted traditional approval to selpercatinib (Retevmo, Eli Lilly and Company) for adult and pediatric patients 2 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
Selpercatinib received accelerated approval for this indication for patients 12 years of age and older in 2020.
The recommended selpercatinib dose for pediatric patients 2 to less than 12 years of age is based on body surface area. It is based on weight for patients 12 years of age and older.
This review used the, Assessment Aid a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted breakthrough designation and orphan drug designation.
First nasal adrenaline spray for emergency treatment against allergic reactions
EMA’s human medicines committee (CHMP) has recommended granting a marketing authorisation in the European Union for Eurneffy (epinephrine), the first medicine to be taken through the nose for the emergency treatment of allergic reactions (anaphylaxis).The opinion adopted by the CHMP is an intermediary step on Eurneffy’s path to patient access. The opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation.
Conferences / webinars etc
Joint HMA/EMA Big Data Steering Group workshop on RWE methods
Friday, 14 June 2024
This one-day hybrid Big Data Steering Group (BDSG) workshop will bring together representatives of regulatory agencies, pharmaceutical companies, patients, healthcare professionals, academia, and health technology assessment bodies to address the following objectives:
· Hear the views of stakeholders and experts:
o On the draft RWE reflection paper
o on priorities for further regulatory guidance development and collaboration beyond the reflection paper.
· Engage with stakeholders on RWE methods in regulatory decision making.
And finally…
Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.
We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.
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