Review of Developments in GMP and the Regulation of Medicines September 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 Active Substance and Biosimilar Work Sharing Initiatives
Advice on ingredients in nicotine-containing liquids in electronic cigarettes and refill containers (N Ireland)
Advice on names, presentation and packaging of nicotine-containing electronic cigarettes and refill containers
EU
European Medicines Agency (EMA)
ICH reflection paper on pursuing opportunities for harmonisation in using real-world data to generate real-world evidence, with a focus on effectiveness of medicines
New pilot programme to support orphan medical devices
Compilation of Union procedures on inspections and exchange of information
History of changes to the Compilation of Procedures
Compilation of Union procedures on inspections and exchange of information procedures and templates
Q&A on the impact of Mutual Recognition Agreement (MRA) between the European Union and the United States
Real-world evidence framework to support EU regulatory decision-making 2nd report on the experience gained with regulator-led studies).
ICH Guideline M13A on bioequivalence for immediate-release solid oral dosage forms - Scientific guideline
ICH E11A Guideline on pediatric extrapolation
Meeting Summary - Medicine Shortages (SPOC) Working Party
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Update on BSP study on the evaluation of a replacement method for the potency control of whole cell pertussis vaccines
Reference Standards
PDG announces global membership initiative
USA
The US Food and Drug Administration (USFDA)
M12 Drug Interaction Studies Q&A & a Guidance for Industry
Reprocessing Single-Use Medical Devices: Information for Health Care Facilities
Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA
US Department of Health & Human Services (HHS)
Negotiating for Lower Drug Prices Works, Saves Billions
International
Australia
Therapeutic Goods Administration (TGA)
Guidance changes are coming soon India
Central Drugs Standard Control Organization (CDSCO)
GDP for Pharmaceutical Products
Products
FDA grants accelerated approval to afamitresgene autoleucel for unresectable or metastatic synovial sarcoma
MHRA approves Zolbetuximab to Treat Adults with Stomach or Gastro-oesophageal Junction Cancer
Lecanemab licensed for adult patients in the early stages of Alzheimer’s disease
COVID-19 Tests granted traditional Marketing Authorization by the FDA
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
Medicines and Healthcare products Regulatory Agency (MHRA)
Access - New Active Substance and Biosimilar Work Sharing Initiatives
The New Active Substance Work Sharing Initiative (NASWSI) has successfully approved several medicines through this international collaboration and continues to foster cooperation and strong relationships between its Access partners. The Biosimilar Work Sharing Initiative (BSWSI) builds on this success.
By engaging in these partnerships, ‘Access’ is able to co-ordinate regulatory review procedures, and increase each agency’s capacity to ensure consumers have timely access to high quality, safe and effective therapeutic products.
Advice on ingredients in nicotine-containing liquids in electronic cigarettes and refill containers (N Ireland)
This Guidance, updated 16 Aug 2024 applies to Northern Ireland.
Article 20(2) of Directive 2014/40/EU [TPD] places an obligation on the manufacturers and importers of electronic cigarettes to submit a notification to the competent authorities of the member states of such products they intend to market.
Article 20(2)(b) and (c) of the Tobacco Products Directive (TPD) requires the notification to include a list of all ingredients in the product and toxicological data regarding the product’s ingredients and emissions.
The TPD requires information about each ingredient in notifiable products to be included in the submission. The information should include identifying details, the quantity and function of the ingredient and further information about its classification and various aspects of its toxicity. Details of all available toxicological studies on the ingredient in unheated and heated form and emissions should be submitted.
The notifier should consider carefully the implications for their product of the toxicological data for the safety of each ingredient and its associated emissions as part of their responsibilities under the TPD and general consumer safety legislation to ensure that products supplied to consumers are safe. You must include in your notification a declaration that you bear full responsibility for the quality and safety of the product when placed on the market and used under normal or reasonably foreseeable conditions.
Advice on names, presentation and packaging of nicotine-containing electronic cigarettes and refill containers
This guidance, updated 16 Aug 2024, sets out MHRA’s interpretation of article 13 of the TPD as it applies to electronic cigarettes and refill containers.
Europe
European Medicines Agency (EMA)
ICH reflection paper on pursuing opportunities for harmonisation in using real-world data to generate real-world evidence, with a focus on effectiveness of medicines
The EU Committee for Medicinal Products for Human Use (CHMP) adopted this reflection paper on 25 July 2024.
The Reflection Paper outlines a strategic approach for ICH to address some of these challenges. The goal is to further enable the integration of RWE into regulatory submissions and timely regulatory decision-making
The objectives of this Reflection Paper are:-
· To engage ICH on convergence of terminology for RWD and RWE, on the format for protocols and reports of study results submitted to regulatory agencies throughout the lifecycle of medicinal products, and on promoting registration of protocols and reports;
· To inform the assessment of RWD and RWE for regulatory purposes.
The ultimate benefit of this work is expected to be higher quality of RWE that can substantively contribute to the body of evidence supporting the benefit and risk of medicines whilst maintaining evidentiary standards in regulatory decision-making.
New pilot programme to support orphan medical devices
EMA has launched a pilot programme for expert panels to support the development and assessment of orphan medical devices in the European Union (EU). The pilot programme offers free advice from the medical device expert panels to selected manufacturers and notified bodies on the orphan device status and the data needed for their clinical evaluation. While the pilot programme is currently scheduled to run until the end of 2025, the aim is to establish a long-term process for orphan device support.
Compilation of Union procedures on inspections and exchange of information
The EMA maintains a compilation of inspection-related procedures and templates used by the good manufacturing practice (GMP) and good distribution practice (GDP) inspectorates in the European Union (EU) and European Economic Area (EEA).
These procedures and templates cover the basis for national procedures that form part of the national inspectorates' quality system.
This facilitates cooperation between EU Member States and supports harmonisation and exchange of inspection-related information.
The compilation comprises the following:
· Procedures to support inspections of manufacturers and wholesale distributors
· Templates used in the common EudraGMDP database and guidance on how to use them
History of changes to the Compilation of Procedures
In August 2024 Compilation of Union Procedures on Inspections and Exchange of Information (CoUP) was restructured from 1 document into single documents for every procedure/template.
The updates for every procedure/template will be from now on recorded in each document published on EMA website.
Compilation of Union procedures on inspections and exchange of information procedures and templates
These procedures and templates cover the basis for national procedures that form part of the national inspectorates' quality system.
This facilitates cooperation between EU Member States and supports harmonisation and exchange of inspection-related information.
The compilation comprises the following:
· Procedures to support inspections of manufacturers and wholesale distributors
· Templates used in the common EudraGMDP database and guidance on how to use them
As stated in the previous item, in August 2024, the Compilation of Union Procedures on Inspections and Exchange of Information (CoUP) was restructured from one document into separate documents for every procedure/template. From August 2024 onwards, updates for every procedure/template are recorded in these individual documents.
Q&A on the impact of Mutual Recognition Agreement (MRA) between the European Union and the United States
This Q&A from May 2023 has been updated as of 7 Aug 2024.
Real-world evidence framework to support EU regulatory decision-making - 2nd report on the experience gained with regulator-led studies).
This report builds on the experience previously acquired during the period from September 2021 to February 2023 in conducting regulatory-led studies using real-world data (RWD) to support EU regulatory decisions. It covers the period from 8 February 2023 to 7 February 2024, which corresponds to year 2 of DARWIN EU and provides a review of the progress made in delivering on the vision of EU regulators to enable the use of RWE and establish its value for regulatory decision- making by 2025’
Compared to the previous report, this time all studies conducted by EMA were considered, including those conducted in response to the Pharmacovigilance impact strategy or to inform vaccine safety and effectiveness as well as public health emergencies. In addition, information on the use of RWD by national competent authorities (NCA) was collected.
ICH Guideline M13A on bioequivalence for immediate-release solid oral dosage forms - Scientific guideline
ICH M13A Guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.
The ICH M13A Guideline is the first guideline in a foreseen ICH series describing the scientific and technical aspects of study design and data analysis to support BE assessment for orally administered IR solid oral dosage forms.
On 25 January 2025, the date of coming into effect, ICH M13A will supersede applicable parts of the EMA Guideline on the investigation of bioequivalence related to bioequivalence study considerations and data analysis for a non-replicate study design.
ICH E11A Guideline on pediatric extrapolation
The purpose of this guideline is to provide recommendations for, and promote international harmonization of, the use of pediatric extrapolation to support the development and authorization of pediatric medicines.
Regional guidelines discussing pediatric extrapolation have previously been issued by various regulatory agencies. Pediatric extrapolation is defined in the ICH E11(R1) guideline as “an approach to providing evidence in support of effective and safe use of drugs in the pediatric population when it can be assumed that the course of the disease and the expected response to a medicinal product would be sufficiently similar in the pediatric [target] and reference (adult or other pediatric) population.” The reference population can include other pediatric age subsets. Pediatric extrapolation can extend what is known about the reference population (e.g., pharmacokinetics (PK)/dosing, efficacy, and safety) to the target population based on an assessment of the relevant similarities of disease, drug pharmacology, and response to treatment between the two populations.
Historically, extrapolation of safety generally was considered unacceptable. However, understanding of similarities and differences between reference and target populations with respect to safety has evolved. As described in the ICH E11(R1) guideline, the principle of using data generated in a reference population to define the scope and extent of data that should be collected in a target population can also apply to the generation of safety data.
EMA’s CHMP adopted the document in July 2024 and was adopted by the Regulatory Members of the ICH Assembly under Step 4 on 21 Aug 2024. It will come into effect 25 Jan 2025.
Meeting Summary - Medicine Shortages (SPOC) Working Party
The summary of the 20 June 2024 meeting has now been published.
[Why does it take so long for such summaries to be released? MBH.]
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Update on Biological Standardisation Programme (BSP) study on the evaluation of a replacement method for the potency control of whole cell pertussis vaccines
The preparatory Phase 1 of the study evaluated two variants of a serological method, the Pertussis serological potency test (PSPT, in guinea pigs and in mice).
The results indicated that product-specific references are required to ensure data parallelism with the tested vaccines. However, the data did not demonstrate sufficient precision and reproducibility nor did they demonstrate reliable discriminatory power.
In the absence of convincing scientific evidence to support a large-scale collaborative trial, the Steering Committee of the BSP recommended not to proceed with further experimental work and decided to discontinue the BSP project. Thus, the EDQM will neither publish nor authorise the publication of data generated in the BSP104 project.
Reference Standards
4 new Ph. Eur. reference standard and 19 replacement batches released in July 2024
PDG announces global membership initiative
The Pharmacopoeial Discussion Group (PDG) has announced the launch of the next phase of its global expansion initiative aimed at increasing convergence of harmonised pharmacopoeial standards. This initiative will be the start of a process over the next couple of years to welcome additional pharmacopoeias as new members.
Pharmacopoeias interested in becoming members are encouraged to review the entry criteria, framework and reference information. They are required to submit a statement of intent to the PDG by 15 September 2024 and the formal application by 31 December 2024.
The PDG has successfully harmonised and maintains 31 general chapters, including key analytical procedures such as chromatography, dissolution testing, sterility and microbiological examination. In addition, the PDG has harmonised 48 excipient monographs and has approximately 20 new texts in its pipeline The PDG remains committed to promoting the recognition of harmonised pharmacopeial standards to achieve global convergence.
United States of America
The US Food and Drug Administration (USFDA)
M12 Drug Interaction Studies Q&A & a Guidance for Industry
In response to questions posted to the International Council for Harmonisation (ICH) draft guidance for industry M12 Drug Interaction Studies comment period, several questions and answers have been developed to provide clarity around some of the concepts related to evaluation of drug interaction covered in the guidance.
This question and answer (Q&A) document is intended to provide additional clarification and improve harmonization of drug interaction assessment.
The scope and organization of this Q&A document follow that of the ICH guidance for industry M12 Drug Interaction Studies (August 2024) (ICH M12)
FDA Now has issued this document as a Final Guidance along with a Q&A
Reprocessing Single-Use Medical Devices: Information for Health Care Facilities
This page provides information to help health care facilities understand the use of reprocessed medical devices originally labeled for single-use, and to clarify the level of FDA’s regulatory oversight of these reprocessed single-use medical devices to remain as safe and effective as the original manufactured devices.The practice of reprocessing devices that are intended for single-use (known as single-use devices, SUDs) began in hospitals in the late 1970s. Since that time, this practice has become widespread as a mechanism to save costs for health care facilities and reduce medical waste. For example, use of reprocessed SUDs may reduce environmental impact by limiting the use of non-renewable resources and decreasing the amount of medical waste that requires treatment and disposal. The FDA ensures the safety and effectiveness of reprocessed SUDs by regulating device manufacturers, third party reprocessors, and hospitals that reprocess SUDs in the same manner as the original equipment manufacturer (OEM).
Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA
This guidance provides recommendations to industry on product-specific guidance (PSG) meetings between FDA and a prospective applicant preparing to submit to FDA, or an applicant that has submitted to FDA, an abbreviated new drug application (ANDA) under the Federal Food, Drug and Cosmetic Act (FD&C Act).
Specifically, this guidance provides information on requesting and conducting PSG meetings with FDA as contemplated in the Generic Drug User Fee Amendments (GDUFA) Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). This guidance provides procedures that will promote well-managed PSG meetings and help ensure that such meetings are scheduled and conducted in accordance with the time frames set forth in the GDUFA III commitment letter. This guidance finalizes the draft guidance for industry of the same title issued on February 21, 2023.
US Department of Health & Human Services (HHS)
Negotiating for Lower Drug Prices Works, Saves Billions
In August 2023, HHS announced the first 10 drugs covered under Medicare Part D selected for the first cycle of negotiations.
The selected drugs accounted for $56.2 billion in total Medicare spending, or about 20 percent of total Part D gross spending in 2023. Overall, total Part D gross spending for the 10 selected drugs more than doubled from 2018 to 2022, from about $20 billion to about $46 billion, an increase of 134 percent. Medicare enrollees paid a total of $3.4 billion in out-of-pocket costs in 2022 for these drugs.
In a historic moment that will help lower prescription drug prices for millions of people across America, the Biden-Harris Administration announced that it has reached agreements for new, lower prices for all 10 drugs selected for negotiations. These negotiated drugs are some of the most expensive and most frequently dispensed drugs in the Medicare program and are used to treat conditions such as heart disease, diabetes, and cancer. The new prices will go into effect for people with Medicare Part D prescription drug coverage beginning January 1, 2026. These negotiated prices range from 38 to 79 percent discounts off of list prices. About nine million people with Medicare use at least one of the 10 drugs selected for negotiation. People with Medicare prescription drug coverage are expected to see aggregated estimated savings of $1.5 billion in their personal out-of-pocket costs in 2026.
CMS will select up to 15 more drugs covered under Part D for negotiation for 2027 by February 1, 2025. CMS will select up to 15 more drugs covered by Part B or Part D for 2028, and up to 20 more Part B or Part D drugs for each year after that, as required by the Inflation Reduction Act.
International
Australia
Therapeutic Goods Administration (TGA)
Guidance changes are coming soon
Some changes are coming soon to improve user experience using guidance on TGA’s website. Useful new features will make content clearer to understand, more accessible and easier to navigate.
User research on ‘guidance’ content on the website with industry indicated that guidance content needs improvement to make it more user friendly. Users have told TGA that they find guidance:-
· difficult to navigate and find
· unclear, as to what the ‘rules are’
· difficult to know what’s been updated.
From September, TGA will be reorganising our guidance, so it only includes content that is an explanation of the law and regulations on therapeutic goods. This will make it clearer that guidance is about the rules you need to follow.
New features, include-
· improved page navigation, so that you can easily jump to headings on long pages
· colourful indicators, so you can see when content is new or has been updated
· headings that will allow you to bookmark and share parts of content.
We will also be working to improve our page history, providing clear descriptions of what’s updated when version changes are made to guidance.
[This sounds most useful. I particularly find it frustrating and it is often time consuming to identify what changes have been made, to a document, unless a ‘Track Changes’ document is provided. A rationale for the changes will also be most useful. – In concept, Well Done TGA! MBH]
India
Central Drugs Standard Control Organization (CDSCO)
GDP for Pharmaceutical Products
This initial draft document has been issued for comment for a period of 30 days from issue (from Aug 9 2024)
This document prepared in line with WHO TRS on Good Storage and Distribution practices for Pharmaceutical products sets out steps to assist in fulfilling the responsibilities involved in the different stages within the supply chain and to avoid the introduction of spurious, adulterated, misbranded and not of standard quality products into the market and is intended to be applicable to all entities involved in any aspect of the storage and distribution of pharmaceutical products, from the premises of the manufacturer of the medical product to his or her agent, or the person dispensing or providing medical products directly to a patient.
The guideline has been prepared for inclusion as a schedule under the drug rules which would make it mandatory rather than a non mandatory guideline.
Products
FDA grants accelerated approval to afamitresgene autoleucel for unresectable or metastatic synovial sarcoma
This application is approved under the accelerated approval pathway. To verify the clinical benefit of afamitresgene autoleucel, the FDA and the sponsor agreed upon a postmarketing requirement for an ongoing study in adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Regenerative Medicine Advanced Therapy, priority review, and orphan drug designation.
MHRA approves Zolbetuximab to Treat Adults with Stomach or Gastro-oesophageal Junction Cancer
Zolbetuximab (Vyloy) is a monoclonal antibody that can recognise and attach itself to certain cancer cells to destroy them.
This new targeted cancer treatment, is given in combination with a standard chemotherapy, for adults with stomach (gastric) or gastro-oesophageal junction cancer. The gastro-oesophageal junction is the place where the gullet (oesophagus) joins the stomach.
Lecanemab licensed for adult patients in the early stages of Alzheimer’s disease
MHRA has approved a product licence for the medicine lecanemab (Leqembi) for use in the early stages of Alzheimer’s disease, following a thorough review of the benefits and risks.
Lecanemab is the first treatment for Alzheimer’s disease licensed for use in Great Britain that shows some evidence of efficacy in slowing progression of the disease.
[However the National Institute for Health and Care Excellence (NICE) subsequently issued draft guidance for consultation not recommending lecanemab for use on the NHS because it is not a cost effective use of limited NHS funding.]
COVID-19 Tests granted traditional Marketing Authorization by the FDA
The FDA has been working with COVID-19 test developers seeking to pursue marketing authorization through the traditional premarket review pathways, which will allow these tests to continue to be used beyond the time allowed by emergency use authorization (EUA). The EUA process is different than traditional clearance or approval of these products. The FDA may issue an EUA when the FDA has determined, based on the totality of scientific evidence available to the FDA, that it is reasonable to believe that the product may be effective for the intended use relevant to the emergency and that the known and potential benefits outweigh the known and potential risks of the product. This is different than the traditional device premarket review pathways, where the FDA considers whether there is a reasonable assurance of safety and effectiveness when the device is used as intended.
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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