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Review of Developments in GMP and the Regulation of Medicines November 2022


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INTRODUCTION


During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. 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:



Medicines and Healthcare Regulatory Authority (MHRA)

  • European Commission Decision Reliance Procedure (EC DRP) now continues to be available until 31 December 2023

  • MHRA appoints first new UK Approved Body to certify medical devices since Brexit

  • Medical devices: guidance for manufacturers on vigilance

  • MHRA response to contaminated paediatric medicines identified in WHO region of Africa

  • Annual accountability review


  • IRIS guide for Parallel Distribution applicants

  • High-quality data to empower data-driven medicines regulation in the European Union

  • EMA Management Board: highlights of October 2022 meeting

  • Mid-year report 2022

  • ICH guideline S1B(R1) on testing for carcinogenicity of pharmaceuticals Step5

  • ICH Guideline Q5A(R2) - viral safety evaluation of biotechnology products derived from cell lines of human or animal origin Step 2b

  • Work programme until 2025 of the HMA/EMA task force on availability of authorised medicines for human and veterinary use

  • Joint EDQM–EPAA event on the future of pyrogenicity testing: phasing out the rabbit pyrogen test

  • CEP of the future”: second project update

  • CEP holders invited to comment on draft monographs

  • Changes to CEP policy regarding chemical applications for polymorphs

  • General chapter 2.2.46. Chromatographic separation techniques: comparison of requirements in the Ph. Eur. 10th and 11th Editions

  • Ph. Eur. publishes Cannabis flos draft monograph in Pharmeuropa for comment


  • Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products.

  • Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

  • Physicochemical and Structural (Q3) Characterization of Topical Drug Products Submitted in ANDAs

  • In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs

  • Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA

  • Facility Readiness: Goal Date Decisions Under GDUFA

  • Competitive Generic Therapies

  • Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA

  • Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA



World Health Organization (WHO)

  • Substandard (contaminated) paediatric medicinesAustralia


  • New vaccine to protect people in the EU and worldwide against dengue

  • First therapy to treat transplant patients with post-transplant lymphoproliferative disease

  • EMA recommends approval of second adapted Spikevax vaccine

  • EMA recommends approval of Comirnaty and Spikevax COVID-19 vaccines for children from 6 months of age

  • Urgent Product Recall- Targocid 200mg

  • EMA confirms recommendation to withdraw marketing authorisations for amfepramone medicines


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

European Commission Decision Reliance Procedure (ECDRP) now continues to be available until 31 December 2023

The ECDRP allows a company to submit a product that has received approval from the EMA to the MHRA. The MHRA can grant a licence with a lighter touch review than they would normally conduct for that medicinal product, relying on the EMA’s decision.

The MHRA has extended the ECDRP to apply until 31 December 2023, in order to ensure GB patients continue to access the latest innovative medicines that meet high standards of safety as soon as possible. The continuation of the EC DRP includes variations and extensions.

MHRA appoints first new UK Approved Body to certify medical devices since Brexit

MHRA has confirmed that DEKRA Certification UK Ltd has now joined the three current UK Approved Bodies, increasing the UK’s capacity to process conformity assessments for medical devices to ensure safe and effective devices reach the UK public.

DEKRA has become the first organisation to complete the new designation process that any potential organisation must now go through in order to become approved to certify medical devices in the UK.

There are a further six organisations who are currently in the assessment process and there is active engagement with several further organisations who are preparing to submit their initial submission.

Medical devices: guidance for manufacturers on vigilance

The MHRA is responsible for the UK medical device market. Adverse incidents involving medical devices that occur in the UK must be reported to the MHRA.

The manufacturer, UK Responsible Person or Authorised Representative shall notify the MHRA about incidents and field safety corrective actions (FSCAs) which meet the reporting criteria; this includes Periodic Summary Reports (PSR) and Trend Reports.

The manufacturer has the responsibility for investigating incidents and for taking any corrective action necessary.

The manufacturer should also ensure that these guidelines are made known to their UK Responsible Person or Authorised Representative, who should be kept informed of incident reports. This will enable their UK Responsible Person or Authorised Representative to fulfil their obligations.

From 21 November 2022. Reports relating to adverse incidents for devices to the MHRA must be submitted via the new Manufacturer's On-line Reporting Environment (MORE) portal or via MHRA’s custom Application Programming Interface (API) for direct submission from your internal systems.

MHRA response to contaminated paediatric medicines identified in WHO region of Africa

The products referred to in the WHO Medical Product Alert are not authorised for use in the UK and nor are the active ingredients used in any UK authorised products. If you have acquired any of these cough syrups (Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup and Magrip N Cold Syrup) in The Gambia or through informal routes, do not use them. These are substandard products which are unsafe and their use, especially in children, may result in serious injury or death. If you are unsure, please check with your pharmacist.

  • Laboratory analysis of samples of each of the four products confirm that they contain unacceptable amounts of diethylene glycol and ethylene glycol as contaminants. To date, these four products have been identified in The Gambia, but may have been distributed, through informal markets, to other countries or regions.

  • Maiden Pharmaceuticals is not named as marketing authorisation holder or manufacturer on any UK licences. Nor it is listed as active substance manufacturer on any licences for other companies. Therefore, no licensed UK medicinal products are likely to be impacted.

Annual accountability review

A summary of key achievements and objectives delivered in the first year of MHRA’s 2-year Delivery Plan 2021-2023 was provided which included:

  • The focus on enabling MHRA to adapt to the new regulatory environment in order to develop new services and embed patient involvement.

  • The work on building effective partnerships with national and international partners, striking the right balance between alignment and being an innovative regulator.

  • The success of bringing promising drugs to patients through Project Orbis and the early access to medicines scheme, which was put on a legal footing in early 2022.

Upcoming deliverables in 2022 to 2023

In the second year of the Delivery Plan the focus will be on making the organisation come alive, embedding new services that will reduce their time-frames and developing MHRA’s culture, as well as completing transformation with a focus on developing staff. MHRA will also focus on inclusivity and contributing towards reducing inequalities in healthcare.

While the first year’s focus was on setting the strategy and structure, the second year will focus on ensuring MHRA embeds new ways of working to deliver lasting change. This will include investment in new IT systems, cultural change and service redesign.


Europe


European Medicines Agency (EMA)

Biosimilar medicines can be interchanged

EMA and the heads of Medicines Agencies (HMA) have issued a joint statement confirming that biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar.

While interchangeable use of biosimilars is already practiced in many Member States, this joint position harmonises the EU approach. It brings more clarity for healthcare professionals and thus helps more patients to have access to biological medicines across the EU.

A biosimilar is a biological medicine highly similar to another already approved biological medicine (the 'reference medicine'). Interchangeability in this context means that the reference medicine can be substituted by a biosimilar without a patient experiencing any changes in the clinical effect.

“EMA has approved 86 biosimilar medicines since 2006. These medicines have been thoroughly reviewed and monitored over the past 15 years and the experience from clinical practice has shown that in terms of efficacy, safety and immunogenicity they are comparable to their reference products and are therefore interchangeable”, says Emer Cooke, EMA’s Executive Director. “This is good news for patients and healthcare professionals, who have wider access to important therapeutic options to treat serious diseases such as cancer, diabetes and rheumatoid arthritis.”

EMA pilot offers enhanced support to academic and non-profit developers of ATMPs

EMA is launching a pilot to support the translation of basic research developments into medicines that could make a difference in patients’ lives in the European Economic Area (EEA). The pilot is open to academic sponsors and non-profit organisations who are developing advanced therapy medicinal products (ATMPs). These medicines for human use are based on genes, tissues or cells and might offer ground-breaking treatment options to patients.

The pilot will focus on the needs of non-profit academic developers. They are a major contributor to the development of ATMPs and diagnostic and delivery devices, but experience has shown that navigating regulatory requirements can be challenging.

During the pilot, EMA will provide enhanced regulatory support for up to five selected ATMPs that address unmet clinical needs and are solely developed by academic and non-profit developers in Europe. EMA will guide the participants through the regulatory process with the aim to optimise the development of the ATMPs, starting from best practice principles for manufacturing to planning clinical development that meets regulatory standards.

The pilot’s first participant has already been selected. This ATMP is ARI-0001, a chimeric antigen receptor (CAR) product based on patients’ own T-cells, that is developed by the Hospital Clínic Barcelona.

Big Data Update

A good practice guide for the use of real-world metadata is available for public consultation until 16 November 2022.

This draft guide aims to help regulators, data holders, researchers, pharmaceutical companies and other interested stakeholders to use the catalogue of data sources that will replace the currently available ENCePP [a publicly available register of non-interventional post-authorisation studies (PAS)]catalogue.

For instance, it provides recommendations on how to identify suitable real-world data sources for studies, and describes the required metadata elements.


EDQM

IRIS guide for Parallel Distribution applicants

This guide has been produced to help individuals using the IRIS | Regulatory & Scientific Information Management platform understand how to use the portal to submit a notification for parallel distribution.

This document is intended for Industry users who have already been granted Industry user access roles for the IRIS portal.

High-quality data to empower data-driven medicines regulation in the European Union

EMA and the Heads of Medicines Agencies (HMA) in the EU Member States are moving ahead with their ambitious agenda to increase access and improve the quality of the data that underpin decision-making on the benefits and risks of medicines in the European Union (EU).

The draft Data Quality Framework for EU medicine regulation, now open for public consultation, sets out quality criteria for data used in medicine regulation to ensure they are fit for purpose to support benefit-risk decisions. The framework addresses principles and procedures that apply across data types and across regulatory activities. It also provides considerations on data quality, definitions for data dimensions and sub-dimensions, as well as their characterisation and related metrics.

The second document out for public consultation is a draft good practice guide for the use of the EU metadata catalogue of real-world data sources. It is the first guide produced worldwide to focus on metadata to empower systematic integration of real-world evidence in medicines regulation. The guide provides recommendations on how to use the catalogue of real-world metadata that is currently being built and in late 2023 will replace the existing catalogue.

The public consultation is open until 16 November 2022.

EMA Management Board: highlights of October 2022 meeting

The management Board heard updates on topics including:-

  • EMA’s extended mandate

  • Its Working Parties

  • The clinical trials information system

Mid-year report 2022

This report was prepared by the Executive Director of the EMA and presented to the Agency's Management Board on 6 October 2022.

ICH Guideline Q5A(R2) - viral safety evaluation of biotechnology products derived from cell lines of human or animal origin Step 2b

This guideline was adopted by CHMP 21 July 2022 and is now released for public consultation.

The deadline for comments is 10 February 2023

ICH guideline S1B(R1) on testing for carcinogenicity of pharmaceuticals Step5

This guideline was first Transmitted to EMA’s CHMP 25 February 2016 it received final adoption by CHMP 16 September 2022 and will come into effect 16 March 2023.

Work programme until 2025 of the HMA/EMA task force on availability of authorised medicines for human and veterinary use

Unavailability of medicines in the EU, either because medicines are not marketed or due to supply disruptions, has been recognised by HMA and EMA as an area of great concern affecting all stakeholder groups.

The Task Force will function as a “supply and availability hub” and will track progress of supply and availability activities that the European medicines regulatory network is undertaking under the following EU projects:

  • the European Medicines Agency’s network strategy to 2025

  • the European Commission's Pharmaceutical Strategy for Europe

  • the 'Joint Action on Shortages', a three-year plan, starting at the end of 2022, to enhance national systems in tackling medicines shortages in a harmonised way.

The work programme covers centrally and nationally authorised products, both for human and veterinary medicines, in the following cases:-

  • when medicines are authorised but not marketed (or no longer marketed)

  • when authorised and marketed medicines are affected by supply-chain disruptions that directly affect their availability.

Such disruptions may occur due to problems with good manufacturing practice (GMP), good clinical practice (GCP), good distribution practice (GDP)3 or quality defects, or because of commercial interruptions or an increase in demand.


EDQM

Joint EDQM–EPAA event on the future of pyrogenicity testing: phasing out the rabbit pyrogen test

In June 2021, the Ph. Eur. Commission took the decision to engage on a path that should ultimately lead to the complete replacement of the rabbit pyrogen test (RPT) in the Ph. Eur. within approximately 5 years.

There are a number of Ph. Eur. texts – covering a variety of topics, including vaccines for human use, blood products, antibiotics, radiopharmaceuticals and containers – that refer to the RPT and will be affected by this decision.

The Ph. Eur. Commission is committed, for all these texts, to replacing the test for pyrogens with a suitable in vitro alternative, leading to the complete elimination of the RPT.

A three-day event, from 14 to 16 February 2023, in Brussels, Belgium, will focus on the future of pyrogenicity testing.

Topics on the agenda include an in-depth presentation of the Ph. Eur.’s strategy for phasing out the RPT, the use of the monocyte activation test (MAT), the viewpoints of regulators and industry representatives, as well as perspectives from outside Europe on animal-free pyrogenicity testing. The event will also include a training session on the MAT.

CEP of the future”: second project update

Since conducting a wide public survey on the Certification of suitability to the European Pharmacopoeia monographs (CEP), EDQM has been working on the design of the CEP of the future.

Different aspects were presented to stakeholders at three targeted consultation workshops in September 2022. The EDQM’s CEP of the future project team will analyse the feedback received during these discussions with the decision-making bodies to fine tune the design of the CEP of the future. The EDQM will then initiate a large communication campaign to explain the proposed changes.

CEP holders invited to comment on draft monographs

Holders of Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) are requested to consult the list of substances for which draft revised monographs of the European Pharmacopoeia (Ph. Eur.) have been published in Pharmeuropa 34.4. The substances affected by these revisions and for which a CEP has been granted are:- Acamprosate calcium (1585), Aluminium oxide, hydrated (0311), Calcitriol (0883), Mefloquine hydrochloride (1241), Oxytetracycline dihydrate (0199) and Suxamethonium chloride (0248)

Changes to CEP policy regarding chemical applications for polymorphs

EDQM has recently modified its policy on chemical applications for polymorphs. A request for a CEP for a specific polymorphic form (as a grade) is now possible even if the statement “the substance shows polymorphism” is not mentioned in the “Characters” section of the corresponding individual monograph in the European Pharmacopoeia.

General chapter 2.2.46. Chromatographic separation techniques: comparison of requirements in the Ph. Eur. 10th and 11th Editions

A new document has been added to the knowledge Database page for revised general chapter 2.2.46, under Additional Information. This document provides a useful and easy reference guide to the main changes made to the general chapter recently published in the 11th Edition of the Ph.Eur (PDG harmonised chapter) versus the 10th Edition version.

Please also note that new FAQs on the application of revised general chapter 2.2.46 (11.0) have been added to the existing series of FAQs.

Ph. Eur. publishes Cannabis flos draft monograph in Pharmeuropa for comment

The draft text covers the herbal drug defined as dried, whole or fragmented, fully developed shoot apices of female cultivars of Cannabis sativa L. It is to be read in conjunction with the general monograph Herbal drugs (1433), which includes additional requirements that are applicable unless otherwise stated in the Cannabis flos draft. The monograph takes into account information received from a number of national authorities concerning the use of this herbal drug in their jurisdictions


United States of America


The US Food and Drug Administration (USFDA)

Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products.

The guidance encourages manufacturers of medically necessary drug products (MNPs) and components to develop production plans in the event of an emergency that results in high absenteeism at one or more production facilities. The purpose of the guidance is to provide to industry considerations for developing plans for these types of emergencies, as well as to discuss the Center for Drug Evaluation and Research's (CDER's) intended approach to assist in avoiding drug product shortages that may have a negative impact on the national public health during such emergencies.

Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

Tablets and capsules are widely manufactured and prescribed and may provide a number of advantages over other dosage forms, including ease of storage, portability, ease of administration, and accuracy in dosing. While generic formulations of these drug products are required to be both pharmaceutically and therapeutically equivalent to a reference listed drug (RLD),2 we are concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors. FDA believes these patient safety concerns are important, and we are recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates.

The recommendations in this guidance apply to abbreviated new drug applications (ANDAs) and their supplements for additional strengths that are submitted to the Office of Generic Drugs (OGD).

This guidance does not apply to approved ANDAs (generic drugs) already on the market. However, if the Agency determines that an approved product should be modified because the size or shape of a product poses a risk to public health, it will notify the holder of the ANDA.

This guidance revises the guidance of the same name issued in June 2015 to clarify that the largest dimension of a tablet should not exceed 22 mm and that capsules should not exceed a standard 00 size.

Physicochemical and Structural (Q3) Characterization of Topical Drug Products Submitted in ANDAs

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products.

Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products.

This guidance provides recommendations for physicochemical and structural (collectively, Q3) characterizations that can be used to identify the dosage form of a proposed generic (test) topical product and to describe properties of the drug product that may be critical to its performance (to support a demonstration of bioequivalence (BE). When comparing the Q3 attributes of two topical products (e.g., to support a demonstration of BE), FDA generally advises that applicants conduct a comparative Q3 characterization of their proposed generic product against the reference standard, which ordinarily is the reference listed drug (RLD).

This guidance does not address Q3 characterization of topical products for purposes of product quality control.

In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products. Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. This guidance provides recommendations for in vitro release test (IVRT) studies that can be used to compare a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD.

In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs

This guidance provides recommendations for in vitro permeation test (IVPT) studies comparing a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD.

Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA

This draft guidance is intended for holders of Type II active pharmaceutical ingredient (API) drug master files (DMFs) that will be referenced in an abbreviated new drug application (ANDA), or a prior approval supplement (PAS) to an ANDA. This guidance explains how FDA incorporates a program enhancement agreed upon by the Agency and industry as part of the negotiations relating to reauthorization of the Generic Drug User Fee Amendments (GDUFA), as described in “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027”

Specifically, this guidance describes instances when an early assessment, or “DMF prior assessment,” could be requested by a DMF holder and the circumstances under which FDA would commence an early assessment of Type II API DMFs 6 months prior to an ANDA or PAS submission referencing the DMF. It also provides recommendations for such DMF holders when making a request.

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) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)). This guidance explains how FDA incorporates a program enhancement agreed upon by the Agency and industry as part of the negotiations relating to reauthorization of the Generic Drug User Fee Amendments (GDUFA), as described in “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027”

Competitive Generic Therapies

The FDA Reauthorization Act of 2017, or FDARA, created a pathway by which FDA may, at the request of the applicant, designate a drug with “inadequate generic competition” as a competitive generic therapy (CGT). At the request of the applicant, FDA may also expedite the development and review of an abbreviated new drug application (ANDA) for a drug designated as a CGT.

This guidance provides a description of the process that applicants should follow to request designation of a drug as a CGT and the criteria for designating a drug as a CGT. It also includes information on the actions FDA may take to expedite the development and review of ANDAs for drugs designated as CGTs. Finally, it provides information on how FDA implements the statutory provision for a 180-day exclusivity period for certain first approved applicants that submit ANDAs for CGTs.

Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA

This guidance describes an enhanced pathway for discussions 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) for a complex product, as defined in this guidance. Specifically, this guidance provides information on requesting and conducting product development meetings, pre-submission meetings, mid-cycle review meetings, enhanced mid-cycle review meetings, and post-complete response letter scientific meetings with FDA.

This guidance revises the guidance of the same title issued in November 2020.

Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA

This final guidance is intended to assist original applicants and holders of approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs) with implementing a chemistry, manufacturing, and controls (CMC) postapproval change through the use of a comparability protocol (CP). A CP is a comprehensive, prospectively written plan for assessing the effect of a proposed postapproval CMC change(s) on the identity, strength, quality, purity, and potency of a drug product, including a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality).


International


World Health Organization (WHO)

Substandard (contaminated) paediatric medicines

This WHO Medical Product Alert refers to four substandard products, identified in The Gambia and reported to WHO in September 2022. Substandard medical products are products that fail to meet either their quality standards or specifications and are, therefore "out of specification"[1].

The four products are Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup and Magrip N Cold Syrup. The stated manufacturer of these products is Maiden Pharmaceuticals Limited (Haryana, India). To date, the stated manufacturer has not provided guarantees to WHO on the safety and quality of these products.

Laboratory analysis of samples of each of the four products confirms that they contain unacceptable amounts of diethylene glycol and ethylene glycol as contaminants. To date, these four products have been identified in The Gambia, but may have been distributed, through informal markets, to other countries or regions.

[Tragic incidents such as this involving diethylene glycol and ethylene glycol (anti freeze) as contaminants particularly in children’s cough syrups amazingly continue to be an ongoing issue despite the problem being well known. It is long past time it was stopped.

For a harrowing read from US FDA look up “Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide Incident”.

There have been several repeat incidents resulting in multiple child deaths since that time MBH]


Products


New vaccine to protect people in the EU and worldwide against dengue

EMA’s human medicines committee (CHMP) has adopted a positive opinion for Dengue Tetravalent Vaccine (live, attenuated) Takeda, used to prevent disease caused by dengue virus serotypes 1, 2, 3 and 4 in people from four years of age.

According to WHO, there are approximately 390 million dengue infections per year worldwide, with an estimated death rate of 20,000 to 25,000 per year, primarily in children. Before 1970, only nine countries had experienced severe dengue epidemics, while today the disease is endemic in more than 100 countries, including in Europe. It is the second most-diagnosed cause of fever after malaria among travellers returning from low- and middle-income countries.

This is the first time the CHMP simultaneously reviews a medicinal product meant for the European Union (EU) market, under the centralised procedure and non-EU countries, under the ‘EU-medicines for all’ programme – or EU-M4all. EMA's initiative to support parallel aplications for the EU-M4all opinion and the centralised procedure aims to make innovative or generic medicines and vaccines that address unmet medical needs or are of major public health interest available in Europe and globally faster, while avoiding duplication of efforts from regulators.

Medicines submitted under the EU-M4all programme are assessed by the CHMP in collaboration with the WHO and the target countries, combining EMA’s scientific review capabilities with the epidemiology and local disease expertise of WHO and experts and national regulators in the target countries.

[Another example of regulators working together in a faster / smarter way to bring about early benefit to patients. MBH]

First therapy to treat transplant patients with post-transplant lymphoproliferative disease

EMA has recommended a marketing authorisation EU for Ebvallo (tabelecleucel) for the treatment of adult and paediatric patients who experience a serious complication following solid organ transplantation (SOT) or bone marrow transplantation (hematopoietic cell transplant - HCT) called EBV+ PTLD. This is one of the most important malignancies after transplantation. It is a result of the immunosuppression caused by the medication required to reduce the possibility of rejection of the transplanted organ or cells and the most common form of this condition is associated with the Epstein-Barr virus. Ebvallo is indicated in patients after a transplant and who have received at least one prior therapy when the symptoms of the disease come back after treatment (relapsed) or when the treatment does not work (refractory).

A significant unmet need exists for patients who fail first-line therapies as they have only weeks to a few months’ survival after treatment failure, and other treatment options are limited.

EMA recommends approval of second adapted Spikevax vaccine

EMA’s CHMP has recommended authorising an adapted Spikevax COVID-19 vaccine targeting the Omicron subvariants BA.4 and BA.5 in addition to the original strain of SARS-CoV-2.The adapted vaccine, Spikevax bivalent Original/Omicron BA.4-5, is recommended for adults and children from 12 years of age who have already had a primary vaccination course against COVID-19.Adapted vaccines are vaccines that have been updated so they better match the circulating variants of SARS-CoV-2. They are expected to broaden protection against different variants and help maintain optimum levels of protection against COVID-19 as the virus evolves.

EMA recommends approval of Comirnaty and Spikevax COVID-19 vaccines for children from 6 months of age

EMA’s CHMP has recommended extending the use of Comirnaty and Spikevax targeting the original strain of SARS-CoV-2. The Committee recommended including the use in children aged 6 months to 4 years for Comirnaty and use in children aged 6 months to 5 years for Spikevax. Comirnaty and Spikevax are already approved in both adults and children aged from 5 and 6 years, respectively.

Compared to the doses for already authorised age groups,1 the doses of both vaccines in these new younger age groups will be lower.

Urgent Product Recall- Targocid 200mg

Two batches of Targocid 200mg powder for solution for injection/infusion or oral solution are being recalled by Sanofi UK after they were found to contain high levels of bacterial endotoxins, a toxic compound found in bacterial cell walls that can cause inflammation-related symptoms, high fever and, in very serious cases, septic shock.

The issue was detected when four patients experienced high fevers approximately three hours after being given a dose from one of the affected batches, with the batch numbers 0J25D1 and 0J25D2.

[Fortunately it is very unusual to see such a recall in the UK MBH]

EMA confirms recommendation to withdraw marketing authorisations for amfepramone medicines

EMA’s safety committee (PRAC) has confirmed its recommendation to withdraw the marketing authorisations for amfepramone obesity medicines. This follows a re-examination of its previous recommendation of June 2022, which was requested by the companies that market these medicines.

The recommendation follows a review which found that measures to restrict the use of these medicines for safety reasons have not been sufficiently effective.

The PRAC recommendation will now be sent to the CMDh1 for its consideration.


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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