Review of Developments in GMP and the Regulation of Medicines February 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, PIC/S and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
MHRA
Clinical trials for medicines: apply for authorisation in the UK
A stronger role for EMA
Union Product Database –Q&As for industry users
Regulatory harmonisation of clinical trials in the EU
New EU rules for safe and high-quality medicines for animals become effective
Learnings initiative for optimal use of Big Data for regulatory purpose - meeting report
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (Draft Rev2)
Concept paper on quality, safety and efficacy of bacteriophages as veterinary medicines
Concept paper on the development and data requirements of potency tests for cell-based therapy products and the relation to clinical efficacy (veterinary medicines)
Overview of comments received on ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products (Step 2)
Updated Q&A on repurposing pilot project
Reflection paper on GMP and Marketing Authorisation Holders (v2)
Guidance for Applicants seeking scientific advice and protocol assistance
Ph.Eur reference standards
Pharmeuropa 34.1 released
CEP of the future”: project update
Non-liquid, non-parenterally administered veterinary vaccines
Revising ANDA labeling following revision of the RLD labeling
Australia TGA
Advanced therapies
International Coalition of medicines regulatory Authorities (ICMRA) & World Health Organisation (WHO)
Recommendations on COVID-19 vaccines and the Omicron variant
New gene therapy treatment for patients with relapsed or refractory large B-cell lymphoma
EMA recommends conditional marketing authorisation for Paxlovid
Increase in manufacturing capacity for Vaxzevria
TGA grants provisional determination to AstraZeneca Pty Ltd for COVID-19 prophylaxis and treatment, tixagevimab and cilgavimab (EVUSHELD)
TGA recognises the Gamaleya Institute vaccine (Sputnik V, Russian Federation)
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Clinical trials for medicines: apply for authorisation in the UK
This document covers how to apply for a clinical trial including eligibility, phases, model IMPDs, costs and how to make changes to your application.
As of 1 Jan 2022 the combined review service, (formerly known as Combined Ways of Working (CWoW), is the way that all new Clinical Trials of Investigational Medicinal Products (CTIMPs) applications are prepared, submitted and reviewed. Combined review offers a single application route and co-ordinated review leading to a single UK decision for CTIMPs.
Please note: CTIMP applications via combined review should be started and submitted using the new part of Integrated Research Application System (IRAS) and not in the standard part of IRAS.
While the regulatory requirements and fees remain the same, the application submission, processing and assessment steps outlined refer to non-combined review applications. For Combined review applications please refer to the Health Research Authority website.
Europe
EMA
A stronger role for EMA
The regulation reinforcing EMA’s role has been published in the Official Journal of the EU. The new regulation becomes applicable as of 1 March 2022, except for the provisions on shortages of critical medical devices which will apply as of 2 February 2023. It puts structures and processes established by EMA during the COVID-19 pandemic on a permanent footing, while entrusting several new tasks to the Agency.
As part of its extended mandate, EMA will be tasked with the monitoring of events, including medicine shortages, which might lead to a crisis situation, as well as with the reporting of shortages of critical medicines during a crisis.
The adoption of an extended mandate for EMA is part of the European Health Union package proposed by the European Commission in November 2020.
Union Product Database –Q&As for industry users
This document (Version 1.1 – January 2022) consolidates questions and answers asked by marketing authorisation holders (MAHs) on the usage of the Union Product Database (UPD).
[A very useful document, but to make reading easier I would advise printing out the list of acronyms on page 24 –( there are 32 of them!)-and keeping it handy for reference whilst you read MBH]
Regulatory harmonisation of clinical trials in the EU
On 31 January 2022, the Clinical Trials Regulation (CTR) came into application harmonising the submission, assessment and supervision processes for clinical trials in the European Union (EU).
The backbone of the changes brought about by the CTR is the new Clinical Trials Information System (CTIS). CTIS is a single entry point for sponsors and regulators of clinical trials for the submission and assessment of clinical trial data which includes a public searchable database for healthcare professionals, patients and the general public.
In the past, sponsors had to submit clinical trial applications separately to national competent authorities (NCAs) and ethics committees in each country to gain regulatory approval to run a clinical trial, and registration and posting of results were also separate processes. With CTIS, sponsors can now apply for authorisations in up to 30 EU/EEA countries at the same time and with the same documentation. Publication of the trial information is built in the system.
The application of the CTR and the go live of CTIS in the EU and the European Economic Area (EEA) countries (Iceland, Liechtenstein and Norway) - will strengthen Europe’s position as an attractive location for clinical research.
New EU rules for safe and high-quality medicines for animals become effective
As of 28 Jan 2022 the Veterinary Medicinal Products Regulation becomes applicable. It contains new measures for stimulating innovation and increasing the availability and access to safe and high-quality veterinary medicines for veterinarians, farmers and pet owners to treat and prevent animal diseases and also supports the European Union (EU) action against antimicrobial resistance (AMR).
The new rules put in place a range of measures to limit the development of AMR, while ensuring that necessary treatments remain available for animals and people, a true ‘One Health’ approach. The new provisions foresee that preventive antimicrobial use is permitted only in exceptional circumstances and introduce the possibility to restrict or prohibit the use of important antimicrobials in animals, reserving the most important of them for treatment of certain conditions in humans.
The new Regulation contains measures that will simplify regulatory processes, striving to reduce administrative burden for current marketing authorisation holders and developers of new and innovative veterinary medicines to further encourage medicine innovation and development.
Learnings initiative for optimal use of Big Data for regulatory purpose - meeting report
[Big Data, Real World Evidence and Real World Data are becoming ever more important terms in the scientific vocabulary of our industry. This valuable, detailed summary from HMA /EMA of the November 2021 meeting provides valuable insight and direction. MBH]
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (Draft Rev2)
The guideline is to be seen in connection with Regulation (EU) No. 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, which came into force on June 20, 2014. Since clinical trials will often be designed as multi -centre studies, potentially involving different Member States, it is the aim of this guideline to define harmonised requirements for the documentation to be submitted throughout the EU. It should be clearly differentiated between the requirements for a dossier for a clinical trial and a marketing authorisation dossier. Whilst the latter ones have to ensure a state-of-the-art quality of a product for wide use in patients, information to be provided for investigational medicinal products (IMPs) should focus on the risk aspects and should consider the nature of the product, the state of development/clinical phase, patient population, nature and severity of the illness as well as type and duration of the clinical trial itself. As a consequence, it will not be possible to define very detailed requirements applicable to all sorts of different products. However, guidance on standard information which should normally be presented in the quality part of an IMPD is provided in this guideline. This guideline addresses the documentation on the chemical and pharmaceutical quality of IMPs and Auxiliary Medicinal Products containing chemically defined drug substances, synthetic peptides, synthetic oligonucleotides, herbal substances, herbal preparations and chemically defined radio-active/radio-labelled substances to be submitted to the competent authority for approval prior to beginning a clinical trial in humans. It includes the requirements for IMPs and Auxiliary Medicinal Products to be tested in phase I, phase II, phase III and phase IV studies as well as the requirements for modified and unmodified comparator products and IMPs to be tested in generic bioequivalence studies.
[This is a 42 page document containing much important information. The comment period closed in Aug 2021, but if your work touches on this topic then it is well worth a read / re-read. MBH]
Concept paper on quality, safety and efficacy of bacteriophages as veterinary medicines
Regulation (EC) No 2019/6 of the European Parliament and of the Council refers, for the first time in European legislation on veterinary medicinal products, to novel therapy veterinary medicinal products (Article 4 (43)). Section V.1 of Annex II of the Regulation 2019/6 amended by Commission. Delegated Regulation (EU)2021/805 of March 2021 lays down general requirements for marketing authorisation applications for novel therapy veterinary medicinal products, together with specific requirements for identified veterinary medicinal products related to the nature of the active substances contained therein.
There is an increased interest on the use and promotion of bacteriophage therapy in particular because of its potential use as an alternative to antibiotics. The biological characteristics of these viruses and the reciprocal evolution between bacterial hosts and bacteriophage, are very particular. Bacteriophage therapy, originally undertaken during early 1900s, was stopped when antibiotics therapies were developed, but has been used again in humans in the 90’s for last-resort treatments of multi-resistant bacteria which have escaped multiple-line antibiotic treatments. As bacteriophage medicinal products are classified as novel therapies, the centralised marketing authorisation procedure is mandatory. There is currently no detailed guidance for quality, safety and efficacy requirements for this product class. Thus, the novel therapies working party (NTWP) has been tasked with the preparation of a general guidance with a focus on the establishment of a suitable regulatory framework for bacteriophage products, to encourage the development of these innovative therapies.
Concept paper on the development and data requirements of potency tests for cell-based therapy products and the relation to clinical efficacy (veterinary medicines)
Continuous progress in the fields of biology, biotechnology and medicine has led to the development of new treatments and highly innovative medicinal products, which might include viable cells. These cell-based medicinal products have a high potential in the treatment of various diseases where there is a previously unmet medical need. The mechanism(s) of action is/are not fully characterized for cell-based products and a link between the potency assay and relevant biological properties is thus missing in many cases. It is proposed to draft guidance on requirements for potency testing of veterinary cell-based products. The purpose of the guideline to be developed is to provide clear advice for applicants and assessors on potency testing of veterinary cell-based products by considering the mechanism(s) of action that is most relevant (most likely) for the clinical indication.
Overview of comments received on ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products (Step 2)
EMA has published this overview of comments received on the draft ICH guideline.
Updated Q&A on repurposing pilot project
Repurposing of medicines is about identifying a new therapeutic use for an existing medicine/active substance for an indication outside its existing authorised indication(s). It is a way of making new treatment options available to patient EMA recently has updated this Q&A.
Reflection paper on GMP and Marketing Authorisation Holders (v2)
EMA has issued version 2 of this recent document.
Guidance for Applicants seeking scientific advice and protocol assistance
This guidance document is updated regularly to reflect new developments and include accumulated experience.
In particular, this version (v11) was amended to modify the submission process
EDQM
Ph.Eur reference standards
Three new reference standards and eleven replacement batches were released in December 2021
Pharmeuropa 34.1 released
All new Ph. Eur. texts and texts that have undergone technical revisions are published in Pharmeuropa for public consultation. The deadline for comments on Pharmeuropa 34.1 is 31 March 2022.
CEP of the future: project update
The consultation phase of the project to design the CEP of the future has been completed.
The EDQM has published the survey outcome and a roadmap for further action.
This initiative was undertaken to develop a modern CEP that will better fit the current needs of stakeholders and offer both greater transparency and enhanced user-friendliness. The first phase, starting in late 2020, involved gathering feedback from stakeholders through a wide public consultation on various aspects connected with the CEP. Responses were then compiled and reviewed in detail, making it possible to identify work areas and prepare the roadmap.
Non-liquid, non-parenterally administered veterinary vaccines
Sterility requirements in non-liquid and non-parenterally administered veterinary vaccine monographs have been replaced by a maximum bioburden limit to allow the development of new innovative vaccine presentation forms while maintaining the same safety guarantees.
These innovations are directed both at increasing user safety and convenience for the customer and at improving product consistency and product presentation (direct packaging) flexibility.
These changes must be adequately justified and agreed by the competent authority.
European Pharmacopoeia Supplement 10.8
Supplement 10.8 of the Ph. Eur. is now available. Holders of Certificates of suitability to the monographs of the Ph. Eur. (CEPs) are invited to update their applications according to the revised monographs that will be implemented on 1 July 2022
Ph. Eur. procedure 4
This document is intended to help stakeholders understand the advantages of applying for a monograph elaboration via Ph. Eur. procedure 4. It describes how Group P4 has elaborated P4 monographs over the last 10 years. It also applies to monographs on biotherapeutics as elaborated by the P4 bio Working Party.
United States of America
The US Food and Drug Administration (USFDA)
Revising ANDA labeling following revision of the RLD labeling
This draft guidance is intended to assist applicants and holders of an abbreviated new drug application (ANDA) in updating their labeling following revisions to the approved labeling of a reference listed drug (RLD). This guidance provides recommendations on identifying RLD labeling updates and submitting ANDA amendments or supplements to update generic drug labeling.
After it has been finalized, this guidance will replace the April 2000 guidance. Significant changes from the 2000 version include updates to outdated details about how to obtain information on changes to RLD labeling and how to submit revised ANDA labeling to FDA.
A generic drug is required to have the same labeling as the RLD, except for changes required because of differences approved under a suitability petition, or because the generic drug and the RLD are “produced or distributed by different manufacturers.” As a general matter, all holders of marketing applications for drug products (both NDAs and ANDAs) have an ongoing obligation to ensure their product labeling is accurate and not false or misleading. When new information becomes available that causes the labeling to become inaccurate, false, or misleading, the application holder must take steps to update its labeling. A drug is misbranded if its labeling is false or misleading or does not provide adequate directions for use and adequate warning.
International
Australia TGA
Australia Therapeutic Goods Administration (TGA)
Advanced therapies
Advanced therapies or advanced therapy medical products is a term used to describe innovative therapies. International regulators use this term to include gene, cell and tissue therapies.
The TGA uses the following definition for advanced therapies:
a. Gene therapies
i. the substance is used in or administered to human beings to regulate, repair, replace, add or delete a genetic sequence
&
ii. the substance is involved in the therapeutic, prophylactic, or diagnostic effect of the product
b. Gene modified cell therapies
c. Cell and tissue therapies that:
i. are not devices
ii. have been classified as class 3 or 4 biologicals.
d. Either a or b in combination with a device
The TGA regulates therapeutic goods consisting of gene, cell and tissue therapies under the Therapeutic Goods Act 1989 (the Act).
Any biological or prescription medicine that involves genetic modification must also be approved by the Office of the Gene Technology Regulator (OGTR). OGTR approval is needed before TGA approval. OGTR applications should be done before or concurrently with an Australian register of Therapeutic Goods (ARTG) applications.
International Coalition of medicines regulatory Authorities (ICMRA) & World Health Organisation (WHO)
Recommendations on COVID-19 vaccines and the Omicron variant
International regulators have published a report highlighting their discussions on the effectiveness of current vaccines against the COVID-19 Omicron variant, regulatory requirements for a variant vaccine and considerations on clinical study design. The workshop on the global response to the COVID-19 Omicron variant was organised under the umbrella of the ICMRA
When looking at possible vaccination approaches against Omicron and other virus variants, the meeting participants agreed that the administration of multiple booster doses at short intervals is not a sustainable approach in the longer term. There is a need to develop a long-term strategy on the types of vaccines needed to manage COVID-19 in the future. This is an ongoing global discussion, that sits at the crossroads of science, public policy and public health and will require coordination among public health decision-makers at all levels.
In the regulators’ view, companies should also explore the feasibility of developing bivalent or multivalent variant vaccines to determine if they offer advantages to monovalent vaccines.
Products
New gene therapy treatment for patients with relapsed or refractory large B-cell lymphoma
EMA has recommended granting a marketing authorisation in the EU for Breyanzi (lisocabtagene maraleucel), a gene therapy for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), whose cancer has come back or who have not responded to treatment after two or more lines of systemic therapy. Breyanzi is an ATMP belonging to a new generation of personalised immune-cell-based-gene-therapies that are based on collecting and genetically modifying a patient’s own immune cells to treat their cancer.
[Exciting stuff! There must be many more such developments in the pipeline, bringing about a different approach to many aspects of our industry .”Physician Patient heal thyself!” MBH]
EMA recommends conditional marketing authorisation for Paxlovid
Paxlovid is the first antiviral medicine to be given by mouth that is recommended in the EU for treating COVID-19. It contains two active substances, PF-07321332 and ritonavir, in two different tablets. PF-07321332 works by reducing the ability of SARS-CoV-2 (the virus that causes COVID-19) to multiply in the body while ritonavir prolongs the action of PF-07321332 enabling it to remain longer in the body at levels that affect the multiplication of the virus.
The majority of patients in the study were infected with the Delta variant. Based on laboratory studies, Paxlovid is also expected to be active against Omicron and other variants.
Paxlovid was evaluated as part of ‘OPEN’, an initiative started in December 2020 with the aim of increasing international collaboration in the EU review of COVID-19 vaccines and therapeutics.
Increase in manufacturing capacity for Vaxzevria
EMA’s CHMP has approved a scale up of manufacturing of Vaxzevria.
An existing manufacturing site operated by Universal Farma in Guadalajara, Spain, will add a second filling line for the finished product.
TGA grants provisional determination to AstraZeneca Pty Ltd for COVID-19 prophylaxis and treatment, tixagevimab and cilgavimab (EVUSHELD)
The original determination of 4 November 2021 was for prevention in adults 18 years and older. This new determination now includes prevention and treatment of COVID-19 in individuals aged 12 years and older.
TGA recognises the Gamaleya Institute vaccine (Sputnik V, Russian Federation)
The TGA determined that an additional COVID-19 vaccine, the two-dose course of the Gamaleya Institute vaccine (Sputnik V, Russian Federation) would be 'recognised' for the purpose of establishing a traveller's vaccination status.
The TGA obtained additional information demonstrating this vaccine provides protection and potentially reduces the likelihood that an incoming traveller would transmit COVID-19 infection to others while in Australia or become acutely unwell due to COVID-19. The supporting information was based on published studies provided to the TGA by the Russian Government with the assistance of the Australian embassy in Moscow.
The recognition of Sputnik will expand options for the return of international students, travel of skilled and unskilled workers to Australia, and travel by business people and elite sports people to the country.
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.