Review of Developments in GMP and the Regulation of Medicines January 2023
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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, US, PIC/S ICMRA and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
Medicines and Healthcare Regulatory Authority (MHRA)
List of medicines that cannot be parallel exported from the UK or hoarded
Horizon Scanning Case Study: Guiding principles that can inform the development of Good Machine Learning Practice
Joint Statement on Medical Devices Regulatory Reform
Department for Business, Energy & Industrial Strategy BEIS funding to unlock digital, data and scientific regulatory innovation
End-of-year message from EMA’s Executive Director
Implementation of the Clinical Trials Regulation
Facilitating Decentralised Clinical Trials in the EU
ECDC and EMA collaborate on vaccine safety and effectiveness monitoring studies
EMA Management Board: highlights of December 2022 meeting
Reference Standards
How CEP holders can avoid the rejection of notifications.
European Paediatric Formulary: Chloral Hydrate Oral Solution monograph open for public consultation in Pharmeuropa PaedForm
European Paediatric Formulary: Revised Phosphate Oral Solution monograph published
Thefts, losses & diversions of medicinal products
ANDAs: Pre-Submission Facility Correspondence Related to Prioritized Generic Drug Submissions
Controlled Correspondence Related to Generic Drug Development
Statistical Approaches to Establishing Bioequivalence
Drug Products Labeled as Homeopathic Guidance for FDA Staff and Industry
Failure to Respond to an ANDA Complete Response Letter Within the Regulatory Timeframe Guidance for Industry
Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims
Switzerland
Agreement with the USA in the field of GMP for pharmaceuticals
First gene therapy to treat haemophilia B
Pfizer/BioNTech COVID-19 vaccine authorised for use in infants and children aged 6 months to 4 years in UK
Bivalent original/Omicron BA.4-5 mRNA vaccines may be used for primary vaccination
EMA recommends withdrawal of pholcodine medicines from EU market
ETF warns that monoclonal antibodies may not be effective against emerging strains of SARS-CoV-2
Update on UK MHRA review into safe use of valproate
Microbiological Risk of Contamination Assessment tool for tissues and cells.
The future of pyrogenicity testing: phasing out the rabbit pyrogen test
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
List of medicines that cannot be parallel exported from the UK or hoarded
As of 13 December 2022 ten medicines have been removed from the list of medicines intended for the UK market that cannot be exported from the UK.
A further 4 products - amoxicillin, cefalexin, phenoxymethylpenicillin (Penicillin V) and azithromycin oral suspension - have been added to the list.
Horizon Scanning Case Study: Guiding principles that can inform the development of Good Machine Learning Practice
Through horizon scanning and analysis of operational business and interactions with both domestic and international stakeholders, it was noted that increasing growth in the number of AI/ML related technologies being developed and, due to the lack of consensus in the field, began discussing the topic with other regulators. A collaboration with colleagues at the U.S. Food and Drug Administration (FDA) and Health Canada resulted in the development of 10 Good Machine Learning Practice (GMLP) guiding principles that can inform the development of AI/ML enabled medical devices for a range of applications including disease prediction, diagnosis, monitoring and treatment. The aim is that these GMLP guiding principles lay the foundation for developing safe and effective products, and helps to cultivate future growth in this rapidly developing field. The 10 guiding principles identify areas where the International Medical Device Regulators Forum (IMDRF), international standards organizations and other bodies could work to advance GMLP.
Joint Statement on Medical Devices Regulatory Reform
The Life Sciences Council has issued a Joint Statement on a new agreement to accelerate the delivery of the future UK HealthTech regulatory system.
The advisory group has agreed that aligned proposals will be published on three priority areas:
international recognition;
routes for innovation; and
system capacity.
Initial proposals will be published in February 2023. Joint working in these areas will support the delivery of a system that protects patient safety whilst accelerating access to innovative technologies.
The MHRA will also publish a comprehensive UK roadmap of activities, milestones and timelines to deliver the required regulatory infrastructure. Any timelines will ensure sufficient time to allow the regulators and industry to prepare.
Department for Business, Energy & Industrial Strategy (BEIS) funding to unlock digital, data and scientific regulatory innovation
MHRA has received a total of £970,688 from BEIS’ Regulators’ Pioneer Fund for three projects that aim to unlock cutting edge regulatory innovation, to drive real world benefits for patients, the healthcare sector and clinical research.
The first project has been awarded £750,387 to tackle the challenges of finding control groups for clinical trials, through the development of alternative synthetic datasets.
The second project (£167,863) aims to address the issue of how to safely introduce complex ‘black-box’ AI products into clinical settings, so that clinicians can be confident that the decision from the AI device is appropriate and suitable in that specific context.
The third project has been awarded £52,438 to explore the development of guidelines around regulating microbiome therapeutics and diagnostics, a rapidly emerging field that poses a challenge for regulators and companies due to its novel and complex nature.
Europe
European Medicines Agency (EMA)
End-of-year message from EMA’s Executive Director
Today EMA is in a much better place with COVID-19. We have seven COVID-19 vaccines and four vaccines tailored to specific strains of the SARS-CoV-2 virus authorised for use in the EU. Thanks to the rapid pace of scientific progress, and to EMA’s and the regulatory network’s ability to adapt during these times of crisis, we are able to experience some return to normality again. The knowledge we gained with COVID-19 also helped us mount a rapid response to mpox which was declared a public health emergency by the World Health Organization (WHO) in the middle of the year.
Beyond EMA’s work on these public health crises, It has recommended 89 human medicines for approval. Under the Eumedicines for all procedure, EMA evaluated a new vaccine against dengue and two diabetes treatments that address important public health issues outside the European Union (EU). In the veterinary area, EMA recommended ten new medicines for approval.
It progressed the implementation of two new major pieces of legislation, with profound effects and changes in the way clinical trials are regulated and veterinary medicines are supervised in the EU.
EMA will carry out its work on more flexible regulatory processes while maintaining high standards for quality, safety and efficacy of medicines.
Implementation of the Clinical Trials Regulation
On 31 January 2023, the clinical trial information system (CTIS) will become the 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 public.
The system was launched on 31 Jan 2022, starting the clock for the one-year transition time for all sponsors of clinical trials. During the transition period clinical trial sponsors can still choose whether to submit an initial clinical trial application in line with the Clinical Trials Directive or under the Clinical Trials Regulation, via CTIS. On 31 January 2023, the use of CTIS will become mandatory. CTIS is the information system supporting the implementation of the Clinical Trials Regulation, which changes the way that applications for authorisation of clinical trials in the EU are submitted, how the clinical trials are authorised and supervised. The provisions of the Clinical Trial Regulation bring extensive changes in practices by all stakeholders and require effective change management.
Facilitating Decentralised Clinical Trials in the EU
The European Commission (EC), the Heads of Medicines Agencies (HMA) and the European Medicines Agency (EMA) have published recommendations that aim to facilitate the conduct of decentralised clinical trials (DCTs) while safeguarding the rights and well-being of participants as well as the robustness and reliability of the data collected. This is an outcome of their joint initiative to accelerate Clinical Trials in the European Union (ACT EU) Traditionally, clinical trials have been conducted at specific clinical trials sites, to which patients had to travel to. The aim of DCTs is to make it easier for patients to participate in clinical trials by reducing the need to travel to central trial sites. This approach has the potential to make clinical trials available to a wider demographic of participants and reduce drop-out rates.
ECDC and EMA collaborate on vaccine safety and effectiveness monitoring studies
EMA and the European Centre for Disease Prevention and Control (ECDC) convened on 6 and 7 December 2022, in Amsterdam the first meeting of the Immunisation and Vaccine Monitoring Advisory Board (IVMAB) of the Vaccine Monitoring Platform (VMP). Through the VMP, EMA and ECDC will coordinate and oversee EU-funded, independent post-authorisation studies on vaccines use, safety and effectiveness conducted in EU countries. The first EU-funded study is already underway. It is a pre-exposure prophylaxis study to assess the effectiveness of Imvanex (monkeypox vaccine) in 15,000 individuals, which was launched by the VMP in October 2022.
EMA Management Board: highlights of December 2022 meeting
At its meeting of 14-15 December 2022 the EMA Management Board heard an update on the recent activities related to the response to COVID-19. Since the start of the pandemic, a total of seven vaccines, four adapted booster vaccines and eight treatments have been authorised for use in the European Union (EU).
Additional topics were:-
EMA multiannual programming and 2023 budget
Implementation of the Clinical Trials Regulation
Implementation of the Veterinary Medicinal Products Regulation
Committee for Advanced Therapies Report
Audit strategy 2023-2025 and audit plan 2023
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Reference Standards
The EDQM announced the release of 5 new European Pharmacopoeia (Ph. Eur.) and 12 replacement batches in November 2022.
How CEP holders can avoid the rejection of notifications.
In order to facilitate the acceptance of proposed changes in a timely manner, CEP holders are reminded that the European Directorate for the Quality of Medicines & HealthCare (EDQM) Guideline on requirements for revision/renewal of Certificates of Suitability to the European Pharmacopoeia Monographs (PA/PH/CEP (04) 2, 7R corr) lists different notifications and associated conditions, and that any change not classified as a notification or a major change should be classified as a minor change by default (with the exception of editorial changes for which specific guidance is given in the policy document). If the change cannot be classified by the document and specifically as a notification, a minor revision (by default) should be submitted. Any submission of a notification which includes changes not classifiable as a notification will be rejected and the changes will then need to be resubmitted using the correct classification - with associated documentation and fee.
[give it a read and avoid delay and duplication of effort for both regulator and applicant. MBH]
European Paediatric Formulary: Chloral Hydrate Oral Solution monograph open for public consultation in Pharmeuropa PaedForm
EDQM has just released Issue 5 of Pharmeuropa PaedForm, in which the draft text for Chloral hydrate 100 mg/mL Oral Solution is published for public consultation prior to its inclusion in the European Paediatric Formulary. The deadline for comments on the text in Pharmeuropa PaedForm is 31 March 2023.
This is the sixth monograph elaborated by the PaedF Working Party. The formulation described in the Chloral hydrate 100 mg/mL Oral Solution monograph was selected on the basis of the inclusion and evaluation criteria established for the European Paediatric Formulary that were adopted at the end of 2015. The European Paediatric Formulary gathers together, at European level, monographs on formulations for extemporaneous preparations that are either described in national formularies or well established in Europe. Once these monographs (which are not legally binding) have been approved by the European Pharmacopoeia Commission and adopted by the European Committee on Pharmaceuticals and Pharmaceutical Care, they are made available to pharmacists and clinicians to help them prepare paediatric medicines when no authorised alternative is available.
European Paediatric Formulary: Revised Phosphate Oral Solution monograph published
EDQM has published the revised monograph Phosphate 60 mg/mL Oral Solution in the European Paediatric Formulary (PaedForm). This revised monograph (the first PaedForm text to undergo revision) was published in Issue 4 of Pharmeuropa PaedForm, approved by the European Pharmacopoeia Commission (EPC) and recently adopted by the European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH).
The European Paediatric Formulary gathers together, at a European level, monographs on formulations for extemporaneous preparations that are either described in national formularies or well established in Europe. Once these monographs, which are not legally binding, have been approved by the EPC and adopted by the CD-P-PH, they are made available to pharmacists and clinicians to help them prepare paediatric medicines when no authorised alternative is available.
Thefts, losses & diversions of medicinal products
The Committee of Experts on Minimising Public Health Risks Posed by Falsification of Medical Products and Similar Crimes (CD-P-PH/CMED) has prepared a Council of Europe (CoE) Recommendation on reporting of unaccounted disappearances of medicinal products for human and veterinary use from the legal supply chain. To better formulate this recommendation a CoE-wide survey was carried out in 2021 targeting health regulatory authorities to get their views on the situation.
The goal of this project is to draft a Committee of Ministers recommendation to member states in order to involve health authorities at an early stage by obliging stakeholders to report thefts, losses or diversions of medicines to them; to provide guidance on how authorities should deal with the information they receive and the follow-up action to be taken; and to promote international co-operation.
United States of America
The US Food and Drug Administration (USFDA)
ANDAs: Pre-Submission Facility Correspondence Related to Prioritized Generic Drug Submissions
FDA is issuing this revised draft guidance to incorporate program enhancements related to the content, timing, and assessment of a pre-submission facility correspondence within the abbreviated new drug application (ANDA) assessment program agreed upon by the Agency and industry as part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA III). This guidance replaces the November 2017 draft guidance for industry
Controlled Correspondence Related to Generic Drug Development
This guidance provides information regarding the process by which generic drug manufacturers and related industry or their representatives can submit to FDA controlled correspondence requesting information related to generic drug development. This guidance also describes the Agency’s process for providing communications related to such correspondence.
Statistical Approaches to Establishing Bioequivalence
Requirements for submitting bioavailability (BA) and bioequivalence (BE) data in investigational new drugs (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements; the definitions of BA and BE; and the types of in vitro and in vivo studies that are appropriate to measure BA and establish BE are set forth in part 320 (21 CFR part 320). This guidance provides recommendations on how to meet provisions of part 320 for all drug products.
Drug Products Labeled as Homeopathic Guidance for FDA Staff and Industry
This guidance describes how FDA intends to prioritize enforcement and regulatory actions for homeopathic drug products marketed in the United States without the required FDA approval. FDA has developed a risk-based approach under which the Agency intends to prioritize enforcement and regulatory actions involving certain categories of such products that potentially pose a higher risk to public health.
Failure to Respond to an ANDA Complete Response Letter Within the Regulatory Timeframe Guidance for Industry
This guidance is intended to assist applicants of abbreviated new drug applications (ANDAs), which were submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)), in responding to complete response letters (CRLs) from FDA. As described in regulation, ANDA applicants are required to take action after receiving a CRL. The guidance revises the guidance of the same title issued in July 2022. This revision is being issued to incorporate the performance goals outlined in the Generic Drug User Fee Amendments Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). This guidance provides information and recommendations regarding potential courses of action for an ANDA applicant after issuance of a CRL, as well as the actions that FDA may take if the applicant fails to respond to that CRL.
Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims
This guidance is intended to assist applicants in developing labeling for cardiovascular outcome claims for drugs that are indicated to treat hypertension. With few exceptions, current labeling for antihypertensive drugs includes only the information that these drugs are indicated to reduce blood pressure; the labeling does not include information on the clinical benefits related to cardiovascular outcomes expected from such blood pressure reduction.
FDA believes that the appropriate use of these drugs can be encouraged by making the connection between lower blood pressure and improved cardiovascular outcomes more explicit in labeling. This guidance recommends standard labeling for antihypertensive drugs except where differences in labeling are supported by clinical data.
International
Switzerland
Agreement with the USA in the field of GMP for pharmaceuticals
On December 16 2022 the Federal Council approved the agreement between Switzerland and the USA on the mutual recognition of inspections in the field of GMP for pharmaceuticals. The agreement aims to facilitate trade in pharmaceuticals and reduce the administrative burden for the industry. The agreement is expected to come into force in the course of 2023. According to the applicable requirements in Switzerland and the USA, pharmaceuticals must be manufactured in accordance with internationally agreed rules of GMP. Compliance with these rules during manufacture is inspected on site by the national authorities. These inspections are a prerequisite for the approval of medicinal products in many countries - including Switzerland and the USA. Swissmedic is the competent authority in Switzerland and the US FDA.
In the absence of an agreement, pharmaceutical production sites are usually inspected not only by national authorities but also by the authorities of the importing countries. Between Switzerland and the USA, the authority of the importing country should now be able to rely on the inspection of the partner authority based on the present agreement. The approval of medicinal products will continue to be assessed independently by the national authorities.
In order for the agreement to take effect, a corresponding assessment of whether the domestic requirements are met by the other authority must be completed. Completion of this assessment is expected in mid-2023.
[It is really good to see another MRA getting under way. MBH]
Products
First gene therapy to treat haemophilia B
EMA has recommended granting a conditional marketing authorisation in the European Union (EU) for Hemgenix (etranacogene dezaparvovec) for the treatment of severe and moderately severe haemophilia B in adults who do not have factor IX inhibitors (auto-antibodies produced by the immune system which make factor IX medicines less effective).Hemgenix is the first gene therapy to treat haemophilia B. It is delivered as a single infusion. Etranacogene dezaparvovec, the active substance in Hemgenix, is based on a virus (adeno-associated virus or AAV) which has been modified to not cause disease in humans. The virus contains copies of the gene responsible for producing factor IX. When injected into the patient's vein, the virus is carried to the liver where the gene will be taken up into the patient's liver cells and start producing factor IX, thereby limiting bleeding episodes. EMA’s recommendation is based on the results of two prospective, open-label, single dose, single-arm studies, in which 57 adult male patients with moderately severe or severe haemophilia B were enrolled. In the first study, the three patients sustained positive treatment effects up to three years following the infusion. In the second study, 52 patients sustained positive treatment effects up to two years following the infusion. It is yet unknown how long the benefits of this one-time treatment will last.
Pfizer/BioNTech COVID-19 vaccine authorised for use in infants and children aged 6 months to 4 years in UK
The MHRA has authorised the vaccine in this new age group This decision has been endorsed by the Commission on Human Medicines, after a careful review of the evidence. It will be for the Joint Committee on Vaccination and Immunisation (JCVI) to determine if the vaccine will be recommended for use in this age group as part of the UK’s COVID-19 vaccination programme.
This presentation is specially designed for this new age group and given at a lower dose compared to that used in individuals aged 5 to 11 years (3 micrograms compared with 10 micrograms). It is given as three injections in the upper arm, with the first two doses given 3 weeks apart, followed by a third dose given at least 8 weeks after the second dose.
Bivalent original/Omicron BA.4-5 mRNA vaccines may be used for primary vaccination
EMA’s Emergency Task Force (ETF) considers that adapted mRNA bivalent vaccines targeting the original strain and Omicron BA.4-5 subvariants of SARS-CoV-2 may be used for primary (initial) vaccination. These vaccines are currently only authorised as boosters. Data suggest that primary vaccination with these adapted bivalent vaccines should give rise to a broad immune response in people who have not yet been exposed to, or vaccinated against, SARS-CoV-2. The ETF further noted that the safety profile of the adapted vaccines when used as boosters is comparable to that of the original mRNA vaccines, for which the safety profile is well established.
Based on these considerations, national authorities may decide to use these adapted bivalent vaccines for primary vaccination in their national vaccination campaigns, should it become necessary.
The ETF’s statement has been issued in the context of its public health emergency response activities. It does not reflect a change to the product information of the authorised vaccines.
EMA recommends withdrawal of pholcodine medicines from EU market
EMA’s safety committee, PRAC has concluded its review of medicines containing pholcodine, which are used in adults and children to treat non-productive (dry) cough and, in combination with other active substances, for the treatment of symptoms of cold and flu, and has recommended the revocation of the EU marketing authorisations for these medicines. The available data showed that use of pholcodine in the 12 months before general anaesthesia with neuromuscular blocking agents (NMBA) is a risk factor for developing an anaphylactic reaction (a sudden, severe and life-threatening allergic reaction) to NMBAs. As it was not possible to identify effective measures to minimise this risk, nor to identify a patient population for whom the benefits of pholcodine outweigh its risks, pholcodine-containing medicines are being withdrawn from the EU market and will therefore no longer be available by prescription or over-the-counter. The PRAC recommendations has now be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for consideration at its next meeting in December 2022
ETF warns that monoclonal antibodies may not be effective against emerging strains of SARS-CoV-2
EMA’s Emergency Task force (ETF) has cautioned that monoclonal antibodies currently authorised for COVID-19 are unlikely to be effective against emerging strains of SARS-CoV-2.
These monoclonal antibodies are designed to neutralise the virus by binding to the spike protein on its surface. However, emerging strains have mutations in this protein which can reduce the ability of the antibodies to bind to them.
Recent laboratory studies show that monoclonal antibodies targeting the spike protein are poorly effective at neutralising Omicron strains BA.4.6, BA.2.75.2 and XBB. The data also show that these monoclonal antibodies do not significantly neutralise BQ.1 and BQ.1.1, which are expected to become the dominant strains in the EU in the coming weeks.
Antiviral treatments such as Paxlovid (nirmatrelvir / ritonavir) and Veklury (remdesivir), which have different mechanisms of action, are expected to retain their activity against the emerging strains. These treatments are approved in the EU for patients with COVID-19 who do not require supplemental oxygen and are at increased risk of their disease progressing to severe COVID-19.
The ETF therefore encourages EU Member States to ensure that healthcare professionals have access to these antiviral treatments for patients at increased risk of severe COVID-19.
Update on UK MHRA review into safe use of valproate
The CHM has advised that their measures apply to people under the age of 55 because this is the age-group evidence suggests is most likely to be affected by the risks of valproate when taken during pregnancy and the possible risk of impaired fertility in males, which is thought to be reversible upon dose reduction or discontinuation.
Information on how the independent Commission on Human Medicines (CHM) recommendations will be put into practice will be communicated in due course. In the meantime, healthcare professionals are urged to consider alternative options before initiating valproate and to continue to adhere closely to the Pregnancy Prevention Programme in girls and women of child-bearing potential who are taking valproate.
No one should stop taking valproate without advice from their healthcare professional.
Conferences
Microbiological Risk of Contamination Assessment tool for tissues and cells.
This webinar is free of charge and will take place on 19 January from 14:30 to 17:00 (CET, Paris, France).
The procurement, processing, storage and distribution of human tissues and cells (TC) intended for human application must comply with the highest standards of quality and safety, aligned with the current regulatory framework and the latest evidence-based scientific requirements, in order to guarantee their safe and effective use. Procurement and processing of TC, conducted by TEs under aseptic conditions, are among the most critical and complex processes that entail some level of contamination risk. Failure in any step of these processes may lead to microbiological contamination and loss of TC, and may even pose a potential health risk for the recipient if the contamination is not detected before the TC are used.
The online tool for a systematic risk assessment of the microbiological contamination (MiRCA) tool is aimed at:
helping users identify potential risks in novel, existing or modified aseptic processes;
alerting users to the degree of risk of introducing microbiological contamination during the procurement or processing of TC;
supporting decisions and measures to mitigate risks during aseptic processes.
The future of pyrogenicity testing: phasing out the rabbit pyrogen test
This free of charge conference took place in Brussels, Belgium & Online on 14=15 Feb 2023.
In June 2021, the European Pharmacopoeia (Ph. Eur.) Commission (EPC) took the decision to begin a process that will culminate in the rabbit pyrogen test (RPT) being completely replaced in the Ph. Eur. within approximately 5 years.
This event will be of particular interest to professionals from the pharmaceutical and biopharmaceutical industries, contract laboratories and authorities.
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.
