Health Canada, the Therapeutic Goods Administration (TGA) and the Medicines & Healthcare products Regulatory Agency (MHRA), all members of the Pharmaceutical Inspection Co-operation Scheme (PIC/S), International Coalition of Medicines Regulatory Authorities (ICMRA) and Access Consortium, have begun piloting a Good Manufacturing Practice (GMP) Single Inspection Program (SIP).
This pilot aims to establish a coordinated global approach to GMP inspections of foreign manufacturing sites of common interest. Using our collective inspection resources, each authority has agreed to cover the scope of the other where possible, reducing the need for multiple inspections of the same site.
This builds on the success of our existing collaborative GMP arrangements and will allow for more efficient inspection reliance processes, reduced regulatory burden on industry and enhanced collaboration in our regulatory oversight of common global supply chains.
Registration is available on the GPvP Symposium website for in-person attendance in West London and virtual attendance from anywhere in the world. A recording of the symposium will be available to registered delegates for 30 days after the event, allowing access at a convenient time.
What will we talk about?
No other event allows you to hear from so many MHRA pharmacovigilance experts in one place, including assessors and inspectors. The agenda is packed with educational and insightful content including:
Ask your burning questions, or simply say hello at Inspectors’ Surgeries during breaks (in-person attendees only).
Who should attend the 2024 symposium?
The event is a must for anyone working in pharmacovigilance within the biopharmaceutical industry, including:
The GPvP Symposium is held every two years, and the last Symposium was in March 2022. Don’t miss out in 2024—register today. We look forward to seeing you there!
GPvP Compliance Team
]]>Background
Marketing authorisation holders (MAH) for UK authorised products are required by law to keep the MHRA informed at all times of the details of the Pharmacovigilance (PV) system. This includes details of the UK Qualified Person for Pharmacovigilance (QPPV) and Pharmacovigilance System Master File (PSMF) UK location and number. These are submitted to the MHRA within the Summary of the Pharmacovigilance system (SPS) document.
Statutory guidance, effective since 21 December 2020 within the Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK MAHs and the MHRA - GOV.UK (www.gov.uk) and the MHRA website stated changes must be submitted to the MHRA via a Type IAIN variation within 14 days of the change.
What is the new process for notifying the MHRA with changes to the PV system?
Where changes to the PV system have been made but the UK PSMF number remains the same
Where changes to the SPS have been made, a Type IAIN variation will no longer be required to be submitted to notify the MHRA in respect to the following:
Instead, an SPS update notification covering the affected product licenses (PL), needs to be submitted to register these changes. There will be no fee associated with these notifications. SPS update notifications will be processed by the MHRA within 30 days of the receipt of the notice.
How to make a SPS Update notification
All notifications to update the SPS should be submitted via the MHRA Submissions Portal. The following documents will need to be supplied:
It is important to note that the notification for changes can only be processed by the MHRA if all the documents listed above are provided within the portal. A letter of acceptance will be issued once the changes have been made to our system.
Changes to the PSMF number
If you have a change to the PSMF number for product licenses due to Change of Ownership (COA). This will not be able to be submitted via this simplified route and may instead be submitted either as part of the COA application or as a Type IAIN variation within 14 days of the COA being granted. Information referring to the changes to UK QPPV details and UK location of the UK PSMF can be submitted within this process.
If there is a change to the UK PSMF number for PLs for any other reason or after 14 days after the COA grant, these will also need to be submitted as a Type IAIN variation within 14 days of the change taking effect.
Changes to guidance
These changes came into effect on 11 May 2023 and have been updated on 17 November 2023.
Although changes have been made to the MHRA webpage, Guidance on qualified person responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF) - GOV.UK (www.gov.uk) updates are not currently reflected within the Exceptions and modifications document. Updates to this document will be made in due course.
It is important to note that there have been no changes made to the way MAHs should request PSMF numbers or submit applications for marketing authorisations.
]]>In the meantime, we reserve the right to perform risk-based supervision of sites by either on-site or remote inspections and, based on the outcome, may continue to issue, withdraw or restrict GMP and GDP certificates as appropriate.
Inspections will continue to be prioritised based on risk so that the highest priority manufacturers and wholesale distributors are inspected first. In addition, inspections will be prioritised if the GMP or GDP certificate is already five years or older.
It is incumbent upon manufacturers, importers and distributors to continue complying with GMP and GDP as appropriate.
Inspections may be carried out at any time, and in case of serious non-compliance, appropriate regulatory actions will be taken
The inspection information from Mutual Recognition Agreement (MRA) partners and/or Pharmaceutical Inspection Co-operation Scheme (PIC/S) participating authorities should be submitted to support the ongoing verification of the GMP status of manufacturing sites based in third countries.
This information will be utilised in line with the principles of Inspection Reliance to determine the current state of compliance and support the risk-based supervision of sites; https://picscheme.org/docview/2475
The information should be shared between the manufacturing site, QP, MIA holder & MA holder. Responsibility for submitting the information, in a timely manner, to the MHRA should be assigned. To convey the information please complete and submit an Interim Compliance Report: https://www.gov.uk/guidance/good-manufacturing-practice-and-good-distribution-practice along with the relevant Inspection Report(s).
Previous related messages:
https://mhrainspectorate.blog.gov.uk/2022/11/08/return-to-international-gmp-inspections/
https://mhrainspectorate.blog.gov.uk/2017/10/19/international-regulators-inspecting-in-the-uk/
[1] https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic
[2] An explanatory footer has also been introduced in MHRA GMDP database.
]]>We will be including additional inspector profiles as part of our future recruitment campaigns.
Please click on the profile below, to learn more about the Inspector, why they applied for the role, what they love about the role and advice for potential candidates.
See details of our current vacancies and how to apply.
Mandy Budwal-Jagait, Head of GCP and Lead Senior GCP Inspector
Jason Wakelin-Smith, Head of the Expert Circle and Expert GCP Inspector
Hayley Dixey, Lead Senior GCP Inspector
Sophie Radicke, Head of GPvP and Senior Pharmacovigilance Inspector
Claire Longman, Expert Pharmacovigilance Inspector
Hello, I’m Mandy and I am the current Head of GCP at the MHRA and a Lead Senior GCP Inspector. I am responsible for the GCP inspection programme and the recruiting manager for the current GCP inspector vacancy. After completing my BSc in Medical Biochemistry and MSc in Toxicology, I realised that I wasn’t suited to life in a laboratory (for some reason, I would always have something go awry in my experiments)! I learned about clinical research and was immediately drawn to wanting to make a difference and help patients receive lifesaving/changing medicine. I started as a clinical research associate (CRA) in the pharmaceutical industry in 2008, progressing to a quality compliance role, then quality assurance as an auditor. I joined the MHRA as a GCP inspector in 2014.
A site of mine had been selected for an MHRA GCP inspection, where I observed the incredible work of the GCP inspectors. Following the inspection, I had a mindset change and couldn’t look at monitoring in the same way. I was delving into root-causes of issues and wanting to look at the bigger picture in terms of impact. I decided to apply for the role of GCP inspector as I am passionate about championing the voice of patients and keeping them safe. By joining the MHRA, I was able to do this not just within one company, but across the clinical research arena. You’ll read below that most inspectors applied and thought that they wouldn’t get the role, I was one of them too. Applying and saying yes to the role, was the best decision in my career so far.
This is a role of public service and I work with committed colleagues who inspire me every day with the work they do. I love the variety in my work, from inspections, educating and collaborating via stakeholder engagement, policy development and the numerous projects we get involved in. No day is the same and I am constantly learning! This role has accelerated my personal development and allowed me to have purpose every day in the work that I do. The role has also allowed me to balance my family commitments as a working mum of two small children, who keep me on my toes!
My advice to anyone considering applying is to firstly review the advert and job description. Don’t rule yourself out or pre-empt who we are looking for or what previous roles you need to have held to join. Champion yourself, your uniqueness and be authentically you. If you feel that now is not the right time for you to apply, include GCP inspector as part of your career goals and keep an eye out for future vacancies.
My name is Jason Wakelin-Smith and I am the Expert GCP Inspector and Head of the Compliance Expert Circle. I have been at the MHRA for 17 years so I have seen plenty of changes in the world of clinical trials since I joined in 2006 shortly after the introduction of the Medicines for Human Use Regulations in 2004. I initially qualified from university as a Biomedical Scientist but fell into the world of hospital pharmacy where I initially trained as a pharmacy technician; once qualified I moved into aseptic manufacture within the NHS followed a few years later by commencing training to become a Qualified Person (QP) within the NHS. This led to a role in clinical trials as I gained broader skills to support my QP training. At this time the clinical trial regulations and the conduct of clinical trials were very different than they are today and eventually I ended up leading the provision of pharmacy clinical trial services within my NHS Trust. In 2006 I was encouraged to apply for a GCP Inspector’s post by my manager and I admit to applying so that I could cross it off the list when I didn’t get it and continue down the path to becoming a QP. Following the selection process I was offered the job and it was a significant turning point in my life as it meant leaving the NHS and becoming a civil servant and starting a life ‘on the road’.
The change in role very much fitted with my values; in the NHS I could make a difference for the single patient that I was working on behalf of, whether that was making their dose of chemotherapy or ensuring that they had access to the correct medication to support their inclusion in a clinical trial. By becoming an inspector this massively changed my ‘reach’; if I do a good job then it could potentially impact the current participants involved in that clinical trial as well as any future patient taking medication that had been tested as part of that clinical trial. This has always been a massive driver for me.
The life of an inspector is fascinating! The exposure to the development of cutting edge treatments and technologies, looking at the multitude of ways that a process can be undertaken, the changes to technology and ways of working, meeting interesting people and the ability to effect change globally through partnerships and exchanges of information with other regulators and stakeholders are always examples of that. It’s a vertical learning curve when you start life as a new inspector and it remains steep thereafter but it’s always interesting and challenging. Once qualified there are multiple directions that you can take whether that’s developing additional technical skills within a particular area, cross-training with another inspection team or developing management skills. I have done all of these and I continue to enjoy it every step of the way. We are a close-knit community of inspectors and you are never alone - help, support, encouragement or a suggestion is only ever a phone call away.
In terms of any advice that I can offer to you? I’d encourage you to bring your life experiences to the role. I did not think that I would make the grade to become an inspector as I hadn’t worked in industry. But what I did bring to the role was broad exposure to many areas such as a basic analytical background from my degree, knowledge of the NHS, exposure to GMP and GCP, experience in computer system development, involvement in national pharmacy training provision and an appetite to learn and make a difference. So embrace your life’s journey to date and let us know what you can bring to the team as our next inspector.
I applied for a GCP Inspector job at the MHRA in 2015. The role of a GCP Inspector was of interest to me as I had been working in GCP quality roles for around 7 years and at the time I thought, why not give the application a go? I didn’t really expect to get the position as I doubted that I had enough experience and knowledge. I had been inspected and hosted inspections by the MHRA and respected the inspection process and what the MHRA is there to do.
Eight years later and so much has now changed in my personal life, I am now a parent to two small children and the work life logistics are significantly more complex! However, it is possible! Please don’t immediately be put off by caring responsibilities if this role is something you are interested in.
The role as an inspector is technically challenging and as the clinical trial world evolves, we have to evolve with it, which is fascinating to be a part of. What I have enjoyed in my role, is the people I work with and the people we meet along the way. We are so privileged to be able to go into a vast array of environments and gain such insight into their culture and processes. Going back to my first point, it’s really the people in the agency that make this an enjoyable role. Inspections are intense for all involved (hosts and Inspector’s) but we always manage to have a laugh and this makes being away from home and my children much easier.
During my time at the agency, I have been given many opportunities such as working with international regulatory agencies and have been able to progress to a Lead Senior Inspector despite time out of work for maternity leave.
Recently one of my children for the first time took an interest in what my job is, asking ‘what do you actually do at work mummy?’ after explaining as best as I could to a 4-year-old they responded ‘hmm that sounds important’ (before they turned back to YouTube). We really are trying to ensure that trials are conducted safely and ethically for participants, any of whom could be our family members or us ourselves at some point in our lifetime. So, it makes me proud that my children think what I do is important.
Final bits of advice for anyone considering the role;
My name is Sophie Radicke and I am the Head of the GPvP Compliance Team. My main responsibility is the line management of the MHRA’s pharmacovigilance inspectors and to ensure the operational delivery of pharmacovigilance inspections. I am also a senior pharmacovigilance inspector, and in this capacity, I have conducted over 70 inspections of a variety of organisations and pharmacovigilance systems.
I have degrees in Human Biology and Forensic Anthropology, but after graduating from university, I found myself in a position that is probably familiar to many graduates – I knew what I wanted to do in an ideal world but couldn’t quite achieve it due to various factors. I therefore fell back on my plan B, which was working in the pharmaceutical industry. I subsequently worked for a mid-sized pharmaceutical company in Germany and then a medical information service provider. But after around three years of working in industry, I became curious about how it would be like to work for the medicines regulator.
In 2016, I joined the MHRA as an associate assessor for safety variations in the Patient Information Quality Unit. At the time, I was not even aware that the inspector role existed, but my ignorance didn’t last long as I attended a Lunch-and-Learn talk by one of the GCP inspectors. While the role sounded exciting and like it would match with many of my skills and interests, I did not give it any further thought until the GPvP inspection team opened a recruitment round for a new inspector a year and a half later. I was keen to stay at the MHRA, but to develop further so I leapt at the opportunity to apply. In fact, my manager also encouraged me to apply as she thought the role might be a good fit for me – I am grateful for her encouragement to this day! Due to my limited experience in pharmacovigilance, I started the inspector role at the lower SEO grade.
While I conduct fewer inspections now than I used to, it is still one of my favourite parts of the job. I enjoy the ‘detective’ work of inspections and putting together all the different pieces to build a picture of compliance. It is also a privilege to be able to see so many different organisations and ways of operating a pharmacovigilance system, an experience which would be difficult to achieve otherwise.
Beyond inspections, my work gives me a degree of autonomy and flexibility that I haven’t encountered in any other role before. I also like the mix of working from home, our London office and travelling for inspections. In addition, I work with a talented and supportive group of people which in turn creates an amazing atmosphere at work.
Lastly, I am extremely motivated by knowing that my work is an important cog in the MHRA machinery to ensure that patients have access to safe and effective medicines. I also enjoy sharing my knowledge and expertise with newer inspectors and organisations, supporting them to work towards our common goal of patient safety.
My advice to interested candidates is to give it a shot – while a certain degree of pharmacovigilance knowledge and experience is needed, but it is only part of our requirements. If you are able to organise your own work, to motivate yourself and are eager to continuously learn personally and technically, reflect and develop yourself and others, then you’re already in a good position to succeed in this role.
My name is Claire Longman, I am a mum of 5-year-old twins and the Expert Pharmacovigilance Inspector at the MHRA.
I have been at the MHRA now for nearly 10 years, having 2.5 years off to look after my babies when they were younger.
Becoming an inspector was one of the proudest days of my life and sometimes I still have to pinch myself that I am privileged enough to hold this role. I have a BSc in Human Biology and a MSc in Health Sciences. I had fallen into Pharmacovigilance and spent 6 years in industry working my way up through PV and medical information. I had experience in case management, signal detection, PSURs and had been the Local Safey Officer at a medium sized company. I was contacted about the Inspector role at the MHRA and at the time declined to apply as I did not believe it was something I had enough experience or sufficient knowledge to be successful in applying for. After some persuasion, I submitted my application with the view that I would at least understand how the application process work and in a few years’ time I would be ready to apply ‘for real’, but to my surprise I kept being successful though each round and made it to the final round at the assessment centre. I remember this aspect clearly and enjoyed the environment and experience, I knew then that the job was for me and luckily, I exceeded my expectations and started as a Pharmacovigilance Inspector in 2014.
10 years later and I am still here, still engaged, still learning and still feeling privileged to hold the role I do. I have had exposure to situations and environments I would not have got in other roles. There are frustrations, of course, I am sure they come with every job but there are so many aspects I love about my role and I truly look forward to coming to work every day and giving my all. So what are the top 3 aspects I enjoy about the role of an inspector? Firstly, the amazing people I get to work with, I find the team inspiring, everyone works hard, has a valid opinion and everyone is encouraged to bring their strengths within the team and we celebrate the diversity we have. Secondly, the exposure I get, whether this is on inspection itself and seeing how different companies approach achieving compliance with regulations; training and presenting in front of large audiences; to speaking with other regulators and inputting to discussions on behalf of the MHRA; to imparting knowledge and experience with others, whether trainee inspectors or other departments. Above all the work is always diverse and stimulating. Thirdly, I am often out of my comfort zone, although this can be hard sometimes, it is a feeling you get used to and are rewarded with an amazing sense of achievement pushing yourself to achieve tasks you may not have had chance to be part of in other roles.
But there must be disadvantages to the role? One, which may be considered a disadvantage, is the travel, especially if you have a young family like me. Although it can be hard sometimes to leave, it is achievable and when not travelling work is flexible. I work from home with infrequent trips to London for meetings and I can make work fit around my home life. This is invaluable to me and makes a challenging role achievable and enjoyable whilst still having time to raise my family and spend quality time with them.
If I can give any advice, it would be, if you have an enquiring mind, are a team player and want to be challenged, apply for the role, give it a go. Its highly rewarding, fun, at times exhilarating and you can become part of a very hard working and dedicated team. Be yourself, be open, listen to others but give your opinion and make time to have fun along the way.
My name is Lynsay Hunter, and I am a Scottish-based GLP inspector working within the laboratories team here at the MHRA for the past seven years. I have two daughters whose social lives have eclipsed my own, although they and my husband are great helpers in helping me get rid of the results of my baking obsession which I still get time for!
I left the University of Stirling in 2005 with an honours degree in biochemistry which I put to work as an auditor in a small team at a clinical research organisation (CRO) on my university campus. I then moved into the lab and spent the next five years moving between CROs starting as a lead stability analyst and happily settling as a formulation analysis study director before that CRO site closed and I found myself redundant. After the closure I ended up as a development scientist investigating scale inhibitors in the oil industry. Our ISO9001 auditor left to go on maternity leave which coincided with me returning after a health scare (which limited me physically) so I found myself taking on the audit secondment to get us through our upcoming re-accreditation. On the return of the existing ISO9001 auditor, and being unable to move around brine barrels anymore, I moved to another CRO for a few years before the manager of a local quality assurance consultancy headhunted me and convinced me to join their laboratories team (which I ended up leading).
I applied to be an inspector after a colleague who had left my consultancy and joined the MHRA themselves told me about a vacancy. I had never looked at MHRA positions as I felt I could never be ‘good enough’ to be an inspector despite the role being very appealing, but they persuaded me to apply - and I’m very glad they did. The variety of backgrounds in my own team alone shows that there is no set path to becoming an inspector and the majority of us have been inspected ourselves at some point so we know what it’s like to be an inspectee. It is the very variety in my own background which I think helps me in my role. Being part of the laboratories team (as well as the wider compliance teams) is a huge part of why I love my job as the other inspectors are all very welcoming and supportive – and a lot less scary than I had been led to believe at previous jobs!
My advice to anyone weighing up applying for an inspector role would be to just go for it, and even if you don’t see another inspector with similar experience to you consider that could be because it is exactly what we are missing from our teams.
]]>The ICH Expert Working Group for ICH E6(R3) (EWG) has been updating the ICH E6(R2) GCP guideline (current version). The MHRA represents the Pharmaceutical Inspection Co-operation Scheme (PIC/s) in the EWG and MHRA GCP Inspectors have been attending the EWG meetings. This was initially Gail Francis, Expert GCP Inspector, supported by myself, and after Gail left the MHRA in February 2022, I became the primary representative supported by Jason Wakelin-Smith, Expert GCP Inspector. The EWG has sought input from stakeholders during its work and has met many times since its inception. It has been valuable to have participated in extensive discussions with colleagues from around the world, writing the text and listening to the views of expert stakeholders as we went along. I believe that the ICH EWG worked well together, had good leadership and the extensive and much needed administrative support provided to the group by an FDA colleague was fantastic.
The update is to address the application of GCP to new trial designs, technological innovations and to strengthen a proportionate risk-based approach of its application for clinical trials of medicines to support regulatory and healthcare decision making. This was set out in the ICH Reflection paper on Renovation of Good Clinical Practice and the ICH E6(R3) Concept Paper and a Business Plan was developed. ICH E6(R3) has been restructured and is composed of an overarching principles section, Annex 1 (interventional clinical trials), Annex 2 (additional considerations for non-traditional interventional clinical trials), Glossary and Appendices. The overarching principles, Annex 1, Glossary and Appendices will replace the current E6(R2). The development of Annex 2 will commence once the principles, Annex 1, Glossary and Appendices complete ICH step 1 with the Annex 2 concept paper being recently published. The draft principles of GCP have been released for transparency and common understanding in April 2021 followed by a global web conference to present progress.
ICH E6(R3) GCP Principles, Annex 1, Glossary and 3 Appendices concerning the Investigator’s Brochure, The Clinical Trial Protocol and Essential Records have now reached Step 2b and are available for public consultation.
MHRA became a full regulatory member of ICH in May 2022, and whilst feedback on the ICH E6(R3) can be provided via the ICH website, MHRA is consulting directly with UK stakeholders to compile and co-ordinate their comments to the EWG. I encourage you to provide your comments, in the consultation, whilst we expect comments to be provided via an uploaded Excel® spreadsheet, we have also asked a few questions to obtain UK stakeholder views on whether the revision has realised the objectives set out in the various documents above.
I have reviewed ICH E6(R2) and ICH E6(R3) and examined what changes have been by EWG which was a quite a time-consuming task! The following information is a personal summary of the changes that I have identified and I am not representing the EWG. A presentation is available from the EWG that provides their high-level summary of key changes made to the ICH GCP guideline. This blog is not intended to include every detailed change made or cover all text retained but should give you a flavour of the amendments made by the EWG. I anticipate that there could be publications that set out to discuss the changes in full detail during the consultation period, but this blog should start your understanding of what’s changed. I hope this may be helpful for those who are reviewing the ICH E6(R3) document as part of the MHRA consultation and for those who will be invited to and attending the meeting of the MHRA GCP Stakeholder Engagement Meeting (StEM), a longstanding group, which will take place on 18th July 2023 at the MHRA office in Canary Wharf, London.
I will take each section of the guideline in turn as follows. Once you’ve read this, I’ll leave you to review the revised ICH GCP guideline yourself and you can let the MHRA and EWG know want you think by participating in our consultation.
I Introduction
The introduction has had some amendments made. The first is the use of “conduct” to cover an expanded range of activities for the GCP guidance to cover. There are administration changes relating to ICH membership and some text outlining the new structure of the guideline. A key change is reference to the ICH E8 (R1) general considerations for clinical studies to emphasise designing quality into a clinical trial, identifying factors that are critical to trial quality, engaging stakeholders and using a proportionate risk-based approach. A key objective to the revision was to further embed the proportionate risk-based approach into the guideline.
The applicability of the guideline remains focussed on those clinical trials intended to support applications to regulatory authorities, but the applicability to other trials not intended for submission to regulatory authorities has been clarified to reduce it to those trials of investigational medicinal products and according to local requirements. I believe the aim of this is to discourage the application of the guideline to other trials that do not involve medicinal products. For the UK, the MHRA would expect clinical trials of investigational medicinal products (IMP) with a MHRA Clinical Trial Authorisation that are intended for marketing authorisation submissions to comply with the entire guideline and ALL trials involving an IMP, irrespective of marketing authorisation status of the IMP, to comply with the principles in section II as a minimum legal requirement.
Text from the addendum to the introduction has been removed.
II Principles of ICH GCP (previously ICH E6(R2) section 2)
The introduction to the principles emphasises the importance of clinical trials for new and existing medicines for answering questions in healthcare and drug development and that trials that have inadequate design or poorly conducted may provide unreliable evidence, waste resources and are unethical.
It sets out that the aim of the principles of GCP are designed to provide a flexible framework for trial conduct, and alongside ICH E8, it espouses that a thoughtful evaluation of an individual clinical trial’s characteristics is required to ensure its quality. The introduction states that the principles are intended to be adaptable to innovative trial designs, technological developments, and a variety of data sources and these may assist in diversifying trial populations by wider participation. The input of patient and health care providers into trial design to facilitate trial feasibility and meaningful outcomes is encouraged, and that trials should avoid unnecessary complexity.
Focus is on protection of the rights, safety and well-being of trial participants and the reliability of the trial results by paying attention to risk mitigation and processes relating to those factors that impact on this and to do so is implementing a proportionate, quality by design and risk-based approach. This is a key message of the guidance, which builds on the addendum, and the aim is to consider the guidance for a particular trial and implement it proportionately.
So on to the numbered principles themselves. These are important to those sponsoring and conducting trials in the UK because they will be included in the updated UK legislation, so if there is one part of the guidance that I suggest that you review, this would be it.
The UK Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended) are being updated following United Kingdom’s departure from the European Union (EU) and the changes to the legislation have recently been subject to public consultation. The Government response to the consultation confirms that the numbered principles of GCP, as set out in ICH E6(R3) section II will replace the current GCP principles in the UK legislation that are based on outdated EU legislation (2001/20/EC “Clinical Trial Directive” [principles 10 to 14 in UK SI 2004/1031 Schedule 1 part 2] and 2005/28/EC “GCP Directive” [principles 1 to 9 in UK SI 2004/1031 schedule 1 part 2]). It is important to note that in the original UK SI 2004/1031 Schedule 1 part 2, the first 13 principles were based on ICH E6(R1) Note for Guideline on GCP adopted as CPMP/ICH/135/95 by the European Medicines Agency in July 2002 and the last 3 principles were based upon Clinical Trial Directive 2001/20/EC Article 3.
I think it is important that you see the relationships between the GCP principles in the original and current UK Legislation, the current ICH E6(R2) principles and the updated and expanded principles in ICH E6(R3) and the following table is presented to help you with this.
UK Statutory Instrument 2004/1031
(Schedule 1, Part 2) (original legislation) |
UK Statutory Instrument 2004/1031 Updated by UK Statutory Instrument 2006/1928 (Schedule 1, Part 2) (current legislation) | ICH E6(R2) Note for Guideline on Good Clinical Practice (CPMP/ICH/135/95) (current guideline) | ICH E6(R3) Note for Guideline on Good Clinical Practice (new draft guideline) |
1. Clinical trials shall be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with good clinical practice and the requirements of these Regulations. | 6. Clinical trials shall be conducted in accordance with the principles of the Declaration of Helsinki. | 2.1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). | Section 1 |
2. Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks. | 10. Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks.
|
2.2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
|
Section 1.3 |
3. The rights, safety, and well-being of the trial subjects are the most important considerations and shall prevail over interests of science and society. | 1. The rights, safety and well-being of the trial subjects shall prevail over the interests of science and society. | 2.3. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. | Section 1.3 |
4. The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the clinical trial. | 5. The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial. | 2.4. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. | Section 4.1 |
5. Clinical trials shall be scientifically sound, and described in a clear, detailed protocol. | 3. Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects. | 2.5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. | Section 4.2, 8 |
6. A trial shall be conducted in compliance with the protocol that has a favourable opinion from an ethics committee. | [NOTE: This is a specific requirement of the legislation.] | 2.6. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion. | Section 3.1 |
7. The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist. | 11. The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist. | 2.7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. | Section 1.5 |
8. Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his or her respective task(s). | 2. Each individual involved in conducting a trial shall be qualified by education, training and experience to perform his or her tasks. | 2.8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). | Section 5.1 |
9. Subject to the other provisions of this Schedule relating to consent, freely given informed consent shall be obtained from every subject prior to clinical trial participation. | [NOTE: This is a specific requirement of the legislation.] | 2.9. Freely given informed consent should be obtained from every subject prior to clinical trial participation | Section 2.1 |
10. All clinical trial information shall be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
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9. All clinical information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected. | 2.10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
ADDENDUM This principle applies to all records referenced in this guideline, irrespective of the type of media used. |
Section 9.5 |
11. The confidentiality of records that could identify subjects shall be protected, respecting the privacy and confidentiality rules in accordance with the requirements of the Data Protection Act 1998 and the law relating to confidentiality. | [See 13 below] | 2.11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
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Section 1.6 |
12. Investigational medicinal products used in the trial shall be—
(a)manufactured or imported, and handled and stored, in accordance with the principles and guidelines of good manufacturing practice, and (b)used in accordance with the approved protocol. |
[NOTE: This is a specific requirement of the legislation.] | 2.12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.
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Section 11 |
13. Systems with procedures that assure the quality of every aspect of the trial shall be implemented.
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4. The necessary procedures to secure the quality of every aspect of the trial shall be complied with.
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2.13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
ADDENDUM Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be the focus of such systems. |
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14. A trial shall be initiated only if an ethics committee and the licensing authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored. | 12. A trial shall be initiated only if an ethics committee and the licensing authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored. | Section 3 (partly for ethics committee) | |
15. The rights of each subject to physical and mental integrity, to privacy and to the protection of the data concerning him in accordance with the Data Protection Act 1998 are safeguarded. | 13. The rights of each subject to physical and mental integrity, to privacy and to the protection of the data concerning him in accordance with the Data Protection Act 1998 are safeguarded. | Section 1.6 | |
16. Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to the clinical trial. | 14. Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to the clinical trial | ||
8. The investigator and sponsor shall consider all relevant guidance with respect to commencing and conducting a clinical trial. | |||
7. The protocol shall provide for the definition of inclusion and exclusion of subjects participating in a clinical trial, monitoring and publication policy. |
The principles are updated in ICH GCP(R3) to encourage a thoughtful approach to the planning and conduct of a trial and address its unique aspects in relation to evaluating its design characteristics, the nature of the investigational product, the indication, the potential trial population, its setting, and the data being collected in determining how the principles are required to be applied flexibly. The principles also emphasise the importance of innovative trial designs and technologies and that this could lead to more diverse populations. There is encouragement of input from potential participants, for example to assist with feasible data collection with no undue burden on participants. The principles propose evaluating risks to identified quality factors that could impact on patient safety, rights and well-being and the reliability of the trial results and implement mitigation strategies to support the conduct of the trial efficiently, proportionately and avoiding unnecessary complexities.
The GCP principles in ICH E6(R3) have been significantly expanded but incorporate most of the current principles with little or no change. Four of the current principles (2.1, 2.2, 2.3 and 2.7) are encompassed in new principle 1. This principle also includes a new expectation for periodic review of safety information, to aim to include trial participants that are likely to use the medicinal product in future clinical practice to allow generalisation and that the delivery of medical care and medical decisions concerning participants can be undertaken by other qualified health professionals than physicians and dentists. I anticipate the latter point will be a welcome change so that trials can reflect normal clinical practice. ICH E6(R2) principle 2.9 relating to informed consent had been usefully expanded to include the legally acceptable representative, that the process reflects the situation of the trial (for example emergency research) and ensuring patients can make an informed decision by the provision of the information in a way that is concise, understandable, and using new technology when appropriate. This would facilitate innovative trial design including those trials that wish to use remote consent.
Periodic or new information review during the trial conduct is advocated in the ICH E6(R3) principles in relation to patient safety (1.2), by the IEC (3.2), to determine whether the trial needs modification (4.3) and for risk assessment of quality factors (7.3). The current principle 2.8 has been expanded to include the types of expertise that is required for designing and conducting a trial. It is noted that the guidance later encourages a proportionate approach to training, with that required related to whether the activities are within the individual’s normal clinical practice or a new trial-specific activity.
It should be emphasised that current principle 2.13 has not been directly included in ICH E6(R3) and I suspect that this will be welcomed as this was often subject to over interpretation and lack of proportionally. As a result, a whole new set of principles are set out in section 6, 7 and 9. These concern the identification of critical to qualify factors and conducting a trial of sufficient quality to enable good decision making. There is emphasis on those areas that are beyond standard medical care. There is focus that processes, data capture and management are directly related to the trial objectives, operationally feasible, avoid unnecessary complexity and are proportionate to protection of participants’ safety, rights and well-being and the reliability of the trial results. I suggest that this really builds into the principles a proportionate approach and allows the streamlining of trials to fit in with existing clinical practice.
The current principle 2.10 has been revised in ICH E6(R3) 9.5 and 9.6 to include efficient and well controlled processes for management of records for ensure data integrity and traceability and that records should be retained and available to regulatory authorities. There is a new principle in ICH E6(R3) to encourage transparency by public registration of trials and publishing of trial results (9.7) which I think should be welcomed. A further new principle in section 10 of ICH E6(R3) deals with ensuring sponsors and investigators retain responsibility for activities when delegated, that such delegation should be clearly documented, and the activity overseen by the sponsor or investigator. Finally, the current principle 2.12 relating to manufacture of investigational product to GMP has been expanded to include, ensuring its quality during the trial, used in accordance with the protocol and considers randomisation and blinding and labelling in ICH E6(R3) section 11.
It should be noted that several principles (7, 8, 12 and 14) in the current UK Statutory Instrument are not included in ICH E6(R2) or ICH E6(R3). Of these, principles 8 and 14 will be retained in the updated UK legislation.
Overall, I suggest that the new principles are a significant improvement, being more comprehensive, but at the same time encouraging a proportional approach to how they are implemented and facilitating innovative and efficient trials. It will be interesting to hear your views on them.
III Annex 1
1 IRB/IEC (previously ICH E6(R2) section 3)
There have been a small number of changes to the IRB/IEC section, although some are quite significant.
There has been a restructure to the information to be reviewed to form a bulleted list and to expand this to cover situations using innovative methods, such as electronic informed consent, by adding a description of the consent process to be included and addressing the media of how such information is to be provided. There has also been an expansion of the investigational product information from just the Investigator’s Brochure. Text concerning non-therapeutic trials has been removed.
The guidance has new text to address trials where prior consent is not possible, for example for emergency research and to include the IRB/IEC review of assent materials for trial participants who are minors. There has been a change to state that reasonable travel and lodging expenses being reimbursed to trial participants is not considered coercive. The text has been amended such that there should be a member of the reviewing IRB/IEC who is not involved in “medical sciences”, rather than the existing broader “scientific area”, which I hope you would agree makes sense as the exclusion of all scientists appears unnecessarily restrictive.
There have been some adjustments to requirements to state to be in line with “applicable regulatory requirements” for example, in relation to SUSAR reporting and removal of the 3-year record retention requirement. The language has been simplified relating to deviating from the protocol without approval and text introduced that addresses sponsors communicating with the IRB/IEC, which is possible in some ICH regions, for example in the UK the sponsor makes a single application jointly to the MHRA and the Research Ethics Committee (REC).
2 Investigator (previously ICH E6(R2) section 4)
There have been extensive changes to the investigator section, with significant deletions, additions and restructuring, so I’ve got quite a bit to cover in this section.
There has been removal of text relating to provision of CVs to sponsors. New text has been included relating to the role of the sponsor for service providers of investigator activities and ensuring agreements are in place, and that the investigator retains the decision to allow for their use and the overall responsibility for the work conducted on their behalf. There is some new text that introduces proportionate approaches in relation to training of staff for delegated trial activities that go beyond their usual training and experience and that recording the delegation of individuals whose trial activities are performed in accordance with routine clinical care may not be necessary. I think this could encourage investigators and sponsors that trial specific training and delegation log completion can be risked-based and reduce the burden of documentation.
The restriction of qualified physicians and dentists to be solely responsible for trial related medical care and decisions has been eased to allow other qualified healthcare professionals in line with the normal clinical activities and local regulatory requirements to be involved and I anticipate that this will be welcomed. There has been a strengthening of text relating to informing the participant’s GP of their trial participation, when the participant consents to this, it is no longer just a recommendation to occur.
SAE reporting text has been simplified, for example, removing the text on code numbers and to essentially report SAEs to the sponsor immediately or to follow any differences to this requirement that are specified in the protocol. This therefore supports the protocol having a proportionate approach to SAE reporting. The text on reporting SUSARs to the regulatory authority and IRB/IEC has been removed, I suggest this was removed as this is a sponsor responsibility.
Communication with the IRB/IEC has had some new text added relating to the provision of updated participation information to the IRB/IEC. It also confirms that the sponsor may also make submissions to the IRB/IEC. Frequency of progress report submission has been amended to refer to local regulatory requirements.
Text has been simplified and clarified relating to deviations from the protocol by focussing on prevention of immediate hazards to participants. New text has been added that I think is acknowledging that some deviations are not documented by the investigator but instead provided by the sponsor to the investigator for review. Text has also been added that restricts the requirement to now explain only “important” deviations (as per ICH E3) rather than all of them, which I think would reduce expectations placed on investigators for excessive documentation. There is a new expectation for appropriate measures to be implemented to prevent recurrence of deviations, when applicable.
For the investigator section relating to informed consent of trial participants, there have been numerous changes made. The first is inclusion of additional text to emphasise the importance of the information being sufficiently clear to facilitate the participants’ understanding and that various approaches, including new technology could be used, including remote aspects and electronic signatures. There is new text that addresses considerations of providing new information to participants and whether re-consent would always be necessary, as this could be dependent upon the stage of the trial. I suspect that this should help investigators because it would mean that re-consenting would not be automatically undertaken, as is often seen at present, which I suggest would reduce burden on investigators. New additions address that time for consideration of participation may be reduced where justified (e.g., emergency situations). Additional text means that investigators are asked to ensure that participants are informed how their data will be handled, including if they withdraw from the trial prematurely and that the participants should have access to the trial results and the treatment they have received if they wish to do so. I think this latter point is a welcome addition that trial participants can find out the results of the research they have been involved in. Text relating to non-therapeutic trials has been removed.
New text has been added to address the assent of minors and ensuring consent information provided is compatible with their understanding, and for adults with impaired decision making. For minors, requirements have been added that re-consent may be needed as the participant gets older. Finally, a statement that in exceptional circumstances, for example public health emergencies, other methods of consent may be appropriate in accordance with local regulatory and IRB/IEC requirements has been added.
Text concerning trial participant withdrawal has been expanded. I believe the aim is to reduce dropouts from clinical trials as this can severely impact on the trial quality and reliability of the results. New text added covers discussing reasons for withdrawal with the participant and determining if there would be some way that would address a participant concern. The guidance now considers different types of withdrawal, and that there should be follow up measures to avoid data loss. Finally, there is new text on informing participants of the trials results and details of the treatment that they received when they participated in the trial.
There have been updates made to ensure that decentralised trials can be accommodated, so there are some minor amendments relating to accountability and some new text added that the sponsor may facilitate this. There is also text added that alternative approaches to accountability may be used for authorised medicinal products, which, for example, could allow the use of existing processes for documentation if this is considered sufficient for the trial and reliability of the results, which facilitates the embedding trials in current clinical practice.
There has been an update to include a requirement that unblinding processes for use in an emergency by the investigator are in place at the start of the trial and not subject to any delays or hindrance, which I consider relates to ensuring the investigator does not have to wait for authorisation, for example, from the sponsor.
There are substantial changes relating the records/data/computerised systems, with new text that:
It should be noted text relating to audit trail, data corrections and sponsor making changes to investigator data and requirement for guidance to investigators for data changes and investigator authorisation has been removed because it is now covered elsewhere in the guidance.
There are broader expectations set out for computerised systems and this references the new Data Governance section. I think it is important to note that the updates distinguish between computerised systems that are deployed by the investigator/institution and used in normal clinical practice (this could be for example, the electronic health record) and those deployed and used specifically for clinical trials (this could be for example an electronic investigator site file) as these would have different expectations in relation to validation responsibilities.
For essential records there has been some movement of texts within the guidance, e.g., investigator control of records has been moved here from section 8.1 addendum. There is new text requiring the sponsor to be notified if the investigator is no longer at the institution or the institution has a new individual responsible for the investigator records. Retention times of the essential records has been considerably simplified to remove the text relating to marketing authorisations and discontinuations of the development of the investigational product and instead, it states the applicable regulatory requirements or as per the instruction from the sponsor that they are no longer needed.
Finally, text has been expanded to include consideration for the co-ordinating investigator to sign the clinical trial report.
3 Sponsor (previously ICH E6(R2) section 5)
The sponsor section has had substantial changes and reorganisation, so this section is not going to be a quick read.
In the Trial Design section, reference to other sections and ICH guidance has been removed and most of the content is relocated existing text (e.g., text relating to information about the investigational product(s) in relation to safety and efficacy data is available when planning trials with additional text relating to real-world data), but there is new text on considering input from stakeholders including patients has been added.
In the sections Resources, Allocation of Activities, the significant change is recognition that activities (i.e., duties and functions of the sponsor) can be delegated, but not responsibility and this has led to amendment of the title. There has been new text inserted that the sponsor ensures sufficient resources to conduct the trial.
A new section on Qualification and Training, contains a statement for the sponsor to utilise appropriately qualified individuals, as slighter shorter text than exists currently in the Trial Management, Data Handling and Record Keeping section and the requirement for someone with medical expertise has been retained, but the outside consultants part has been deleted. The text on financing is unchanged.
A new section on Agreements brings together aspects of relationships between parties involved in clinical trial and delegating of activities. The section on Contract Research Organisations (CRO) has been removed, instead, the requirements are now contained in this section. It is important to note that the language now uses the term “Service Provider”, of which CRO is an example. I think this is appropriate as this reflects the increased use of small organisations providing specific services/trial activities to sponsors, for example, those relating to electronic systems. The sponsor’s responsibility for delegated activities has been expanded to include protection of the rights, well-being and safety of trial participants and there is a requirement on service providers to report to the sponsor any incident that could impact this and the reliability of the trial results.
There is new text relating to the requirement for sponsors to assess service providers including obtaining relevant information for this and for their ongoing oversight. The sponsor is also required to provide the protocol and other documents to the service provider that are required for them to undertake the delegated activities. There is new text that the sponsor should provide to the investigator, the information concerning service providers that the sponsor has identified, where the service provider is undertaking investigator activities. This I suggest is to ensure that the investigator is appropriately informed and content about the service provider to which their activities are being delegated.
New text states that service providers are required to comply with the applicable aspects of GCP to the activities they are undertaking but acknowledging that these could be met by the service provider’s existing quality system processes. I suggest that this could be for example for computer systems validation, even if procedures had not developed specifically for GCP compliance, but there could still be GCP gaps, for example, if the service provider makes changes to clinical data or retains essential records. This text replaces the current text that stated that reference to sponsor includes CROs and their trial related duties.
There is text now that states agreements should be documented, rather than in writing as in the current guideline, a new requirement that added that this should be before initiating the activities and that agreements should be updated to reflect any significant change in delegated activities. Current text moved here is that responsibilities of co-ordinating investigators and other investigators needs to be documented prior to starting the trial. It should be noted that the signing of the protocol or alternative document to confirm agreement has been removed.
Finally in this section, there is new text that sets out the requirements for documenting responsibilities if more than one sponsor is involved in the trial. This should be welcomed as it routinely occurs in practice in the UK.
No significant changes have been made to existing text in Investigator Selection, but it does include text relocated from the deleted multicentre trials section.
Two current sections have been combined in a new section Communication with IRB/IEC and Regulatory Authority(ies). The term “in accordance with regulatory requirements” has been used and “before initiating the trial” has been removed. Text has been amended to reflect that the sponsor may submit the trial for IRB/IEC approval as the current text is based around the investigator doing this. Overall, the text has been made more succinct whilst keeping essentially the same requirements for the sponsor obtaining approvals and there has been removal of reference to some specific documents (e.g., protocol, informed consent documents and other information provided to the participants etc.)
There is a new section on Sponsor Oversight and most of the content is new. Whilst this retains text relating to independent data monitoring committees moved from the old Trial Management, Data Handling and Record Keeping section, with additional text concerning expertise and conflict of interests, there is new text concerning committees that are involved with the adjudication of endpoints. New text requires sponsors to ensure the trial design, conduct and processes ensure reliable trial results and protection of participants safety. That the trial processes follow the trial protocol, ethical standards, and applicable regulatory requirements. That the sponsor should ensure criteria are in place for defining deviations as “important” and all decisions are appropriately assessed for impact on participants rights, safety and well-being and the reliability of the trial results.
There is a requirement that the oversight measures are fit for purpose and related to risks associated with trial with the focus on selection and oversight of investigators and service providers and appropriated quality assurance and quality control processes for their activities. It also requires the sponsor to ensure appropriate escalation and follow up of issues identified in a timely manner. I think this is a useful additional text that reminds sponsors that whilst activities can be delegated, responsibility cannot, therefore they need to oversee the conduct of the trial.
In the Quality Management section, the current addendum text has been essentially retained, but has had some restructuring, so that it appears as an introductory line to the whole sponsor section encouraging risk-proportionate approaches, is part of the Trial Design section and finally in the introductory text to the Quality Management section. There has been an alignment with the updated ICH E8. The aim remains for sponsors to focus quality management on those processes and data that impact on the trial participants’ rights, safety and well-being and the reliability of the trial results and is therefore proportionate and risk based.
Risk identification has been updated to reflect the use of critical to quality factors and removed the system and trial level segregation, however, risk evaluation remains the same. Risk control has been revised, the main change being the removal of the phrase “quality tolerance limits”, instead just referring to acceptable ranges. Risk communication has had the sentence relating to document quality management activities removed, Risk Review remains the same and “quality tolerance limits” has been removed from Risk Reporting.
It is now relatively common to see sponsors conducting and documenting risk assessment of a trial, so it is welcome that the guideline expands and continues to encourage risk-based approaches. The assessment is a key feature of adopting a proportionate approach to management of the trial, the processes applied, and how compliance with GCP will be achieved. Often seen, however, is a lack of comprehensive documented risk review, for example, failing to reassess when there is change, for example, a protocol amendment, and make any necessary changes the trial’s quality management processes.
For Quality Assurance and Quality Control section, there has been what I consider to be an appropriate reorganisation of this section to bring in other relevant sections under this heading, i.e., Audit and Monitoring. Current text that relates to agreements has been moved to a new section Agreements and the section discussing stages of data handling to the Data and Records section.
Most of the text is unchanged in the Audit section, but some new significant text to state that the audits should be proportionate to the risks associated with the trial and that the audit should also assess that processes in place to manage and conduct the trial are effective as well as compliant. The auditor no longer needs to be independent of the systems, just the clinical trial and the text requirement for the auditor’s qualifications to be documented has been removed.
The Monitoring section has undergone extensive revision and reorganisation. The changes build on those added by the Addendum and EWG has taken the opportunity to fully integrate the Addendum as part of a restructure of the entire section and to modernise it further. The current sections on Purpose and the Extent and Nature of Monitoring have been replaced with an introduction, a new section added on Investigator Site Monitoring, including that this could be remote, a new section added on Centralised Monitoring, and the Monitoring Plan section brought forward from its current position. The current section on monitor selection and qualifications has been deleted.
The revised text removes the text that central monitoring could be used in exceptional circumstances and instead describes it as an important component of monitoring activities that are part of a risk-based approach. The Purpose of monitoring has been replaced with aims in the introduction and the accuracy of data is replaced with reliability of trial results with the text on compliance now covered in the introduction to the section. There is no longer a statement in the guideline that, “in general there is a need for site monitoring”, which is a significant change. The introduction emphasises that monitoring activities cannot be performed by those involved in the clinical conduct of the trial. The description of site monitoring includes amendment of activities and frequency dependent on knowledge gains, allows remote activities including, significantly, remote access to the source records and other electronic systems. I suggest that these have been introduced because of the experience with monitoring trials during the pandemic. Introductory text emphasises the need for sponsor staff to adhere to data protection and confidentiality requirements, including those of the institutions that are conducting the trial. The description of centralised monitoring acknowledges the role of sponsor staff other than the monitor and its role in supporting site monitoring activities and includes aspects of the current addendum text, however, some of these have been relocated to the new section on Monitoring Clinical Trial Data.
The monitoring plan has been updated to add that monitoring should be tailored to the identified risks to the reliability of the results, that it should ensure oversight whilst considering site capabilities and potential burden and that is should also address key data and processes performed outside of the investigator site. This latter part is also identified in earlier in the quality control section with new text referring to centralised or on-site quality control of such sites.
The current section on Monitor’s Responsibilities has been removed and instead it is now Monitoring Activities, as these are not restricted to role of the monitor, for example, staff involved in central monitoring activities would be involved. I think this is sensible change to reflect modern monitoring practices. New sections of activities are added, these are Communication with Parties Conducting the Trial, Investigator Site Selection, Initiation, Management & Close Out, Monitoring of Investigational Product Management and Monitoring of Clinical Trial Data. Current sections on Monitoring Procedures and Monitoring Reports have been retained but have been modified. Monitoring Procedures has been updated to be more general, no longer referring just to monitors and specifically mentioning the monitoring plan and replacing SOPs with applicable monitoring procedures. Inclusion of following the monitoring plan is a useful addition because I have seen trials where a suitable risk-based monitoring plan is developed, but then not fully implemented. The section on Monitoring Report has changed significantly to become more generalised to cover both on-site and centralised monitoring. It has been simplified, for example referring to sponsor procedures rather than the detail on content and documentation of review but does generally include the current requirements.
Review of the Monitoring Activities section reveals that many of the current requirements have been retained. Additions made include a requirement to focus remediation efforts on important deviations and actions taken in relation to deviations, errors and omissions should be proportionate to their importance. New requirements for the monitoring to clarify the protocol source records and location of these, verifying that blinding is maintained and review and reporting of participant retention rates have been added. Some additional text has been added concerning the monitoring of investigational products. These are confirming products are used within shelf life, used in accordance with randomisation, that instructions on the investigational products are also communicated to the investigator and their staff and other relevant individuals and parties. New text states that some of these considerations may not be applicable to products that are available on the market. This, I suggest, is related to the fact that clinical trials may use authorised products in existing systems for routine clinical practice, therefore expectations and subsequent monitoring requirements would need to be adapted.
For the Monitoring of Clinical Trial Data section there is new text relating to selection of data for verification based on samples supported by data analytics, which relates to the current text related to statistical controlled sampling which has been deleted and that sample size of this may need to be adjusted based on an observed insufficient data quality. There is also new text that the verification of data should be of those identified as critical in the monitoring plan. I would suggest that this is a clear encouragement of proportional data checking. There is current text that has not been included, such as, checks for unauthorised delegation of activities, verifying dose modifications are documented, that concomitant medications and intercurrent illnesses are documented in the Case Report Form (CRF), that missed visits, missed tests, withdrawals and dropouts are reported in the CRF; however, I would suggest that these would be covered under the more general aspects of monitoring clinical trial data.
There have been some minor modifications in the Non Compliance section; that actions should be appropriate and proportionate by the sponsor to secure compliance, that issues that could significantly impact participant’s rights, safety and well-being or the reliability of trial results require reporting to the Regulatory Authority(ies) and IRB/IEC as appropriate and additional text that non-compliance that persists despite efforts at remediation would cause the sponsor to terminate the investigator/institution’s participation in the trial.
Current sections on Safety Information and Adverse Drug Reaction Reporting have seen significant additions that are required to be noted and are contained in this new section of Safety Assessment and Reporting.
New text has been added to state that the Investigator’s Brochure or basic product information forms the basis of the safety assessment, i.e., for assessing expectedness, and that this would contain the Reference Safety Information and refers to ICH E2F. New text emphasises that the sponsor should periodically review the emerging safety information and update the Investigator’s Brochure and any other documents as necessary. The focus of expedited reporting of SUSAR cases is now for the awareness of the Regulatory Authority(ies), and that reporting of such cases to IRB/IEC and investigators may be subject to different expectations; for example, based on urgency and the use of aggregate information rather than individual case reports. Additional text states that alternative arrangements for safety reporting could be implemented and agreed prospectively by Regulatory Authorities when described in the trial protocol and refers to ICH E19. I suggest that this clearly encourages a risk-based approach to safety reporting when this is considered appropriate by the sponsor and the Regulatory Authority(ies).
New text addresses the need for reporting of urgent safety issues without delay in accordance with regulatory requirements and there are new expectations concerning the actions to take to manage immediate hazards to trial participants, in terms of remedial actions and necessary protocol amendments.
There appears to be no significant changes in the Insurance/Indemnification/Compensation to Participants and Investigators.
For the section Information on Investigational Product(s), additional text has been added that basic product information can be identified for authorised medicinal products and the text has been changed that the sponsor should ensure that an Investigator’s Brochure is developed and updated. This slight change would cover situations where the sponsor may not be the manufacturer of the investigational drug and therefore not producing the Investigator’s Brochure themselves.
Current text under Manufacturing, Packaging, Labelling and Coding of investigational products has had no significant changes apart from that about blinding the investigational product. There have been some further additions that strengthens the control of blinding and prevention of additional unnecessary unblinding of other participants if the blind is broken for emergency or regulatory reporting purposes.
For Supplying and Handling Investigational Products, current text has been retained with the addition of supply directly to trial participants and that instructions should be available for trial participants (which would potentially occur in decentralised trials). There has been removal of the text relating to obtaining required documentation in relation to approvals. Further changes made include new text in timely delivery for supply to trial participants and to ensure no interruptions and continuation of treatment, new text relating to alternative disposition of investigational products and for authorised medicinal products, new text has been added that samples of these do not need to be retained. These changes have clearly been made in relation to trials involving authorised medicinal products, for which I suggest would mean that unmodified authorised medicinal products could be released for normal clinical practice after the trial as part of alternative disposition and acknowledging there is no need for retention of samples of such an investigational product.
The section on Data Handling and has had a change of focus to reliability of results, rather than the data and additional text that the sponsor should focus their activities on critical data and relevant metadata. The current requirements on data handling and computerised systems have been significantly expanded and incorporated into this section and/or the new Data Governance section. This is a major update with no loss of current requirements. For example, retained requirements include the principle of risk-based validation, that SOPs are in place, audit trail, security, list of individuals authorised to make data changes, back up, safeguarding blinding, data integrity, traceability of data transformation and the use of unambiguous identification code. This section also contains current text concerning investigator access to data and the sponsor not having exclusive control of data.
It is worth paying particular attention to the significant additions made in this area. These would have been necessary to update the guidance to cover the use of new technologies and to addressing identified gaps the current guidance. These are:
Like the Investigator section, retention times of the essential records has been considerably simplified to remove the text relating to marketing authorisations and discontinuations of the development of the investigational product and instead, it states simply the applicable regulatory requirements. I suggest that it will be important that there is clarity in ICH regions what the local regulatory requirements for retention times are. There has been an update to include informing service providers where appropriate that trial records are no longer needed, acknowledging that these may hold essential records on behalf of the sponsor.
There are no significant changes in the Record Access section.
Text on premature termination or suspension of a trial appears unchanged in the Reports section. There are new requirements added for clinical trial/study reports, with text added that they should be prepared following an interim analysis, that investigators should be provided with a summary of results and consideration should be given to providing details of the treatment taken by trial participants and that it may be provided to participants along with details of overall outcome of the trial, in a way that is in suitable for a lay person and non-promotional.
4 Data Governance (new section)
This is an entirely new section that is relevant to the sponsor and the investigator and therefore avoids duplication of expectations in the sponsor and investigator responsibilities section. With extensive use of computerised systems in clinical trials, that the current addendum partly addressed, this new section provides a higher level guidance that reflects the more detailed guidance that has been published in this area by Regulatory Authorities such as EMA, FDA and the MHRA’s Data Integrity Guidance.
The start of the section again focuses on the quality of the information in the trial being sufficient to provide reliable results and that all processes and systems for the critical data in data life cycle should implemented proportionately to risks to this and to the safety of participants.
There is a much-expanded section on the maintenance of the blinding of treatment allocation and assessment of inadvertent unblinding, which could affect the reliability of the trial results, that it should be part of risk assessment and ensuring processes in place to protect the blinding. This, I suggest, is an important addition because breaches of the blinding, both minor and extensive, have been observed to occur frequently in clinical trials.
The section is based on the data life cycle and includes new and expanded text on data capture, data verification, metadata, data corrections, data transfers and finalisation of datasets prior to analysis. Some significant text that I noted and draw to your attention:
The section on computerised systems explains the importance of the system in terms of whether it is specifically for the purposes of a clinical trial and who has the responsibility for it as this sets the expectations for the system. Some of the expectations are expanded current text, e.g., requirement for documented procedures and back up. Some significant text that I noted and draw to your attention:
For validation of computerised systems, again expanding current text, some significant text I noted and draw to your attention:
Glossary (previously ICH E6(R2) section 1)
There have been changes to text under most terms of the glossary, many of which were relatively minor. Some terms have been deleted, these were “amendment to the protocol”, “Co-ordinating committee”, “Opinion”, “Approval” and “Wellbeing (of trial subjects). Some term titles and content have had minor changes made, for example removing “(product)” from Comparator or “Study” from “Clinical Trial/Study” and some new terms have been added. Some of these changes made are quite significant.
The change to “Trial participant” rather than “Trial subject”, which was known to be thought of in a derogative way by some of those taking part in trials has resulted in many changes throughout the guidance.
Significant changes are the definitions of Documentation and Essential Documents being combined in a new term of “Essential Records”, “Source data” and “Source Documents” being combined and revised in a new term of “Source Records”. This is to reflect changes in the guidance regarding the broadening of trial information to consist of documents and data and that source data is now contained in numerous computerised systems. The data governance section and addressing new technology in data capture etc. merited the inclusion of new terms “Data Acquisition Tool”, “Metadata” and “Signature”.
Changes to the definitions relating to Adverse Events have all been grouped together and have provided greater clarity, in particular regarding the relationship to the investigational product to define adverse drug reactions. Additionally, the Reference Safety Information has been required to be defined due to its inclusion in the Investigator’s Brochure appendix.
The expansion of organisations being delegated trial related duties and functions of the sponsor and investigator, led to the introduction a new term of “Service Provider” to cover all those undertaking such activities and move away from use of CRO only. Finally, Assent has also been defined to reflect the changes made in the IRB/IEC section.
Appendix A: Investigator’s Brochure (previously ICH E6(R2) section 7)
There are no extensive changes to this section, but there is some minor restructuring at the start. Whilst there is clarification that the sponsor is responsible for ensuring an appropriate Investigator’s Brochure is produced, the key change is inclusion of text concerning the reference safety information as the list of expected adverse drug reactions used for determination of whether a serious adverse reaction is a suspected unexpected serious adverse reaction that requires expedited reporting. The Appendix to the current section has been deleted and it did offer little additional value beyond the information in the guidance, with some minor updates to address gaps due to its removal.
Appendix B: Protocol (previously ICH E6(R2) section 6)
Text has been added that encourages use of stakeholders in protocol development where appropriate and to develop a concise and operationally feasible protocol, that reduces unnecessary complexity, but mitigates or eliminates important risks to the rights, safety, and wellbeing of trial participants and reliability of the results. Revisions encourage adaptability in the protocol to reduce deviations and amendments.
Some administrative information requirements have been removed, some example trial designs, estimands and Bayesian design elements have been added and there has been clarification that the protocol should contain information on processes for participants withdrawing consent and discontinuing treatment and the use of their data.
The changes made included an expectation that the protocol contains information about the use of data monitoring committees for efficacy and safety assessments and that the protocol should include a description of identified quality factors and associated risks in the trial, monitoring processes and handling of non- compliance.
There also an expectation from changes made that the protocol contains a reference to the specification of the data to be collected and how, including identification of source data in data collection tools rather than just the CRF and that the protocol includes a statement about retention of the trial records.
Appendix C: Essential Records (previously ICH E6(R2) section 8)
The guidance has moved from using the term “documents” to more generic term “records” to broaden that the information required to assess the trial conduct also includes data. This has led to revision of glossary terms relating to documents and data. Current requirements on timeliness and organisation of filing, completeness of records, retention, access and certified copies has been retained. There has been clarification that the essential records and therefore the content of the TMF would be based upon the design and proportional approach applied to the trial.
The changes made, I suggest, are aimed to discourage the use of the tabulations as a checklist of which records are required, when and where they are located. This is a significant change to the current text section 8 as there is now a list of records that are always expected to be present as essential records and those that should they be produced, would also be essential. The “purpose” and “location” columns in current table have been removed and the new tables have amalgamated the “before”, “during” and “after” which led to unnecessary duplication. The opportunity was clearly taken to review the list of records and add some that were frequently produced and retained and used for compliance assessment.
There has been, in my view, an encouragement of a thoughtful approach by providing more guidance on what makes a record essential, using some of the information from the current “purpose” column. I suggest that this doesn’t mean a new requirement for procedures and new processes for individual record assessment, for example, many existing indices used by organisation for the TMF content have already effectively done this. Instead, it can used as a guide as to why a particular record might be essential and for training individuals who are involved in generating such records.
The revised guidance also addresses the requirement that some essential records are not trial specific and to avoid duplication of such records across TMFs. The updates have also addressed the use of new technology by referring to “access” of records between parties involved in the trial, perhaps say via internet portals and eTMFs rather than just “copies” and have clarified the use of service providers and their role in the management of essential records. Finally, the revision has also addressed version control of records.
]]>The E6(R3) overarching principles, Annex 1, Glossary and 3 Appendices will replace the current E6(R2). These are anticipated to reach Step 2 soon and will be available for public consultation.
MHRA became a full member of ICH in May 2022. Whilst feedback on the ICH E6(R3) can be provided via the ICH website, MHRA wishes to consult directly with UK stakeholders to compile and co-ordinate their comments to the EWG. Please monitor the MHRA website for announcement of the consultation.
A MHRA GCP Stakeholder Engagement Meeting is also planned to be held concerning this document during the consultation period. Invitations to current contacts for this existing stakeholder engagement process will be sent out in due course. If your organisation has been part of previous meetings, please ensure that your contact details are up to date by contacting gcpstem@mhra.gov.uk.
]]>I write this blog post just after returning from the 2023 MHRA GMP Symposium in London. It has been more than two years since we held our last event virtually, and over three years since we were face-to-face for the 2019 symposium. What a pleasure it was to once again be meeting with our industry stakeholders, providing them with an opportunity to network with their peers, and sharing updates and knowledge from the MHRA GMP Team. This was also our first hybrid GMP symposium, which allowed us to deliver a focussed one-day in-person event in London, while opening the event to a significant number of additional delegates online. I was honoured to chair the day’s events and have the best seat in the house as the results of so many hours of hard work came together.
The day began with a welcome and introduction from Chris Gray, Head of Compliance Team 2. Chris has taken over leadership of the GMP and GDP teams since the last GMP symposium and expressed her delight at being able to hold this event again. This was followed by a keynote address from James Pound, Deputy Director of Standards and Compliance. James shared an overview of the MHRA’s updated role as a sovereign regulator, enabling innovation through supportive and proportionate regulatory processes. Closer to home, James also provided a brief outline of the ‘Compliance Strategy’ that will define how the Compliance Teams (which include GMP and GDP Teams) will work in the future to support the medicines and blood for transfusion sectors to produce high quality, safe products for patients.
I then shared updates to the GMP Team since the virtual GMP symposium in 2020. I outlined changes within the team and how we are working to fill our current vacancies. I also explained how industry can help us to help them by making full use of our published resources and ensuring that queries they submit are clear, structured, and directed to the appropriate mailboxes for triage and assessment.
Ian Jackson’s session followed, providing an update on the MHRA’s regulatory positioning in 2022 and into the future. It was eye-opening to take stock of all the changes that have occurred since we last held the event. There have been significant updates not only to regulations and guidance, but also in areas such as our partnership working under Mutual Recognition Agreements (MRAs) and through the Pharmaceutical Inspection Co-operation Scheme (PIC/S), the International Coalition of Medicines Regulatory Authorities (ICMRA), and the Australia-Canada-Singapore-Switzerland-United Kingdom (Access) Consortium. Ian shared a range of examples showing how the MHRA is collaborating with various groups, not least in the area of GMP inspection recognition, reliance, and work sharing. Reflecting on this session I felt it provided excellent reference material for delegates, who would be able to make use of the many summaries and links within the presentation to ensure their operations remain up to date with current and impending regulatory expectations.
It was then time for our first refreshment and networking break of the day. This is where our in-person delegates had an advantage over virtual delegates, with an opportunity to discuss what they had heard in the sessions and share experiences, helping to drive forward quality and compliance across the sector. Significant quantities of coffee and pastries helped to fuel these discussions! Our presenters were also on hand at each break to answer follow-up questions from delegates.
Returning to the presentations, our next session was led by Ian Rees and Martine Powell. Their session ‘Enabling Innovation’ took a deep dive into how the MHRA is supporting disruptive changes in the manufacture and delivery of medicines. We had presented at a previous GMP symposium on how Point of Care (PoC) manufacturing was an emerging challenge to how we regulate; with new legislation now progressing that addresses the specific needs of this sector, this was a clear and compelling example of the MHRA fulfilling its brief to be an enabling regulator.
At this point in the day our delegates may have been forgiven for any confusion as the theme tune for ‘The Ewan Me Show’ began to play and our host, Ewan Norton, bound onto the stage thanking his studio audience for their warm welcome after several years away from the limelight. Ewan is well known for his creative approach to presentations and this year he created a TV chat show format, complete with themed props, to interview Chris Jones and Jo Parkin on the Inspection Action Group and the Compliance Monitor programme respectively. It was a fantastic way to share information about these two very important topics.
At lunchtime we provided a series of ‘Lunch and Learn’ videos for delegates to watch while having their lunch, or to review at their leisure later if they preferred to focus on networking opportunities. We shared updates on our work with the blood for transfusion sector, the recent Annex 1 revision, parallel imports, the Defective Medicines Report Centre (DMRC), cannabis-based products for medicinal use (CBPMs) and the British Pharmacopeia (BP). My thanks go to our presenters Callum McLoughlin, Alan Moon, Ghazal Rehman, Himal Makwana, Ewan Norton and Peter Crowley for their excellent presentations.
After lunch we went courageously where no symposium has gone before. Leading a session on root cause analysis, bias, and effective decision making, Chris Gray provided an overview of the various cognitive biases that can catch us out when trying to establish why things have gone wrong. Officer Gray then called to the stage her assistants, Captain Martin Reed and First Officer Jo Parkin of the Starship Compliancewise, resplendent in their space officer uniforms. The Starship Compliancewise was having problems with its neutron imploder, which we learnt was fundamental to the basic life support and navigation systems on board. If any of our delegates had previously read a ‘choose your own adventure’ book, they would have felt at home as they were given the power to decide how the investigation would proceed via our interactive voting technology. Thank you to our delegates who helped Captain Reed and First Officer Parkin navigate around the potential pitfalls of their cognitive biases and conduct a successful investigation.
We then had the first of our two Panel Q&A sessions. I was joined on stage by Chris Gray, Ian Jackson and Jo Parkin, and together we answered a range of questions from the audience related to our earlier presentations.
At the final refreshment and network break of the day, as was the case during the earlier breaks, our delegates had the opportunity to meet with representatives from DMRC, the British Pharmacopeia (and their publisher, TSO), and Pharmaceutical Press (publisher of the Orange and Green Guides). Our GMP and GDP Inspectors were also on hand at our recruitment stand, helping to answer questions from delegates considering an inspector role as their next career step. I make no apology for taking time in my presentation earlier in the day to share what a fantastic opportunity the inspector role is, not just in terms of developing new skills and experience but also making a hugely significant difference to public health.
We returned for our final presentation of the day, ‘Quality System Robustness’ by Shirley Stagg and Julio Benitez. This built on previous symposium sessions in 2017 and 2019 on organisational culture and knowledge management, quality risk management, and control strategies. Through the analogy of putting up and securing a tent, Shirley and Julio outlined the multifaceted nature of an effective quality system, described the elements needed for success, and shared examples of failure indicators. Special thanks go to Shirley’s family whose tent building skills were put to the test in aid of this session!
We ended the day with a second Panel Q&A session; this time I was joined on stage by Alan Moon and Ewan Norton as well as Chris Gray and Ian Jackson. Alan and Ewan expanded on their earlier presentations in response to specific queries, while Chris and Ian fielded more general questions. We then closed the day with Chris’s reflections on the event.
Feedback received, both in person on the day and via email and social media after the event, indicates that we delivered an engaging and thought-provoking agenda. This is thanks to several key groups who were all instrumental in making the event a success:
If you attended, we really hope you found the event to be useful and engaging; if you haven’t already completed your feedback form please do so as soon as you can, so we can make the next event even better. If you couldn’t join us, then please do keep an eye out for our future events; we’d love to see you at the next one!
]]>Delegates were first greeted by Chris Gray, Head of Compliance Team 2, who welcomed everyone and provided an overview of the interactive elements for audiences attending in person and online.
Tanya Giles, GDP Inspector and Head of GDP Team 1, gave an update on the changes within the team. Tanya also presented the new inspection strategy in GDP, which now features licence inspections covering all sites on a licence as opposed to previous our previous inspection strategy which was primarily site-specific. With this holistic approach the intention for inspection periods is to be around 3 to 4 years. Where a licence inspection has been conducted, this will be reflected in the text of the corresponding GDP certificate, which will state compliance with GDP across all sites approved on the licence. Tanya also reminded delegates that short-notice and unannounced inspections remain part of our risk-based approach.
Peter Brown, Expert GDP Inspector, and Cheryl Blake, Lead Senior GDP Inspector, jointly presented the MHRA Regulatory positioning since the last GMDP symposium in 2020. Peter talked about changes following the UK’s departure from the EU. He focused on the changes to supply chains of medicines to Northern Ireland. Peter also discussed the current positioning regarding the Falsified Medicines Directive. He further focused on the MHRA’s international partnering. Cheryl then discussed border formalities pertaining to goods flowing through the UK and Crown Dependencies. Cheryl also provided further insight on expectations for exporting medicines and compliance with the export ban list. Cheryl updated delegates on the extension of the validity of GDP Certificates until the end of 2023. Cheryl introduced the ‘Single Trade Window’ project, which is still in its early stages and involves collaboration between different Government departments. Delegates also were provided an update on the Covid Flexibilities, which were introduced in March 2020. Lastly, Cheryl presented the concept of the Compliance Monitor which is currently being piloted across GMDP cases at Inspection Action Group.
Andy Morling, Enforcement Deputy Director, introduced the problem-oriented approach to medicrime. He also provided an insight on the strategy of the Enforcement Unit within the MHRA. Terry Madigan, Senior GDP Inspector, presented an overview of referral data pertaining to theft and loss of medicines in 2022. Terry shared several case studies pertaining to reports received by the Criminal Enforcement Unit. Terry discussed some of the methodologies used by criminals, the classes of medicinal products and location of reported theft of medicinal products. Peter Brown presented some of the new and emerging security trends in industry. He discussed further case studies pertaining to falsification of medicines and diversion of medicinal products outside the legal supply chain.
Cheryl returned to the stage for the first session of the afternoon, which was the recurring presentation on Deficiency Data. Cheryl shared the deficiency data covering October 2021 until November 2022. She discussed the main areas of non-compliance based on the 1189 deficiencies, which were recorded over 473 inspections conducted in that period. Cheryl presented the top 5 deficiencies; she also explored the underlying contributing factors for IAG and CMT referrals. Cheryl also contrasted the most recent data with historical data from 2001-2005.
Chris Watson, GDP Inspector, delivered a session dedicated to environmental changes and their impact on GDP activities. Chris explored the effect of adverse weather events on the storage and distribution of medicinal products. With the weather becoming more extreme, he emphasised the need to adopt a risk-approach when dealing with extremes of temperatures.
John McNulty, GDP Inspector and Head of GDP Team 2, provided insights to the role of Responsible Person (Import)- RPi, which was introduced following the UK’s departure from the EU. John reminded delegates that the transition period to name an RPi on existing licences, where licensed products were imported from countries on a list, had passed and companies who had failed to name an RPi on their licence would not be allowed to import from countries on a list. John also explained the scope of each category pertaining to importation from countries on a list and its interpretation.
I delivered the history lesson of the day providing a retrospective review of how the guidelines on Good Distribution practice have shaped our expectations of minimum standards. I also shared the main changes that have been introduced to the guidelines since they first came into force in November 2012.
As it has now become a tradition, the GDP day ended with the Quiz which was presented by Lia Zelou and Claire Downes, GDP Inspectors. It provided an opportunity to delegates to test their knowledge and to race to be the first one to answer all questions. After the quiz, Chris Gray returned to the stage to deliver the closing remarks, which marked the end of the GDP day.
We previously published this ‘frequently asked questions’ blog related to manufacture and supply of IMPs back in 2016, and it was based on an original publication on the earlier MHRA website. As there have been some changes since this was published, including the introduction of an import oversight process for QP certified IMPs into Great Britain from approved countries, we thought it would be beneficial to review and update this blog.
The most common query we receive relates to deciding if an activity should be considered as manufacture or reconstitution. EU GMP Annex 13 in Eudralex Volume 4 provides guidance on this as follows:
Annex 13, 2010:
“Manufacturing authorisation and reconstitution
Both the total and partial manufacture of investigational medicinal products, as well as the various processes of dividing up, packaging or presentation, is subject to the authorisation referred to in Article 13(1) Directive 2001/20/EC, cf. Article 9(1) Directive 2005/28/EC. This authorisation, however, shall not be required for reconstitution under the conditions set out in Article 9(2) Directive 2005/28/EC. For the purpose of this provision, reconstitution shall be understood as a simple process of:
Reconstitution is not mixing several ingredients, including the active substance, together to produce the investigational medicinal product.
An investigational medicinal product must exist before a process can be defined as reconstitution.
The process of reconstitution has to be undertaken as soon as practicable before administration.”
This process has to be defined in the clinical trial application / IMP dossier and clinical trial protocol, or related document, available at the site.
Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use (“Updated Annex 13”):
“The reconstitution is understood as the simple process of dissolving or dispersing the investigational medicinal product for administration of the product to a trial subject, or diluting or mixing the investigation medicinal product with some other substance(s) used as a vehicle for the purpose of administering it to a trial subject.
Reconstitution is not mixing several ingredients, including the active substance, together to produce the investigational medicinal product. An investigational medicinal product must exist before a process can be defined as reconstitution.
The process of reconstitution has to be undertaken as close in time as possible to administration and has to be defined in the clinical trial application dossier and document available at the clinical trial site.”
So what does this mean? Well, a ‘simple process’ means just that. Dissolving or dispersing the IMP in a diluent immediately prior to administration or diluting with a vehicle for administration (commonly water for injection, saline or glucose – perhaps in an IV bag) would most likely be considered reconstitution activities. Measuring or weighing out quantities of several materials to be combined in a defined sequence or with a specified mixing time that perhaps includes some in-process test to confirm details such as concentration or pH, sterile filtration into another container and integrity testing of the filters prior to making a release decision would all be considered manufacture, must therefore be conducted at a facility that holds an MIA(IMP) and must be certified by a Qualified Person prior to release to the Sponsor for use in a clinical trial. Scenarios are considered on a case-by-case basis – if in doubt ask us via the clinical trials helpline (details provided below).
Our interpretation of ‘as soon as practicable before administration’ is ideally at the bedside, however it may be acceptable for the activities to be performed in the clinic’s pharmacy e.g. where IMP reconstitution is required to be performed in a clean area such as a laminar air flow cabinet. Preparation of IMP to be subsequently stored for use at a later date would not be considered reconstitution.
We hope that you find the following Q&A’s helpful. If you have any further queries relating to clinical trials, please continue to send these to the clinical trials helpline at ctdhelpline@mhra.gov.uk
Note: The UK CT Legislation is currently under review. Any changes to this position will be updated as necessary.
Alan Moon, Lead Senior GMDP Inspector
Martine Powell, Lead Senior GMDP Inspector
Jason Wakelin-Smith, Expert GCP Inspector & Head of GxP Expert Circle
Manufacture / Reconstitution
A simple reconstitution or dilution (including serial dilution) of an IMP including a sterile injection for the purpose of administration falls outside the definition of manufacture and so no Manufacturer’s Authorisation for Investigational Medicinal Products (MIA(IMP)) would be needed. It is also permissible without an MIA(IMP) to label them after reconstitution with an identifier to ensure that the dose goes to the correct subject. See also Q23 for further information.
1a. The reconstitution we are carrying out involves the addition of another material as well as the diluent. Does this still fall outside the definition of manufacture?
This may fall within the scope of manufacture; however it depends upon the nature of and reasons for multiple additions. Any operation such as weighing out, adding other materials, or combining IMPs is not considered to be for the purposes of administration and so would require appropriate authorisation under a MIA(IMP). This situation is potentially complicated and should be considered on a case-by-case basis by the MHRA. Ideally this should be discussed with a MHRA Clinical Trials pharmaceutical assessor pre-submission.
Licensing and Testing
The Human Medicines Regulations 2012 applies to therapeutic doses. In this legislation there are some exemptions from the need for a manufacturing licence such as the 'Section 10' exemption which can be invoked here. There is no such exemption for the manufacture of IMPs. So, the manufacture of even one dose for immediate use requires an MIA(IMP) authorisation and Qualified Person (QP) certification.
2a. Does this mean that all such manufactured IMPs need to be analytically tested before they can be certified, even if the quantity is very small?
Yes. The analytical requirements should be agreed with MHRA Clinical Trials via the clinical trial application (CTA). If an activity defined as manufacture takes place (see above) then the resultant IMPs should be tested to confirm that the specification submitted in the CTA is met. There may be exceptions for certain types of products, e.g. ATIMPs or radiolabelled IMPs where testing may not be performed prior to release due to very short shelf life, however the associated rationale should be documented and agreed by MHRA Clinical Trials in advance.
2b. Does the release testing for my IMP need to be carried out in a GMP-certified laboratory?
It would be expected that the analysis would be performed in a GMP-compliant laboratory. Testing in support of certification and release is considered part of manufacturing and therefore compliance with GMP is expected. For an IMP, the certifying QP may rely on the results of analysis from a non-EU laboratory and not repeat testing on import to the EU/UK, however they must assure themselves that the laboratory is compliant with EU GMP as part of the process of supply chain assurance and issuance of the QP Declaration for import. This is described in the sections relating to release of batches within EU GMP Annex 13.
Paragraph 8 in Part 2, Schedule 7 of the Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004 1031] requires the manufacturing authorisation holder to keep samples of each batch of formulated products readily available for examination. There should be enough finished packs for testing in duplicate. As IMPs are often small packing runs from one bulk batch, EU GMP Annex 19 accepts a justification for retaining the required sample quantity of the bulk batch and separate samples of packaging components used on each packing run. The sample of the bulk batch should be in the final primary pack in order to be representative of the materials supplied for use on a clinical trial. The requirements are also detailed in EU GMP Annex 13.
Samples of IMPs used in UK clinical trials should be stored within the UK, EEA or an MRA country unless suitably justified and defined in a technical agreement between the sponsor, importer and third country manufacturer (cost of the IMP itself would not be considered an acceptable justification to not hold appropriate samples).
'Specials' are unlicensed medicines which are manufactured under a manufacturer’s specials licence (MS) for a special clinical need and are under the responsibility of the prescribing doctor. There is no requirement for QP certification of products manufactured under the provisions of an MS. IMPs are governed by different legislation (The Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004 1031]). IMPs are not 'Specials'. A clinical trial authorisation application including a description of the IMPs has to have been submitted to the MHRA. A QP certification against that clinical trial authorisation is required for each batch of IMP.
Regulation 37 of The Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004 1031] contains a specific exemption which is relevant here. This provides an exemption from the need for a hospital or health centre (both are defined in Regulation 2 of the Clinical Trials Regulations) to hold a MIA(IMP) authorisation to assemble an IMP in a hospital or health centre, when the 'assembly' is carried out by a doctor or pharmacist, or under the supervision of a pharmacist. 'Assembly' is related to packaging and labelling only and not to the preparation of medicines from their ingredients. The exemption applies only if the product is to be used exclusively in that hospital or health centre or any other that is a trial site for the same clinical trial in which the product is to be used. This exemption does not apply to anyone else such as separate organisations which happen to be situated within a hospital or to companies which have a contract to supply hospitals or health centres.
No. Capsules are specifically excluded from the definition of a container in the Clinical Trials Regulations SI 2004 1031. An MIA(IMP) with 'capsule manufacture' listed as authorised would be necessary in this case.
No. An organisation cannot act as a contract batch certification site only. The sponsors of a clinical trial may wish to keep the final QP certification step of IMP manufacture in house as they carry ultimate responsibility for the trial. Otherwise, any contract organisation such as yours must be involved with some manufacturing or importation of an IMP if they wish to carry out batch certification.
There is no requirement within the legislation for any MHRA licence to carry out storage and distribution of IMPs. In this respect, the legislation differs from that for medicinal products. However, you will need to be named within the appropriate annex of your client’s MIA(IMP) as a site of storage and distribution. Therefore, any clients who wish to make use of your services will need to vary their MIA(IMP) accordingly.
Note that the storage and distribution of a licensed medicinal product must remain in the licensed distribution chain until it is supplied to the Sponsor for use in a trial.
The preparation of such radiopharmaceuticals using Technetium generators is considered to be manufacture and so an MIA(IMP) would be required if they were to be used as IMPs. Note that the Clinical Trial Regulations define an investigational medicinal product (including a licenced medicinal product) as being:
(a) used or assembled (formulated or packaged) in a way different from the form of the product authorised under the authorisation
(b) used for an indication not included in the summary of product characteristics under the authorization for that product
(c) used to gain further information about the form of that product as authorised under the authorization (Article 2).
Note: The UK CT Legislation is currently under review. Any changes to this position will be updated as necessary.
However, it may be that the radiopharmaceutical used in a clinical trial may not be an IMP. There are classes of products used in clinical trials which are 'not IMPs' (NIMPs) and details of the definitions can be found in Eudralex Volume 10 on Clinical Trials. NIMPs include challenge agents, rescue medication, agents used to assess end points and others. Clinical trial legislation does not apply to these as long as a), b) and c) don’t apply.
Further information relating to NIMPs is included in Q18 and Q25.
Yes. The MHRA does need to know about such manufacture which brings with it special GMP considerations (the manufacture of doses containing potent Active Pharmaceutical Ingredients (APIs) would be another example). Please include the relevant information in the application form describing such manufacture.
In addition, details of the active materials / product types handled within your facility are requested as part of the pre-inspection compliance report and cross-contamination prevention is a focus of inspections following the revisions to EU GMP chapters 3 and 5.
Yes. An MIA(IMP) licence is required for the manufacture of an IMP regardless of whether the IMP is for use in the UK, an EEA Member State or a non-EEA Member State (Third Country).
The Veterinary Medicines Directorate is responsible for such regulatory issues and contact details are available on the following link: https://www.gov.uk/government/organisations/veterinary-medicines-directorate.
You should inform the Defective Medicines Report Centre (DMRC) at the MHRA as you would for a licensed or unlicensed medicinal product. It will also be necessary to inform the MHRA Clinical Trials at the MHRA. The Clinical Trial Regulations make provision for notification of adverse events and notification of suspected unexpected serious adverse reactions. Further guidance for handling investigations into possible product defects and product recall actions is detailed in Chapter 8 of the EU GMP Guide (Eudralex Vol 4).
Import
All sites involved in manufacturing steps starting with the conversion of the API into the dosage form and including primary and secondary packing and also any contract laboratories involved with release or stability testing. A guidance template for the information that should be included on the QP Declaration is provided in Eudralex Vol 10 Chapter III.
Note: Import of finished IMPs that have been QP certified in an EEA country into Great Britain requires an oversight process under the supervision of a UK MIA(IMP) holder (see Q15b), however this does not require a UK QP Declaration.
No. The starting point for a QP declaration of EU GMP should be an audit conducted by or on behalf of the importing company. Any departure from this should be justified and documented and will be subject to scrutiny during an MHRA inspection. It may be possible to use the fact of a regulatory inspection by an EU Competent Authority as part of this justification, but these are general inspections which may not address the specific technical or GMP issues associated with your product. It may not even have covered the same factory or part of the factory. A regulatory inspection cannot be used unconditionally to remove the need for your own audit. The audit does not need to be done by the QP, however the QP needs to be satisfied that it has been done correctly by an appropriately trained individual as the QP will be taking final responsibility.
15a. We also intend to use some IMPs that were manufactured at a site in Switzerland. Do we need to include a QP import declaration with the CTA submission? This will have been certified by a Swiss Responsible Person (RP) so does this also require certification by an EU QP?
Although there is a Mutual Recognition Agreement (MRA) with Switzerland, it remains a third country therefore the IMP would need to be imported by an MIA(IMP) holder. As such, a QP Declaration of EU GMP compliance would need to be included as part of the CTA for each site outside the EU and the IMP would need to be certified by a QP upon import prior to release for use in the clinical trial.
15b. We intend to use some IMPs for our trial in Great Britain that were manufactured at a site in the EU/EEA. Do we need to include a QP import declaration with the CTA submission? This will have been certified by an EEA QP so does this also require certification by a UK QP?
Since the UK’s exit from the EU, and from January 2022, import of finished IMPs into Great Britain from EEA countries requires oversight by a UK MIA(IMP) holder. Additional certification by a UK QP is not required, however the UK MIA(IMP) holder responsible for the import oversight process needs to be listed in the UK CTA along with the site of final certification in the EEA.
The import oversight activity needs to be specifically authorised in the UK MIA(IMP) and an application or variation to an existing licence should be submitted and approved prior to undertaking this activity.
Further details on the requirements for this process can be found at the following link: https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries.
Once a trial has stopped, the product ceases to be an IMP and becomes a medicinal product. If it is a licenced medicinal product then it can be purchased and supplied as normal from the authorised supply chain. However, more often than not, the ex-IMP will not be licenced.
Material already existing physically as an IMP in the UK can be retrospectively notified to the MHRA Import Notification System (INS) as an importation of unlicensed medicines according to MHRA Guidance Note 14. This regularises the stock as an unlicensed medicine and the packs can be supplied as such, should MHRA not object to it. The clinical trial particulars should be removed from the product particulars (labelling and product information) ahead of supply taking place. Any stock not currently in the UK must be notified to INS ahead of the importation taking place.
The importer of an unlicensed medicinal product (a “special”) into the UK must hold; (a) a Wholesale Dealer’s Licence (WDA (H)) if the product is to be imported from an EEA member state i.e. the EU plus Norway, Iceland and Liechtenstein, or (b) a Manufacturer’s “Specials” Licence if the product is to be imported from a third country i.e. a non-EEA country.
The holder of the Wholesale Dealer’s Licence or Manufacturer’s “Specials” Licence, must comply with certain obligations in relation to the import of an unlicensed medicinal product, which are set out in Schedule 4 of the Human Medicines Regulations 2012. These are explained and summarised in MHRA Guidance note 14.
There is no requirement for APIs used in IMPs to comply with EU GMP Part II in full, but there remains a responsibility for IMP manufacturers to assure themselves that the API is of an appropriate quality. Section 19 of Part II of the GMP Guide describes the expectations. The EMA has also published a Q&A concerning the GMP status of APIs used in IMPs.
However, for Biological Products and Advanced Therapy Investigational Medicinal Products (ATIMP), there is a requirement for EU GMP Part I / Part IV to apply across all manufacturing steps as applicable, including from cell banks and vectors onwards, as detailed in EU GMP Annex 2 and in the PIC/S GMP Guide Annex 2A for manufacture of ATMPs for Human use for example. This is due to the ways in which Biological and Advanced Therapy medicinal products are manufactured and controlled, and the greater significance of the first steps in the manufacture of these products. As such all sites in third countries should be listed in the associated QP declaration for import as part of the submission for UK CTAs.
As such products are not IMPs, then the general requirements relating to medicinal products come into force, in particular the need for a Marketing Authorisation under the Human Medicines Regulations 2012. Where a medicinal product is not the subject of a valid Marketing Authorisation, the process for the supply of an unlicensed product provides a means of actually getting the NIMP into the UK for use in a clinical trial. The framework described in Guidance Note 14 is seen as an appropriate means of giving the legal method for the sponsor to actually obtain the NIMP, otherwise there would be no legal basis for supply. Further information on the importation of unlicensed medicines is available on the MHRA website: Supply of unlicensed medicinal products.
Stability / Shelf Life
Firstly, MHRA Clinical Trials would need to be informed via a variation to the CTA. Extension of shelf life represents a substantial amendment, unless you have previous agreement within the approved IMP Dossier to extend the shelf life when more stability information becomes available.
Secondly, the Product Specification File (PSF) would need to undergo a controlled change such that manufacturing sites and the QPs can take appropriate action such as updating labelling instructions, certification criteria etc.
Thirdly, if advantage of the longer shelf life is to be taken for IMPs already manufactured, these IMPs will need to be relabelled. This relabelling will need to be conducted, checked and documented in accordance with EU GMP Annex 13 (see also the following question).
No. Although this would be preferable, it is recognised that this shipping backwards and forwards could cause more GMP problems than it solves. It is permissible in these circumstances for the relabelling to be done at the clinical site. The certifying QP should certainly be aware of this and be involved in setting up the required GMP systems. The relabelling should be done by appropriately trained staff, documented, and the records stored in the original trial file. Any stock not already supplied to clinical sites should be relabelled prior to shipping.
Note that the EU GMP Annex 13 deals specifically with this issue. It states:
“If it becomes necessary to change the expiry date, an additional label should be affixed to the investigational medicinal product. This additional label should state the new expiry date and repeat the batch number and clinical trial reference number. It may be superimposed on the old expiry date, but, for quality control reasons, not on the original batch number.
The re-labelling operation should be performed by appropriately trained staff in accordance with good manufacturing practice principles and specific standard operating procedures and should be checked by a second person. This additional labelling should be properly documented in the batch records. To avoid mistakes the additional labelling activity should be carried out in an area that is partitioned or separated from other activities. A line clearance at the start and end of activity should be carried out and label reconciliation performed. Any discrepancies observed during reconciliation should be investigated and accounted for before release.
The re-labelling operation may be performed by authorised personnel at a hospital, health centre or clinic.”
This approach is usually not acceptable, as this is not compliant with EU GMP or Annex 13 requirements, except where provision of IMP is critical to the ongoing care of trial participants and has been agreed by MHRA Clinical Trials in advance of implementation. It is expected that relabelling processes should be fully explored before seeking approval to bypass relabelling activities. It is likely that additional mechanisms will be required to manage the continued use of incorrectly labelled products whilst correctly labelled stock is made available. Any additional handling or cumulative time out of storage for the relabelling should also be considered in line with the available stability data and this should be appropriately documented within the associated records.
A new certification after relabelling is required for stock which has not been shipped to an investigator site. For product held at the trial site, QP certification is not required if the relabelling activity is carried out by, or under the supervision of a pharmacist, or other healthcare professional, with appropriate documented evidence in accordance with EU GMP Annex 13.
QPs and Packaging / Labelling Activities
Confirmation that a transitional IMP QPs has been assessed as being suitable and eligible to act as a QP at a given site can be verified by referring to list of authorised personnel within the appropriate UK MIA(IMP) licence. Eligibility certificates for transitional IMP QPs were not issued by MHRA, however if a TQP has been previously named on a UK MIA(IMP) they will continue to be recognised as eligible in this capacity. On receipt of an application to name a TQP on an MIA(IMP), the individual’s suitability will be assessed based on experience of both the authorised dosage forms and the company’s systems.
Where an application to name a TQP on an MIA(IMP) is received, it is expected that this only applies to those already named on a previous MIA(IMP) licences. Any QP not yet known to the MHRA via inclusion on an MIA(IMP) will be expected to have undergone the applicable assessment via the Joint Professional Bodies on behalf of the MHRA.
The MHRA are no longer reassessing TQPs in line with the requirements of the EU Clinical Trials Regulation 536/2014 following the UK exit from the EU. This is a change from the approach indicated prior to leaving the EU.
This 'post certification labelling' can be used for the following and is expected to be performed prior to despatch in the distribution area at the MIA(IMP) holder site; or where justified and controlled then immediately prior to administration to a subject or patient:
It should, in the first instance, be done at a site with an MIA(IMP) unless the risk to the quality of the product is unacceptably elevated by any required transportation back to this site. The level of assurance of product quality should not be less than if this labelling were performed prior to QP certification. It should also be noted that there is no expectation for hospital pharmacy or investigator sites involved in the application of labels as part of the final dispensing process to return packs to a licensed facility for this process.
NOTE: Such labelling should not effectively incorporate allocation of doses against a randomisation code. It is important that allocation takes place before this to ensure adequate QA scrutiny and QP confirmation and to ensure that staff applying such post certification labels are not accidentally unblinded.
GMP expectations for 'post certification labelling' are:
Medication pooling is the production of IMPs which may be used in a number of clinical trials and which are left in a "generic" state until after QP certification. This would usually be by leaving a space for the protocol number to be added at the point of dispensing, or where multiple protocol numbers are on the label with the others being deleted at the point of dispensing. Only after certification is it decided which protocol the particular IMPs are destined for, this is when it is being dispensed to the patient. This is acceptable provided that the QP certification is against all of the possible clinical trials which may use the IMP, the protocol number is added to the IMP doses prior to release to the trial, and the GMP points outlined in Q23 (above) are considered.
Non investigational medicinal products (NIMPs) are not IMPs and so the legislative requirements of The Medicines for Human Use (Clinical Trials) Regulation 2004 (as amended) [SI 2004/1031] (as amended) do not apply to such products. There is therefore no requirement to source such products from a site holding an MIA(IMP) or for QP certification of the product. There is an expectation for the Sponsor to ensure that NIMPs are of the necessary quality for human use. Further guidance on sourcing NIMPs is included in Eudralex Volume 10 Clinical Trials Notice to Applicants.
As for licensed products, there is no such discretion available to a certifying QP. However, if a batch is manufactured and does not meet the authorised specification then a substantial amendment to alter the specification may be submitted to MHRA Clinical Trials provided it is deemed that safety, quality and efficacy are not compromised. If required, an expedited review may be requested via the Clinical Trials Helpline.
Administration of an Out of Specification (OOS) ATIMP may be acceptable in exceptional circumstances without or prior to a Substantial Amendment; however, these must be discussed with MHRA Clinical Trials with regards to impact to the trial prior to administration.
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