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NAVIGATING NEW HORIZONS:

AN OVERVIEW OF THE ICH E6 (R3) GOOD CLINICAL PRACTICE (GCP) GUIDELINES

The unveiling of the International Council for Harmonisation’s (ICH) E6 (R3) draft guidelines in mid2023 marked an important moment in the evolution of clinical trial standards globally. Responding to the rapid advancements in clinical research methodologies, technological innovations, and the increasing focus on patient-centric approaches, R3 aims to modernise and adapt Good Clinical Practice (GCP) for the future.

This article explores the origin, major revisions, regulatory expectations, operational impacts, and the future direction of clinical trials considering these latest draft guidelines.

The ICH E6 guidelines have been the foundation of clinical trial conduct worldwide since the first version went live in 1996, ensuring the integrity, safety, and quality of pharmaceutical research. The current version ICH E6 (R2), last updated in 2016, seeks to establish a common standard across ICH regions, ensuring regulatory authorities mutually accept clinical data.

The introduction of the R3 draft in May 2023 signals a strategic advancement, aiming to align with the changing dynamics of clinical research. This shift represents a new era that emphasises the incorporation of modern-day technologies, enhanced risk management, and a stronger focus on protecting trial participants. It represents not only a reaction to technological progress but a comprehensive effort to navigate and address the intricacies characterising today’s clinical trial landscape.

THE ORIGINS OF CHANGE

The motivation for the R3 revisions is complex, reflecting an acknowledgment of a ‘perceived problem’ of the shifting paradigms in clinical research. Traditional trial models are increasingly supplemented or replaced by innovative designs that leverage digital technologies, demanding a framework that accommodates this diversity. The collaborative development process of R3, involving a wide array of stakeholders from regulatory bodies through to academia, underscores a shared vision for a more flexible, adaptable, and participantfocused approach to clinical trial governance.

MAJOR REVISIONS AND THEIR IMPLICATIONS

At the core of the R3 revisions is the redefinition of GCP principles to better align with current trial practices. This includes a renewed emphasis on electronic data integrity, the facilitation of decentralised and pragmatic trials, and a quality-by-design approach to trial planning and execution. Moreover, R3 addresses the expanded scope of data sources and trial settings, aiming to ensure data reliability and participant safety across varied research contexts.

The introduction of a risk-based quality management system, something very familiar to those working within bio-pharmaceutical development, indicates a pivotal shift towards proactive risk identification and mitigation. This approach is designed to prioritise resources effectively, ensuring that critical aspects affecting trial outcomes are rigorously managed.

REGULATORY PERSPECTIVES AND EXPECTATIONS

Regulatory authorities view R3 as a crucial step towards harmonising clinical trial practices on a global scale. The latest guidelines, which amend and adapt rather than replace the previous versions, are seen as an essential tool to modernise GCP, ensuring that it remains relevant in an era of rapid technological change and increasingly complex trial designs. The emphasis on planning for compliance underscores the expectation that quality and risk management should be integral to the trial design process, rather than retroactive measures.

OPERATIONAL IMPACT ON SPONSORS AND CLINICAL RESEARCH ORGANISATIONS (CROS)

For sponsors and CROs, adapting to the R3 guidelines necessitates a thorough reassessment of trial operations. This includes the integration of electronic systems for trial management, the adoption of new trial designs, and a stronger focus on participant engagement and data integrity. Organisations must cultivate a culture of quality and risk awareness, embedding these principles into every aspect of the trial process. This shift demands not only operational adjustments but also a mindset change towards a more proactive, participant-centred approach to clinical research.

LOOKING FORWARD: THE FUTURE OF CLINICAL TRIALS

The R3 revisions are poised to redefine the landscape of clinical trials, fostering innovation while ensuring the reliability of trial data and the safety of participants.

As the guidelines progress towards their final form, encompassing the overarching principles, Annex 1 on ‘considerations for interventional trials,’ and Annex 2 on ‘further considerations for non-traditional interventional trials’ (expected between March and September 2024), the clinical research community stands at the beginning of a new era. Full adoption of these comprehensive guidelines is projected for 2025, emphasising the need for a unified effort among all stakeholders. This collaboration highlights a shared duty to meet the highest GCP standards, ensuring the successful transition to, and implementation of, R3’s holistic framework.

The ICH E6 (R3) guidelines represent a transformative update to the framework governing clinical trials worldwide. By addressing the complexities of modern clinical research and embracing technological advancements, R3 sets a new standard for the conduct of clinical trials. When navigating these changes, the collaborative spirit that has characterised the development of R3 will be crucial in ensuring its successful adoption and implementation. The future of clinical research, shaped by the principles of R3, promises to be more adaptable, innovative, and, most importantly, centred on the safety and well-being of trial participants.

For further information, please contact Nicholas Wells nik@regconsult.co

Nicholas Wells Founder, RegConsult®

PIPA Guidance Document

Responding to Patient Enquiries

(Revised 2024)

PIPA Guidance Document: Responding to Patient Enquiries – 2024 update

Patients are becoming increasingly aware of, and involved in, their own medical care. As a result, MI teams are receiving a growing number of enquiries from patients who have an in-depth understanding of their condition and treatment. Feedback from the PIPA membership indicated that the information provided in response to patient enquiries varied significantly between companies and that guidance in this area, to ensure consistency across the industry, would be welcomed.

To this end, in 2019, the PIPA MI workstream created a guidance document to help MI departments provide informative and helpful responses to patient enquiries that provide meaningful information to patients without either contravening the Code of Practice or interfering with the important patient-doctor relationship. This document was updated in 2022, and we are publishing the latest version of the guidance here. It is also available to download from the PIPA website via https://pipaonline.org/medical-information/mi-guidance-documents/

Introduction

Increasing awareness of, and involvement in, their own medical care has resulted in more patients contacting pharmaceutical medical information departments about the medications they are taking. The knowledge and understanding of each patient will vary greatly, but some may have an indepth understanding of their condition and treatment.

Guidance about how enquiries from patients should be handled is included in section 1.4 of the PIPA UK Guidelines for the Pharmaceutical Industry Medical Information Departments (Revised 2024), accessible via https://pipaonline. org/medical-information/mi-guidancedocuments/

All responses to enquiries originating from members of the public / patients must conform with the Association of the British Pharmaceutical Industry (ABPI) Code of Practice (specifically clause 26). Historically, this often meant that pharmaceutical companies gave little or no information in answer to such enquiries.

However, with an increasing number of trusted and reliable sources of information in the public domain that can be accessed by patients, responses to such enquiries can, and should, go much further in providing helpful information to patients without either contravening the Code of Practice or interfering with the important patientdoctor relationship.

PIPA has created this document to help medical information (MI) departments provide informative and helpful responses to patient enquiries. These responses should:

— Include appropriate factual information relevant to the question being posed and the understanding of the patient, presented in a clear and unambiguous manner

— Use plain English and patient friendly language. Patients need to understand the information provided without any further need for explanation

— Explain or simplify any complex medical words or terms that are used to avoid causing

confusion e.g. dyspepsia could be written as ‘indigestion’ or ‘upset stomach’

— Consider enclosing some printed information rather than only providing links as not everyone will have digital access

— Sign post to other relevant sources of information in the public domain (e.g. patient organisations)

— Include a clear explanation of the limitations placed on the pharmaceutical industry regarding what information can and cannot be shared, and why these limitations exist (for example, why the industry cannot give medical advice)

— Include a statement referring the patient back to their doctor / appropriate healthcare professional (HCP) for further advice and information, also stating that their HCP can contact MI for further specialist information if necessary, which they can then discuss with the patient.

It is important that MI professionals use their professional judgement when selecting which sources of information would be appropriate for the enquirer they are dealing with.

Some patients will have a high level of scientific knowledge and understanding about their medical condition and / or the medicine they have been prescribed, while others will have relatively little knowledge. It is important that the MI professional identifies the patient’s level of understanding to ensure they provide a useful and beneficial response to the customer whilst remaining compliant with the Code of Practice.

It is also important to ensure that the language used in patient responses is appropriate, as literacy levels will vary greatly between

individuals. The Patient Information Forum (https://pifonline.org.uk/) recommends using short sentences, an active voice and simple, friendly language. They also suggest aiming for a reading age of 11-14 years. Should a patient have demonstrably higher literacy skills, the language used can be adjusted accordingly.

The following table provides guidance on how to gauge the level of scientific knowledge the patient has.

Patient with a low level of scientific understanding around their medicine, disease or therapy area

Patient:

— Is not aware of the information in the Patient Information Leaflet (PIL)

— Has not used the product yet or not used it for very long

— Has limited or no knowledge around the product and/or disease area.

Patient with a high level of scientific understanding around their medicine, disease or therapy area

Patient:

— Is already aware of the information in the PIL and/or Summary of Product Characteristics (SmPC)

— Has used the product for many years

— Has good knowledge of the product and the disease area

— Has done their own research online and still cannot locate answer

— Confidently and accurately uses scientific / medical terms

— States that they are / were a healthcare professional / work in healthcare.

Written responses to patients –examples of wording

The following information is for guidance only. We have included examples and suggestions for text you can use, but we recommend that you adapt the wording, and order of the text, to fit with your company’s policies, internal style and the level of scientific understanding of the patient. You may also find some of the wording helpful when communicating with patients / members of the public by telephone.

Introductory sentence:

Include an appropriate introduction, for example:

“Thank you for contacting us regarding X. I understand you have requested X.”

You may wish to include a subject line at the start of the letter, for example:

Subject: {Product}® { } {Active ingredient}

We recommend that if a product is subject to additional monitoring, then the black triangle should be included next to the product name. Check that the triangle is the required size – a minimum of 5 mm per side and that it is visible on

different devices e.g. phones/tablets/mobile email apps. We would also recommend including an explanation using wording based on clause 26.4 of the Code:

“ Where you see a black triangle next to a medicine’s name, this means that its safety is being carefully looked at. This is usually because it is a new medicine, but it can be for other reasons too. When a new medicine is first used in lots of people, new and important information about the medicine’s safety can be found. You can help by reporting any side effects that happen to you when you are taking a medicine to your doctor, pharmacist, nurse or by going to https:// yellowcard.mhra.gov.uk/”

Continue with an expression of empathy and understanding of the question (if appropriate).

Examples of wording include:

“I am sorry to hear that….”

“I understand this must be difficult for you…”

“I understand it must be frustrating that…”

“I can see that you are concerned…”

You may wish to change the use of ‘I’ to ‘we’ depending on your company’s internal style, and

whether the response signature is a department rather than an individual.

Explain what information is provided in the response

To engage the enquirer with your response, use this part of the letter to provide a top-level explanation of what is included in the email / letter. Sample wording is provided below which can be modified, as appropriate, to your response:

“In this email (/letter) I/we have included information that I/we feel would help to answer your question. I / we always make sure that I / we only give you information you can trust. I/ we have also explained why I / we cannot always give you lots of detailed information or advice about your medicine or illness.”

Explain the limitations on the data provided

Here, clearly explain about the ABPI Code of Practice and why this means that there are limitations on the information provided. Explain why you have been able to share some information – or explain why there is no available information to share – and outline why the pharmaceutical industry cannot give medical advice.

Sample wording is provided below, which can be modified, as appropriate, to your response:

“In our country, most pharmaceutical companies who make medicines are members of the Association of the British Pharmaceutical Industry (ABPI - https://www.abpi.org.uk/). The ABPI makes sure that the pharmaceutical industry follows rules to look after patients. These rules are written in the Code of Practice for the Pharmaceutical Industry (https://www.pmcpa. org.uk/the-code). One part of these rules tells us what information we can share with patients and members of the public about the medicines we produce and which are prescribed for you by your doctor or nurse.

Although we are allowed to give you information that may help to answer your question, it does not allow us to give you medical advice. We are also not allowed to comment on your personal medical issues, or suggest medicines for your treatment. This is to make sure that we do not affect the relationship you have with your doctor.

Provide any relevant information available in the public domain that could help answer their enquiry

Build an appropriately worded response using any applicable resources from the list of suggestions in the table at the end of this document, depending on the customer’s level of scientific understanding. Ensure you put the information provided in the context of the question asked and doesn’t go beyond the scope of the enquiry. Include links to where the information can be found for future reference.

If the patient is already taking the medication they are enquiring about, provide a link to the PIL or, if speaking to them directly, guide them to where this can be found.

We also suspect that some people with lower literacy levels could be asking questions because they find the PIL too complex to understand. The questions posed should be considered with this in mind, and answered in plain English. You may wish to include the relevant text from the PIL to support your response.

Signpost to reliable, evidence based information

When referring patients or members of the public to patient organisation or charity websites, it is important to check if the information is evidence based and a reliable source of information. The Patient Information Forum (PIF) run the only health information accredited scheme. You can look for the PIF tick symbol when researching appropriate webpages to use in your response (insert PIF tick symbol). However, the lack of a PIF tick symbol does not necessarily mean the website can not be suggested, as this scheme is still in its infancy.

Refer the patient back to their prescriber

The previous section naturally leads on to wording that refers the enquirer back to the healthcare professional (HCP) who prescribed the medication for them.

Sample wording is provided below, which can be modified, as appropriate, to your response:

“As a healthcare professional, your GP - or other member of your healthcare team - can use their

experience, knowledge of your medical history and available information to make the right decision about your treatment.

They can also ask for further information from us to help them with their decision, which they can then explain to you.

We would therefore always advise you to discuss any worries or questions that you have about your medicine with your doctor.”

Adverse event statement & disclaimer

If the patient’s enquiry included an adverse event, or a potential adverse event, include a suitable statement here, including any requests for followup information. For example:

— for when the enquirer reported an adverse event within their enquiry:

“All pharmaceutical companies must follow up on any reports of side effects involving their medicines. We will ask your doctor for a medical report where possible, as it is important that we know about all possible side effects. This helps us makes sure that the medicine can be used safely in patients. As you have told us about a side effect that you have experienced whilst taking <PRODUCT>, I have sent details of your side effect(s) to our Drug Safety department. They may contact you to ask whether you are happy for them to contact your doctor for more information. This is a normal thing that we do and your details will not be used for anything else.”

— for suspected adverse events:

“Reporting side effects

If you experience side effects with any medicine you are taking, talk to your doctor, pharmacist or nurse. This is important even if the side effect is not in the information leaflet that comes in the medicine pack.

You can also report side effects via the Government’s Yellow Card Scheme at www.mhra. gov.uk/yellowcard. By reporting side effects you can help give more information on the safety of your medicine.”

Other company disclaimers

Companies may require other disclaimers to be included in correspondence with patients,

including:

— product quality complaints (where applicable)

— data protection (GDPR) and confidentiality

— copyright

— company-specific disclaimers etc.

Review of patient responses

To satisfy the requirements of the supplementary information for clause 8.3 (14.3) “Examination of other material” of the ABPI Code, ensure written patient responses are examined or peer reviewed.

Summary and examples of resources to be used

Patient with a low level of scientific understanding around their medicine, disease or therapy area

— Confirm question and include introductory sentence

— Provide any relevant information that addresses their enquiry, e.g.

— Provide information from PIL (or SmPC in those cases where info is in SmPC and not PIL)

— Provide information from relevant sources listed below

— Include link to PIL or guide patient to where this can be found

— Explain the limitations on the data provided (e.g. Code of Practice)

— Refer patient back to their healthcare professional (HCP) and advise them that their HCP can contact us if they would like to discuss this further

— Include AE statement & other relevant company disclaimers as appropriate

Patient with a high level of scientific understanding around their medicine, disease or therapy area

— Confirm question and include introductory sentence

— Provide any relevant information that addresses their enquiry, e.g.

— Re-iterate the information from PIL (or SmPC in those cases where info is in SmPC and not PIL)

— Confirm information that they are already aware of (own research)

— Provide information from relevant sources listed below

— Ensure to only direct customers to more complex sources if they have demonstrated a high level of scientific knowledge or have confirmed they are healthcare professionals (e.g. PubMed, IDAPs)

— Include link to PIL or advise patient where this can be found

— Explain the limitations on the data provided (e.g. Code of Practice)

— Refer patient back to their healthcare professional (HCP) and advise them that their HCP can contact us if they would like to discuss this further

— Include AE statement & other relevant company disclaimers as appropriate

Sources of information in the public domain that patients in this category can be referred to include:

electronic medicines compendium (emc) for Patient Information Leaflet (PIL) and / or Summary of Product Characteristics (SmPC):

— www.medicines.org.uk (UK)

— www.medicines.ie (IRELAND)

ClinicalTrials.gov: https://clinicaltrials.gov/

EU clinical trials register: https://www. clinicaltrialsregister.eu/

UK Clinical Trials Gateway: https://bepartofresearch. nihr.ac.uk/

NHS website: https://www.nhs.uk/

Relevant Patient Organisation/Charity websites in the public domain as agreed with relevant internal colleagues

Helpline numbers as well as web addresses would be of benefit to those with lower digital health literacy.

Sources of information in the public domain that patients in this category can be referred to include:

electronic medicines compendium (emc) for Patient Information Leaflet (PIL) and / or Summary of Product Characteristics (SmPC):

— www.medicines.org.uk (UK)

— www.medicines.ie (IRELAND)

European Public Assessment Reports (EPARs): https://www.ema.europa.eu

ClinicalTrials.gov: https://clinicaltrials.gov/

EU clinical trials register: https://www. clinicaltrialsregister.eu/

UK Clinical Trials Gateway: https://bepartofresearch. nihr.ac.uk/

UK Teratology Information Service (UKTIS) bumps: http://www.medicinesinpregnancy.org/

The UK Drugs in Lactation Advisory Service (UKDILAS) is operated by the UK Medicines Information (UK MI) Network. The service provides evidence-based information on the use of drugs during the breastfeeding period to all UK healthcare professionals. HCPs can access this website for further information: https://www.sps.nhs.uk/articles/advisingon-medicines-during-breastfeeding/

This service is for HCPs only and it is included here as it could be relevant for patients to know about UKDILAS to discuss with their HCP.

TIC TAC visual drug identification and information system: https://www.tictac.org.uk/

NHS website: https://www.nhs.uk/ Interactive Drug Analysis Profiles:* https:// yellowcard.mhra.gov.uk/idaps

PubMed:* https://www.ncbi.nlm.nih.gov/pubmed

Patient Groups: Internally agreed patient groups relevant to the therapy area.

*To be shared only with patients who are HCPs or have demonstrated a high degree of scientific understanding. We recommend informing patients that if they do their own literature searches, the results may not give a balanced view of all available data.