Clinical Trials, Pharmacovigilance and Medicines Safety

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Objectives

The objective is to have a regional harmonised system for the application and evaluation of clinical trials and pharmacovigilance activities. This is to ensure;

• Expedited approval process for clinical trials.
• Effective safety surveillance system in the West African region.

Clinical Trials

Background

• The past decade has witnessed an increase in the sophistication of biomedical research and the number of products being tested for diseases endemic to Africa for which no prior knowledge and evidence base exists in high income countries. While providing opportunities for enhancing expertise and earlier access to novel therapies, these trends have also underscored the need for a regulatory platform for promoting human resource capacity, best practices, common technical requirements and the efficiency and transparency of the regulatory process. The growing complexity of biomedical reach calls for increase cooperation between partners, including funders, sponsors, researchers, product developers, regulators and the ethics community.

Joint reviews

• This joint review process was initiated by WHO through the African Vaccines Regulatory Forum (AVAREF) in 2006 as an informal capacity building platform aimed at improving the regulatory oversight of interventional clinical trials being conducted in Africa, has demonstrated it’s value in strengthening regulatory and ethics reviews, promoting harmonized standards and approaches and accelerating the review of vaccines of high public health value- most recently in relation to vaccines against Ebola.
• Clinical trials are carefully conducted experiments in humans with the aim of testing products for safety, efficacy and immunogenicity (in the case of vaccines). Applications for clinical trials are usually submitted to National Medicines Regulatory Authorities (NMRAs) and Ethics Committees (ECs) for approval and authorization before the importation and use of new investigational drugs. The trials are then monitored until completed and the data is submitted for the authorization and registration of the final product in the countries of intended marketing.
• Sometimes clinical trials are planned in more than one country and at several sites in these countries for the same product. For such a multi-centre, multi-country clinical trial, clinical trial applications (CTAs) will have to be submitted to individual NMRAs and ECs, often in different formats as defined by each country. Reviews will then be conducted individually and at different times before final outcomes are communicated individually to the sponsor. Furthermore, many of the questions submitted by countries will be similar in nature. To optimize requirements, practice and processes across countries, as well as build capacity for more efficient oversight, WHO introduced the concept of joint reviews in 2016.
• Joint reviews are intended to enhance the quality of the reviews of an application submitted to multiple countries, optimize review timelines for such applications, serve as a platform to allow regulators and ECs to exchange and validate their findings with peers and also act as a capacity building tool. Joint reviews enable NMRAs and ECs to collectively prepare a consolidated list of questions for the sponsor and to discuss directly with manufacturer/sponsor the candidate product, trial design, safety and other aspects of the proposed trial.

Pharmacovigilance

Background

• In fact, the information regarding the safety of medicines at the approval are limited due to methodological aspect of the clinical trials such as the limited number and variability of patient included in the study; limited duration of trials; and the informations about chronic toxicity, drug interactions and use in special groups (such as children, the elderly or pregnant women) are often incomplete or not available . For this reason, the knowledge related to the safety profile of the product may change over time when the product is used in the general population.
• Pharmacovigilance has been defined by the World Health Organization (WHO) as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem”.
  In line with this general definition, underlying objectives of this guideline are to:
  
  • harmonize the requirement for reporting adverse reactions in humans arising from the use of Authorized medicinal products within or outside the terms of marketing Authorization;
  • promote the safe and effective use of medicine, in particular through providing timely information about the safety of medicine to patients, healthcare professionals, marketing Authorization holder and the public.
  • contribute to the protection of patients’ and public health.

Clinical Trials Guidelines

WAHO Guideline for Joint Review of Clinical Trial Application

• The guideline has been developed by AVAREF and adopted by WAHO to provide a model of joint scientific review of CTAs by NMRAs and ECs. This model may also be applied to the review of unconventional regulatory pathways at different stages of the product lifecycle.
• This guideline is intended to assist WAHO, individual countries and sponsors in how to plan, organize and conduct joint review of applications for medical products.
• The guideline is not intended to replace but rather facilitate compliance with the regulatory requirements of countries in the review, approval and authorization of medical products clinical trials as outlined in each country legislation. ECOWAS countries are encouraged to consider this joint review model into their review process as a means of fulfilling regulatory requirements. This guideline should be used together with WHO’s Technical Report Series on review of clinical trials (WHO Technical Report Series No 924-Guidelines on Clinical Evaluation of Vaccines: Regulatory expectations) and other international guidelines for the review of CTAs by ECs/institutional review boards (IRBs) and NMRAs. It is also expected that WAHO will serve to promote convergence of CTA technical requirements and processes.
• The guideline is subject to amendment as further experience is gained with the joint review process.

Scope

• The guideline covers all aspects of the joint review of a qualifying medical product 1 using the WAHO platform specifically:

• Conditions or requirements for joint/assisted reviews, including criteria for triggering a review;
• Key participants as well as their roles and responsibilities in the review process;
• The stops and time lines interview process, from pre-submission meeting to the conclusion of the joint review exercise;
• Expected outcomes from the joint review process; and post-review steps leading to the commencement of the clinical trial2
• For the purpose of this platform, a medical product includes a medicine, vaccine or other biological product and an in-vitro diagnostic
• This would normally include Good Clinical Practice (GCP) inspections, post-review administrative steps and import authorization of investigational products.

Definitions

• Joint review- The WAHO joint review process bring experts from the NMRAs and ECs of two or more countries, together with the sponsor, as well as external experts that serve to guide and support the NMRAs and ECs of the target countries of the CTAs to review a common CTA submitted by a sponsor. Countries may also attend as observers to benefit from the knowledge and experience of other regulators and ECs towards building their capacity.
• Assisted review- The same approach may be used on a case by case basis to assist a single country in the review of a CTA that complies with the criteria. Hereinafter, joint and assisted review will be referred to as joint review, unless otherwise indicated.
• Review participants:
  Convener - Neutral entity responsible for organizing the joint review and for ensuring agreed upon process is respected.The convener will liaise with all respective participants and as such will seek endorsement for the joint review process.The convener will facilitate but not chair the face - to face meeting.For the initial pilot phase of the joint review process, the WAHO will serve as the convener and will work with AVAREF in this respect.This would not preclude working in partnership with the secretariats of regional regulatory networks to organize a joint review when the majority of target countries are members of a regional network. Invited experts - Experts and representatives from more experienced NMRAs from the region and / or country of manufacture of the product or from well-established NMRAs outside the region who act in an advisory capacity.This could include disease - specific experts, statisticians or individuals with relevant expertise.
• Neutral partner- a Product Development Partner (PDP), Non-governmental Organization (NGO) or another non-profit organization that 1) supports the development of a medical product without specific commercial interest in the proposed trial that would constitute a real or perceived conflict of interest and 2) who is also willing to support the regulatory oversight of the clinical trials in target countries. The neutral partner should play a key role in advocating for a joint review facilitated by WAHO
• Observer countries- NMRAs and ECs from countries not involved in the proposed trial who may be invited to the joint review as observers, to learn in anticipation of additional trials of the product in their countries. The convener will select countries based on the need for capacity building. Observers do not participate in the decision-making process.
• Sponsor- Entity that takes responsibility for the clinical trial. In some cases, it maybe one organization, while in other case it might be more than one. Sponsor and manufacturer may also be different companies or organization. The sponsor will designate persons toparticipatein the joint review to ensure that all foreseeable questions presented by the review group can be promptly responded to, ideally during the joint review meeting. They may include the principal Investigators (PIs) of the different sites, company experts in the clinical development of the product, company expert in production and control of the investigational products, etc.
• Target countries – The EC and NMRA representatives of the countries where the clinical trials will take place. The decision of regulators and ethics committee members will be determined by each institution in consultation with the convener.

Pre-requisites for joint review

• The following are important pre-requisites for the successful conduct of joint review:

• A waiver agreement obtained from the sponsors to share existing information about the application.
• Consensus among the countries involved to undertaken the review of the application together and to use a common report as a basis for their national decision to authorize a trial
• A neutral convener to ensure that the clinical trial application review is rigorous and unbiased
• Focal persons for the NMRA and EC in each participating country for continuous communication regarding the entire process.
• Reviewers nominated by the heads of agencies with the authority to act on behalf of their respective agencies
• Expert from supporting agencies who share their knowledge and experience but do not have decision-making roles or responsibilities.

Criteria for joint review

• To be considered for joint review, a candidate medical product of high public health value to countries in West Africa will be considered based on one or more of the following criteria:
• Addresses a neglected tropical disease or other highly prevalent and serious disease (e.g., non-communicable disease –NCD) on the continent
• Addresses an unmet medical need or a significant improvement over available intervention.
• Involves a novel technology
• Product that addresses a disease for which the Director General of the World Health organization has declared a Public Health Emergency of International Concern (PHEIC)
• Responds to request from one or more countries for assistance
• Other criteria may be considered based on the needs of the countries. Furthermore, there must be a candidate medical product which is ready to go into clinical trial. The clinical trial could be multicentre involving more than one country or on a case by case basis involve one country.
• Finally, all participant in the joint review must agree to the provisions of this guideline and the specific agreement reached for the candidate product and trial in terms of roles, responsibilities and timelines.

Joint review process

• The steps in the joint review process are described below.
• The proposal to initiate a joint review using WAHO may come form:
• A sponsor
  A PDP
  An ECOWAS member - state
  WHO or other international organization, for example, in the case of public health emergencies.
• Regardless of who requested the joint review, the same process is set in motion. Request should be placed with the convener (WAHO).
• It is envisaged that a proactive approach to the conduct of joint reviews will be established, including online expressions of interest (EOI) and the development of a medical product pipeline platform that tracks candidate products of interest.
• Finding models to support the joint review process are being explored. Currently, no fees are associated with the joint review beyond those required by participating regulatory authorities and ECs as part of their administrative process.

Process Steps

• Step 1- Screening of request
  Request to utilize the WAHO joint review process will be screened by the WAHO secretariat and the WAHO EWG on pharmacovigilance, medicine safety and clinical trials.
• Step 2- Pre-submission meeting
  Convened by the WAHO in discussion with the sponsor, target countries and the neutral partner(when involved).The objective is to present the product, the clinical trial plan and proposed timelines.A decision is made on whether to proceed with a joint review in accordance with the proviso of this guideline.A date and locat7ion for the face to face meeting is also set.Representatives of ECs and NMRAs attending the pre - submission meeting will have authority to decide on their participation in the joint review and commit to nominate reviewers.The sponsor provides a waiver agreement to share existing information about the application.
• Step 3- Submission to countries
  The WAHO will submit the applications to ECs and NMRAs as agreed during the pre - submission meeting.The goal is to have parallel submissions in all countries.In some countries, the PI submits the protocol to the EC and NMRA.However, in the context of this document, the sponsor is considered the entity responsible for the clinical trial.The CTA submitted to the target countries are not considered valid until they have been screened for completeness and all administrative requirements are fulfilled(including the payment of fees, where relevant).Information on the product and proposed trial must be identical, and attested to in writing by the sponsor prior to all participants.Opportunities of central electronic filing of non - administrative information and subsequent access by the countries will be explored.
• Step 4- Country review of the CTA
  Once the application has passed the screening / validation step, the NMRA and EC in each participating country will upload a list of questions onto the WAHO joint review platform.Supporting agencies and invited experts may also do the same. Comments will be accessible to all joint review participants, including the sponsor.
• Step 5- Joint review
  The WAHO will convene the joint review meeting at the agreed upon date and location.Depending on the anticipated complexity of the review, 2 - 3 working days will be allotted for the review. WAHO will circulate an agenda for the meeting following a standard format for the organization of such meeting.
  
  The structure of the meeting will generally respect the following format:
  Opening session(all participants):
  WAHO’s role:
  Brief summary of joint review project and process
  Objectives of the meeting, format, agenda and expected outcomes
  Confirmation that there is no conflict of interest on the part of participants
  Facilitate the election of chair(s) for the meeting and lead(s) for drafting report
  Sponsors role:
  Introduction of the product, clinical development plan, clinical trial, the protocol.
  Clarification: responses to questions raised by countries of submission package
  Join review session(only country representatives, observers, experts, WAHO, AVAREF and Neutral Partner):
  Participants will agree on time slots to discuss specific section of the application and will develop a list of questions to be submitted to the sponsor at the end of each day.Time in the first portion of the next day will be allocated for responses and discussions with the sponsor
  Closing session(all participants)
  The questions and answers session will continue until all questions are either completely resolved or an agreement is reached on a list of outstanding questions to be addressed by the sponsor.
  The review report will be finalized and signed by the chair(s), countries and sponsor
• Step 6- Resolution of outstanding List of questions (LoQ)
  In the event that the joint review session results in outstanding questions, the sponsor submits pending responses to each country.Participants in the joint review will assess and communicate virtually(via webex, zoom or teleconference) to ensure consistency and reach consensus on resolution of the questions jointly presented to the sponsor.Should they agree that the questions were not satisfactorily responded to, the sponsor will be requested to provide additional information (clock stop). The process will continue until all participating countries agree that the questions have been satisfactorily resolved.
• Step 7- National authorization of CTA
  After the joint review as described above has been completed, each EC and NMRA will proceed according to their national procedures to issue the decision to authorize or not authorize the clinical trial.NMRAs and ECs of participating countries’ will inform WAHO about their decision.In the event trials are not authorized, the NMRA and/or EC will report to WAHO the reasons for non-authorization
• Step 8- Post –authorization steps
  Gains achieved in the joint review of a CTA could be negated by lengthy post - authorization steps required for the trial to begin, including the authorization for import of investigational products.Countries are encouraged to coordinate and streamline these steps to allow for the timely and near simultaneous commencement of trials in the respective countries.
  Figure 2 - Target Timelines for Process Steps

Post-approval collaboration by participating countries

• The cooperation among participating NMRAs and ECs is expected to extend beyond the approval of the clinical trial. The results of GCP inspections and any significant and serious observations from the safety monitoring or any other activity relate to the oversight of the trials in all sites should be shared by the NMRAs and ECs that authorized the trial.

Amendments

• In addition, if the approved protocols are amended by the sponsor, participating countries will communicate and discuss whether the magnitude of the amendments warrant a joint review, in which case, WAHO will facilities such activity.

Implementation of joint review

• The joint review model described in this guideline will be launched as a pilot for a period of two years. Refinements will be made based on experience gained.

Pharmacovigilance Guidelines

WAHO Good Pharmacovigilance Practice Guideline

• This guideline is intended for information guidance for patients, Healthcare Professionals, Marketing Authorization Holders, Manufacturers and the National Medicines Regulatory Authority to help in the continuous monitoring of the safety, efficacy, and benefit to risk balance of medicinal products granted marketing authorization.
• It is composed of six sections:
• Section 1- General Requirements for Reporting Adverse Drug Reactions for healthcare professionals and consumers;
• Section 2 - General Requirements for Reporting Adverse Drug Reactions for Marketing Authorization Holders (MAH)
• Section 3 – Periodic Safety Update Reports
• Section 4 – Risk Management System
• Section 5 - Safety Communication
• Section 6 – Pharmacovigilance Audit and Inspection
• This Guideline is hereby made by WAHO with references from Good Pharmacovigilance guidelines Nigeria, FDA Ghana, Pharmacy Board of Sierra Leone, MCC South African, ICH and WHO to define the general norms and scientific principles and to set applicable standards for the conduct, performance and control of pharmacovigilance activities in West Africa.

General Principles and Scope of Reporting
What to Report
For all products the following should be reported:

• Adverse drug reactions (ADR) resulting from non-prescription and prescription drugs(including biological products and radiopharmaceutical products).
• Adverse reactions resulting from herbal medicinal products .
• Drug abuse, drug overdose, drug interactions, quality defects, poor packaging, questionable stability, suspected contamination, suspected falsified and lack of therapeutic efficacy.
• Adverse reactions occurring in a recipient of blood or blood components
• Information to be provided on the Reporting Form
  Patient Details
• Age/Date of Birth,
  Sex,
  Weight,
  Name of the health facility or treatment centre,
  Telephone number of patient or nearest contact person, if available
• Reaction Details
• A detailed description of the suspected adverse drug reaction.
  Information on dates of onset and stop of the reaction.
  Outcome of the reaction(whether the patient has recovered, not recovered or the outcome unknown).
  Treatment provided for the adverse reaction(if any)
• Details of the Suspected Product
• The name(s) of the suspected medicine(s).
  Provide both the brand and the generic names of the product, batch, number, Manufacturer, route of administration(if known) and daily dose.Attach separate sheet in cases where there is more than one suspected product.
  The date therapy was initiated and the date therapy stopped.
  Reason(s) / indication for use of the product should be indicated.
  Drugs taken within the last three months including concomitant medicines and herbal remedies(if known) should be provided.
• Reporter Details
• The name and contact details of the reporter (phone number, e-mail address and postal address)should be provided to enable the authority to give feedback on the reportsubmitted or contact the reporter for follow up information when needed.
• Additional information, not available at the time of the initial report, should be provided in the form of follow-up reports.

How to Report

• To report a suspected ADR for products marketed, the healthcare professional should complete a copy of the adverse drug reaction reporting form (Appendix 1). This form may be obtained by means disposed by the authority. The completed report may be delivered to the Authority.

Confidentiality of ADR Reports

• Any information related to the reporter and patient must be kept strictly confidential.

Follow-Up Information for an already Reported ADR

• Any follow-up information for an ADR that has already been reported can be sent on another ADR form or on a supplementary sheet.This can also be communicated by telephone, fax or e - mail if convenient.To match this information with the original report, indicate that it is follow - up information, the date of the original report and the report case number if known.It is very important that follow-up reports are identified and linked to the original report.