LIBERIA MEDICINE AND HEALTH PRODUCTS REGULATORY AUTHORITY (LMHRA) 2™4 and 3 Floor, Clay Building Sekou Toure Avenue, Mamba Point Monrovia, Montserrado County Republic of Liberia Guidelines on Post-Authorization Safety Studies Version No. 003 | P.O BOX 1994 Cell: +23 1-777140555/888140555 Email: info@|mhra.gov.Ir Website: www.|mhra.gov.Ir Document Code: DOC-GDL-009 Date of Issue: Apri; 13, 2026 Version: 01 Date of Implementation: April 16, 2026 Guidelines on Post-Authorization Safety Studies i
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ABBREVIATIONS AMA - American Medical Association AVAREF - African Vaccines Regulatory Forum CT - Clinical Trial CIOMS - Council of International Organisation of Medical Sciences EMA - European Medicines Agency EC - Ethics Committee EU - European Union EUDRACT - European Union Drug Regulatng Authorities Clinical Trials GCP - Good Clinical Practice HCPs - Healthcare Professionals ICH - International Conference on Harmonization IMP - Investigational Medicinal Product LMHRA - Liberia Medicines and Health Products Regulatory Authority MA - Marketing Authorisation MAH - Marketing Authorisation Holder MOU - Memorandum of Understanding MP - Medicinal Product PASS-Post-Authorisation Safety Study PRAC - Pharmacovigilance Risk Assessment Committee NRA - National Regulatory Authority PBRER - Periodic Benefit-Risk Evaluation Report PSUSA - Periodic Safety Update Single Assessment PSUR - Periodic Safety Update Reports QPPV - Qualified Person for Pharmacovigilance PV - Pharmacovigilance Risk Assessment Committee RMP - Risk Management Plan WHO - World Health Organization WAHO - West Africa Health Organisation Guidelines on Post-Authorization Safety Studies iii
1.1 Post-Authorization Safety Studies (PASS) 1.1.1 Background In pursuance to the Medicines & Health Products Regulatory Authority (LMRHA) Act of 2010 and the Pharmacovigilance Guideline and Regulation on Pharmacovigilance in Liberia 2025 this guideline is developed by Liberia Medicines & Health Products Regulatory Authority, hereafter referred to as LMRHA, to define a common standard for post-authorisation safety studies (PASS) reporting on marketed products (including approved drugs that are under further study) in Liberia. A clinical study conducted in the post-authorisation phase may be interventional, low- interventional or non-interventional. This guideline concerns both interventional and non- interventional PASS, with a focus on non-interventional. It does not concern pre-authorisation safety studies. Interventional and low-interventional PASS are clinical trials and must follow the Medicines & Health Products Regulatory Authority (LMRHA) Act of 2010 and Regulations on Clinical Trials in Liberia on the CTs. Three criteria should be applied: e Assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice (i.e., the treatment regime typically followed to treat, prevent, or diagnose a disease or a disorder) of the member state concerned. e The decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study. e Diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects. The low-intervention clinical trial must meet all of the following three criteria: e The investigational medicinal products, excluding placebos, are authorized. e According to the trial protocol, the investigational medicinal products/ devices are used in accordance with the terms of the MA or the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned. e The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any member state concerned. Non-interventional PASS should cumulatively fulfil the following requirements (adopted from Volume 10 of The Rules Governing Medicinal Products in the European Union, Questions and Answers, Version 11.0, 2013): e@ the medicinal product/ device is prescribed in the usual manner in accordance with the terms of the marketing authorisation; e the assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and e no additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data. Guidelines on Post-Authorization Safety Studies P
Non-interventional PASSs are defined by the methodological approach and may include: e retrospective studies (case-control, cross-sectional, cohort or other study designs making secondary use of data), or a systematic literature review or a meta-analysis); e prospective studies (e.g., prospective observational studies and registries in which the data collected derive from routine clinical care). In these studies, interviews, questionnaires, blood samples and patient follow-up may be performed as part of normal clinical practice. e@ pharmacoepidemiologic studies, such as: - active surveillance (including intensive monitoring schemes, prescription event monitoring, registries, etc.); - observational studies (including cross-sectional study, cohort study, case-control study, case- only designs; - drug utilisation studies. A PASS is any study relating to an authorised medicinal product (including vaccines, biological, gene-therapy, herbal, homeopathic, generic, radionuclide, blood and blood components medicinal products and medical devices) conducted with the aim of: e identifying, characterizing or quantifying a safety hazard, e confirming the safety profile of the medicinal product, or; e@ measuring the effectiveness of risk management measures. PASSs can be either imposed by LMHRA or conducted voluntarily. Marketing-authorisation holders (MAHs) are obliged to carry out imposed PASSs. These include studies that are a specific obligation for a marketing authorisation granted under exceptional circumstances and other studies that LMHRA requests the company carry out. For imposed PASSs, LMHRA assesses the study protocol and the outcomes of these studies as given in the final study report. Voluntary PASSs are sponsored or conducted by MAHs on their own initiative. They include non- imposed studies that are requested in risk management plans. A PASS is initiated, managed and/or financed by a MAH or its local representative. It is also possible for a third party to conduct a PASS on behalf of a MAH or its local representative, pursuant to an obligation imposed by LMHRA. In case of multinational study, PASS may be required to address issues that are specific to Liberia, either identified in the Risk Management Plan (RMP) or at the time of RMP-assessment, for example, to compare safety profiles and highlight differences in specific populations, such as ethnic groups. Where possible, PASS protocols should be specifically developed or adopted for Liberia, should be agreed with LMHRA and other regional regulatory authorities to facilitate implementation of multi-country PASS. a. Objectives The objectives of PASS are: e to quantify potential or identified risks, e.g. to characterize the incidence rate, estimate the rate ratio or rate difference in comparison to a non-exposed population or a population exposed to another medicinal product or class of medicinal products as appropriate, and investigate risk factors, including effect modifiers; Guidelines on Post-Authorization Safety Studies 2
@ to evaluate the risks ofa medicinal product/ device used in a patient population for which safety information is limited or missing (e.g. pregnant women, specific age groups, patients with renal or hepatic impairment or other relevant comorbidity or co-medication); © to evaluate the risks of a medicinal product/ device after long-term use; e to provide evidence about the absence of risks: @ toassess patterns of drug utilization that add knowledge regarding the safety of the medicinal product/ device or the effectiveness of a risk management measure (e.g. collection of information on indication, off-label use, dosage, co-medication or medication errors in clinical practice that may influence safety, as well as studies that provide an estimate of the public health impact of any safety concern); e@ to measure the effectiveness of a risk management measures. b. Scope This PASS guideline provides general guidance for the transparency, scientific standards and quality standards of non-interventional PASS conducted voluntarily or pursuant to LMHRA’s PV requirements. It also describes procedures whereby LMHRA may impose on a MAH or local representative an obligation to conduct a PASS. c. Requirements Any person who conducts tests which serve the purpose of gathering knowledge resulting from the use of authorised or registered medicinal products in Liberia should immediately inform LMHRA. LMHRA grants the approval only to the registered studies, interventions and non-interventional studies in Liberia. Investigator-initiated studies for authorized medicinal product must be registered at LMHRA. Conduction of any study using the authorized medicinal product/ device without approval from LMHRA will be considered as violation of the law and lead to administrative delinquency and will cause respective sanctions and penalties (see below). An imposed PASS is required to be conducted by MAHs (or their local representatives) under the following conditions: e as part of the initial marketing authorisation (MA) application; e@ aMA may be granted under the condition that a PASS is being conducted and certified. ; e during a post-authorisation phase; the need for a PASS could be identified b y LMHRA (or other competent authorities /or EMA in case of international PASS studies) during a post- authorisation regulatory procedure, such as an extension or a variation to a MA, a renewal procedure of MA or based on the assessment a periodic safety update reports (PSUR/ PSUSA) or periodic benefit risk evaluation reports (PBRER), etc.; e caused by emerging safety concerns; e after the granting of MA, LMHRA (or other competent authorities /or EMA in case of international PASS studies) may impose an obligation to conduct a PASS if there are concerns about the risk of the authorised medicinal product. If safety concern applies to more than one medicinal product/ device, LMHRA may encourage MAHs to conduct a joint PASS. Guidelines on Post-Authorization Safety Studies 3
A voluntary PASS is sponsored or conducted by MAHs (their representatives or in investigator- initiated studies) on their own initiative. They include non-imposed studies that are required in the RMP to investigate a safety concern or to evaluate the effectiveness of risk minimiz ation activities (according to Good Pharmacovigilance Practices (GVP) Module V). d. Procedure for imposing PASS In Liberia, the conduct of any PASS can be imposed by LMHRA during the evaluation of the initial MA application or during the post-authorisation phase. Whenever there are concerns about the risks of an authorised medicinal product/ device for which PASS results would significantly impact on the risk-benefit of the product. This obligation should be duly justified, should be notified in writing and should include the objectives and timeframe for the submission and conduct of the study. The request may also include recommendations on key elements of the study (e.g. study design, setting, exposure(s), outcome(s), study population). e. Study registration All PASS (voluntarily and imposed) should be registered in Liberia's national register upon submission of study application. Registration details should be found in the LMHRA PASS registry on the official website. In cases of multinational PASS, registration should additionally be done in the relevant international databases (e.g. EUDRACT, pan-African registry, www.Clinicaltrials.gov, etc). For non-interventional PASS conducted pursuant to an obligation imposed by LMHRA, the date of study registration in the study register shall be included as a milestone in the final study report. The MAHs should also enter all non-interventional PASS required in the RMP, for studies conducted in Liberia for locally authorised products and for internationally conducted PASS where Liberia is concerned. Non-interventional PASS should be registered in the study register before the study commences or at the earliest possible date but no later than 3 months after data collection commences, for example if data collection had already started for a study included in the RMP. The legislation requires that the public be given important information on PV concerns (this includes information on PASS). Therefore, the MAH is requested to provide all necessary information on PASS to the national register in Liberia, pan-African and international clinical study register, including: @ title of the study, name and address of sponsor, summary of the protocol, countries where the study will be conducted and link to the respective international register, if applicable. The MAH is requested to publish details of PASS imposed as an obligation in the LMHRA and any other relevant public register. Local QPPV (or if QPPV is global/regional), or a local representative should be responsible for submitting and reporting results of PASS. This requirement includes local distributors and suppliers for international companies which are conducting PASS on behalf of the manufacturer (see the responsibility for the QPPV _ in the QPPV Guidelines). The study protocol should be submitted by MAH as soon as possible after its finalisation and prior to the start of data collection. Updated study protocols in case of substantial amendments, progress Guidelines on Post-Authorization Safety Studies 4
reports and the final study report should also be entered in the register (as soon as possible and preferably within two weeks after their finalisation). Study information should normally be submitted in English. If the study protocol or the study report is written in another language, the MAH should facilitate access to study information by including an English translation of the title, the abstract of the study protocol and the abstract of the final study report. A study protocol with redactions made by the MAH, may be entered into the register prior to the start of data collection in cases where prior publication of the protocol could threaten the validity of the study (for example, in studies with primary data collection where prior knowledge of the study objective could lead to information bias) or the protection of intellectual rights. These redactions should be justified and kept to the minimum necessary. Whenever a redacted study protocol is published prior to the start of data collection, the title page of the protocol should include “Redacted protocol” and the complete study protocol should be made available to LMHRA. The complete study protocol without redactions should be entered in the register as soon as possible and preferably within two weeks after the end of data collection. The final report of PASS shall provide the date and the respective number of registration in the national, pan-African or/and international registers (if applicable). f PASS Study Protocol A PASS conducted in Liberia in pursuance to LMHRA PV requirements and obligations; should have a written study protocol and conducted in accordance with the protocol. The study protocol should be developed by individuals with appropriate scientific background and experience in order to be submitted to LMHRA for scientific and regulatory approval and to the Liberian Ethics and Scientific Review Committee for ethical authorization. In order to ensure compliance of the MAH with its PV obligations, the QPPV or his/her delegate should be involved in the review and sign-off of study protocols conducted in Liberia. Any substantial amendment to the protocol should be discussed and _ approved in advance with LMHRA (see below). The time frame for submission of the protocol/protocol amendments and interim/final study report should be approved by LMHRA _ within 3weeks, taking into account factors such as possible third party involvement. Timelines should be agreed at the time of study request and may be further refined at time of protocol finalization/amendment. If the study is discontinued, a final report should be submitted and the reasons for stopping the study should be explained. g. Format and content of the PASS LMHRA should check the submitted PASS. The PASS be structured in accordance with the “Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies” adopted by LMHRA (EMA/623947/2012)° as stated in this guideline. The PASS should not promote the use of the drug. The study protocol should follow the format described in the table below. Title Informative title including a commonly used term indicating the study design and the medicinal product, substance or medicinal product/ device class concerned, and a sub-title with a version identifier and the date of the last version. MAH IName and address of the MAH. Guidelines on Post-Authorization Safety Studies 5
Responsible parties Names, titles, qualifications, addresses, and affiliations of all Iain responsible parties, including the main author(s) of the protocol, the principal investigator, and coordinating investigator A list of all collaborating institutions and nvestigators should be available to LMHRA. Abstract Stand-alone summary of the study protocol including the following sub-sections: | title with subtitles including version and date of the protocol and name and affiliation of main author, -- rationale and background, + research question and objectives, + study design, t- population, t variables, + data sources, - study size, + data analysis, t milestones. Amendments and updates Any substantial amendment and update to the study protocol after the start of data collection, including a justification for each amendment or update, dates of each change and a reference to the section of the protocol where it was changed should be rovided. Milestones (Table with planned dates for the following milestones: + start of data collection, + end of data collection, [- study progress report(s), I interim report(s) of study results, where applicable, in line with phases of data analyses, + final report of study results. Any other important timelines in the conduct of the study should be presented. Rationale and background Short description of the safety hazard(s), the safety profile or the risk management measures that led to the initiation or imposition of the study, and short critical review of relevant published and unpublished data to explain gaps in knowledge that the study is intended to fill. The review may encompass relevant animal and human experiments, clinical studies, vital statistics and previous epidemiologic studies. The review should cite the findings of similar studies, and the expected contribution of the current study. Research question and objectives research question that explains how the study will address the issue which led to the study being initiated or imposed, and research objectives, including any pre-specified hypotheses and Imain summary measures. Research methods Study design: overall research design and rationale for this choice. Setting: study population defined in terms of persons, place, time period, and selection criteria, including the rationale for any inclusion and exclusion criteria. Where any sampling from a source population is undertaken, description of the source Guidelines on Post-Authorization Safety Studies 6
population and details of sampling methods should be provided. Where the study design is a systematic review or a meta- analysis, the criteria for the selection and eligibility of studies should be explained. The study should be conducted in a Liberian population resident in Liberia or in a study population ‘0 be determined in consultation with LMHRA. ariables: outcomes, exposures and other variables including measured risk factors should be addressed separately, including operational definitions; potential confounding variables and effect modifiers should be specified. Data sources: strategies and data sources for determining exposures, outcomes and all other variables relevant to the study objectives, such as potential confounding variables and effect modifiers. Where the study will use an existing data source, such as electronic health records, any information on the validity of he recording and coding of the data should be reported. In case of a systematic review or meta-analysis, the search strategy and processes and any methods for confirming data from investigators should be described. If data collection methods or instruments are tested in a pilot study, plans for the pilot study should be presented. If a pilot study has already been performed, A summary of the results should be reported. Involvement of any expert committees to validate diagnoses should be stated. Study size: any projected study size, precision sought for study estimates and any calculation of the sample size that can inimally detect a pre-specified risk with a pre-specified Statistical precision. Data management: data management and statistical programmes used in the study, including procedures for data collection, retrieval and preparation. [Data analysis: the major steps that lead from raw data to a final esult; including methods used to correct inconsistencies or errors; impute values; modify raw data; categorise, analyse and present results, and procedures to control sources of bias and heir influence on results; statistical procedures to be applied to he data to obtain point estimates and confidence intervals of easures of occurrence or association, and sensitivity analyses. he primary analyses should be clearly identified from sub group analyses and secondary analyses. Quality control: description of any mechanisms and procedures to ensure data quality and integrity, including accuracy and legibility of collected data and original documents, extent of Source data verification and validation of endpoints, storage of ecords and archiving of statistical programmes. As appropriate, ertification and/or qualifications of any supporting laboratory or research groups should be included. Limitations of the research methods: any potential limitations of the study design, data sources, and analytic methods, including issues relating to confounding, bias, generalisability, and random error. The likely success of efforts taken to reduce errors should be discussed. Guidelines on Post-Authorization Safety Studies 7
Protection of human subjects afeguards in order to comply with national requirements for ensuring the well-being and rights of participants in ost-authorisation safety studies. Procedures for the collection, management and reporting of individual cases of suspected adverse reactions and of other medically important events that might influence the evaluation of the risk-benefit balance of the product while the study is being conducted. Management and reporting of adverse events/adverse reactions Plans for disseminating and communicating study results Any plans for submission of progress reports and final reports disseminating and communicating study results of PASS, including joint PASS. References All references cited in the study must be provided in a list. Also an annex should list all separate documents and list or include any additional or complementary information on specific aspects not previously addressed (e.g. questionnaires, case report forms), with clear document references. h. Joint studies for more than one medicinal product/device If safety concerns apply to more than one medicinal product, LMHRA encourages MAH concerned to conduct a joint PASS (as per GVP Module VIII). A joint PASS may also be necessary where there are limited patients (rare diseases) or the adverse reaction is rare. If a joint protocol is not voluntarily agreed and different proposals are submitted, the national competent authorities may define, in consultation with LMHRA, either a common core protocol or key elements (for example, the study design, the study population and the definition of exposure and outcomes) which each MAH will have to implement in the study protocol to be submitted LMHRA. Substantial amendments to the study protocol The study protocol can be amended and updated as needed throughout the course of the study. Any substantial amendments to the protocol after the study start should be documented in the protocol in a traceable and auditable way (including the dates of the changes) and submitted to the Liberian Ethics and Scientific Committee for ethics clearance and to LMHRA for regulatory authorisation. If such amendments are necessary to protect the life of subjects, an urgent amendment may be carried out but the investigator shall inform the Liberian Ethics and Scientific Review Committee and LMHRA of such amendments with an immediate phone call, followed by a written report within forty-eight (48) hours. Reports of all amendments shall include but not be limited to the following: e reasons for the amendments; e possible consequences for subjects already included in the study; @ possible consequences for the evaluation of the report. All amendment should attract a fee which should be determined by LMHRA as stipulated in LMHRA’s fee schedule. Guidelines on Post-Authorization Safety Studies 8
j. Review and Approval of PASS Review by LMHRA (procedure and timelines) The preliminary assessment of the PASS will be done by the PV and CT department and further assessment will be carried out by the Expert Committee of Drug Safety and Clinical Trials. Reports generated from the assessments will be sent to the head of agency who will endorse or refute authorization of PASS. Assessment of PASS should not exceed 2 months. All PASS applications, both obligatory and non-obligatory, attract a fee which shall be determined by LMHRA as stipulated in LMHRA‘s fee schedule. The criteria applied to evaluate PASS applications should be the same regardless of the applicant. All applications should follow the content and format of PASS. Additional documents for PASS submission are the following: e@ cover letter; e CVs, diploma, certificates of investigator and study team; e PASS protocol and protocol summary; © any agreements between MAH and partners (if study services are being outsourced/sponsored by the MAH to another company/organisation e.g. clinical research organisation, academic institution etc.); e proof of payment of application fees. The checklist is provided in the Annex. LMHRA should conduct the review and evaluate the specific requirements of each product class or medical devices; and should grant approval, request for additional information or amendment or to reject the submitted PASS. The criteria and procedures are consistent in the approval or rejection of applications through the application of defined requirements such that the resultant decision would be seen to be based on submitted documentation irrespective of the reviewer and the applicant. k. Review by the External Advisory Committee (procedure and timelines) L. LMHRA has the option, when needed, of using an external advisory committee in the review of PASS applications and PASS reports in the evaluation of post approval safety and compliance issues. This option is particularly important in the event of PASS imposed due to emerging safety concerns, granting of MA under conditional approval or under exceptional circumstances. Where the need arises, the Scientific Advisory Committee for Pharmacovigilance can be contacted for review of PASS report. Review by Ethics Committee (EC) (procedure and timelines) m. Reliance and Recognition Within the scope of reliance and recognition, a review of PASS could be conducted jointly by a group of NRAs. The scope of these activities may include: @ joint review procedures; e work-sharing; @ recognition of PASS assessment reports and decisions of other NRAs and international organisations related to the safety of authorized product based on new data obtained in the Guidelines on Post-Authorization Safety Studies 9
PASS. Joint review procedures can be organised for multicentral PASS or based on specific agreement of collaboration, MOUs between NRAs to get support for the limited-resources NRAs. It may be coordinated by international entities (WAHO, WHO AVAREF, EMA, AMA, US-FDA etc). Work-sharing facilitates the assessment in countries with limited regulatory resources and capacity. In this context, a regional review committee should be established to facilitate cooperation and coordination, as well as oversee the process in reaching valid regulatory decisions that will serve as a reference for relying on NRAs. Activities that could be carried out through work-sharing include: @ joint review multi-centre PASS applications; © joint review of safety data from multi-centre PASS studies, assessment reports and publications based on the conducted PASS. Recognition of decisions of other NRAs and international organisations related to post-marketing safety regulatory procedures aimed to optimise the resources and the capacities within LMHRA This approach will be used in routine regulatory practice and should be included as a mechanism for expedited procedures during a public health emergency. n. Reporting of Pharmacovigilance Data to LMHRA Data relevant to the risk-benefit balance of the product The MAH and local representative shall monitor the data generated while the study is being conducted and consider their implications for the risk-benefit balance of the medicinal product concerned. Any new information that may affect the risk-benefit balance of the medicinal product shall be communicated immediately via email and in writing within 7 days to LMHRA. Information affecting the risk-benefit balance of the medicinal product/ device may include an analysis of adverse reactions and aggregated data. This communication is without prejudice of the information on the findings of studies which should be provided by means of periodic safety update reports (PSURs) and in the RMP updates where applicable. o. Reporting of adverse reactions/adverse events Individual cases of suspected adverse reactions should be reported to LMHRA in accordance with the provisions stated in the Guidelines On Pharmacovigilance In Liberia. Adverse events/adverse reactions collected in studies with primary data collection should be recorded and summarised in the interim safety analysis and in the final study report. Adverse events/adverse reactions collected in studies with secondary data collection should be recorded and summarised in the interim safety analysis and in the final study report unless the protocol provides for different reporting with a due justification. Procedures for the collection, management (including a review by the MAH if appropriate) and reporting of suspected adverse reactions/adverse events should be implemented and summarised in the study protocol. Reporting can be done using the adverse reaction reporting form which can be obtained from LMHRA’s office or applicants may use their in-house reporting forms, provided all the necessary data elements included on the forms are in a readable format and the form also complies with the CIOMS | format. Guidelines on Post-Authorization Safety Studies 10
p. Study Reports Progress report and interim report of study results The progress report should include relevant information to document the progress of the study, for example, the number of patients who have entered the study, the number of exposed patients or the number of patients presenting the outcome, problems encountered and deviations from the expected plan. The progress report should be submitted in the Format approved by LMHRA (please refer to appendix I). The progress report should be submitted within 21 days after the end of the preceding quarter. The quarter starts from the study start date. The progress report may include an interim report of study results. The interim report of study results should include results of any planned interim analysis of study data before or after the end of data collection and should be submitted upon request by LMHRA. q. Final study report The final study report should be submitted to LMHRA no later than 12 months after the end of data collection. If a study is discontinued, the MAH should inform LMHRA with reasons for the termination within 10 days and a final report should be submitted no later than 90 days. The final study report should contain information in the format prescribed in the Guideline on Good Vigilance Practices (GVP), Module VIII — Post-Authorization Safety Studies- VIII.B.4.3.2. Final study report (Rev 3). Where the result of the PASS affects the risk management system or the MA status of the medicinal product, this should be communicated to LMHRA and steps to incorporate these changes in the RMP and variation to the MA described. LMHRA may also request variation to the risk management system or the MA after review of the PASS study report. If a study is discontinued, a final report should be submitted and the reasons for terminating the study should be provided. Transparency r. Registration of PASS The Declaration of Helsinki, last amended in October 2013, requires that every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject. The guiding principles of transparency to the general public about the ongoing research relating to medicines used in clinical practice shall be followed for PASS in Liberia. PASS registry is publicly available at https://www.|mhra.gov.|r/new/ s. Publication of study results The results of PASS should be shared with LMHRA and according to the legal requirement will be made publicly available. The concise information about PASS is to be provided in a form of an abstract. The abstract should provide the context or background for the study and should state the study's purpose, basic procedures (selection of study participants, settings, measurements, analytical methods), main results (i.e. information on the size of the study population, effect sizes and their statistical significance for the main study objectives), and principal conclusions. The conclusions should emphasize the important aspects of the study or observations, note important limitations, and avoid interpretation of the findings not supported by the results. The abstract may Guidelines on Post-Authorization Safety Studies il
be made public by LMHRA in accordance with the Regulation On Pharmacovigilance In Liberia _. For this purpose, the MAH should submit it to the national register and international register (if applicable). LMHRA should check if the abstract: 1) has been structured in accordance with the "Guidance for the format and content of the final study report of non-interventional post-authorisation safety studies" EMA/48663/2013 adopted by LMHRA as stated by this guideline? 2) is consistent with the results and the discussion of the full report, 3) does not promote the use of the drug. Attention should be given to the legibility of the text and clarity of the conclusions. For studies that are fully or partially conducted by investigators who are not employees of the MAH, the MAH and the investigator should agree in advance on a publication policy allowing the principal investigator to independently prepare publications based on the study results irrespective of data ownership. The MAH should be entitled to view the results and interpretations included in the manuscript and provide comments prior to submission of the manuscript for publication. t. Submission of manuscripts accepted for publication In order to allow LMHRA to review in advance the results and interpretations to be published, the MAH initiating, managing or financing a PASS should communicate to LMHRA the final manuscript of the article within two weeks after first acceptance for publication. u. Data protection MAHs and investigators shall follow relevant national legislation and guidance of Liberia. All study information should be handled and stored so as to allow for accurate reporting, interpretation and verification of that information and shall ensure that the confidentiality of the records of the study subjects remains protected. v. Quality systems, audits and inspections The MAH should ensure the fulfilment of its PV obligations in relation to the study and that this can be audited, inspected and verified. For PASS imposed as an obligation, MAH should ensure that the analytical dataset and statistical programmes used for generating the data included in the final study report are kept in electronic format and are available for auditing and inspection. For PASS required in the RMP or conducted voluntarily in Liberia, record management and data retention should follow LMHRA’s requirements as stated in | Document Control SOP #001. Guidelines on Post-Authorization Safety Studies 12
Glossary Adverse drug reaction A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or for modification of physiological function. Adverse event/adverse experience Any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding for example), symptom or disease temporarily associated with the use of the medicine. Audit A systematic, disciplined, independent and documented process for obtaining audit evidence and evaluating the evidence objectively to determine the extent to which the audit criteria are fulfilled Identified risk An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest. An important identified risk is an identified risk that could have an impact on the benefit-risk of the product or have implications for public health. What constitutes an import risk will depend upon several factors, including the impact on the individual, the seriousness of the risk and the impact on public health. Normally any risk that is likely to be included in the contraindications or precautions section of the product information should be considered important. Examples include: * an adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data; * an adverse reaction observed in well-designed clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group on a parameter of interest suggests a causal relationship; * an adverse reaction suggested by a number of well-documented spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility, such as anaphylactic reactions or application site reactions. In a clinical trial, the comparator may be placebo, an active substance or non-exposure. Important identified risk and Important potential risk An identified risk or potential risk that could have an impact on the risk- benefit balance of the product or have implications for public health. What constitutes an important risk will depend upon several factors, including the impact on the individual, the seriousness of the risk and the impact on public health. Normally, any risk that is likely to be included in the contraindications or warnings and precautions section of the product information should be considered important. Local representative The company or legal entity that represents the MAH in Liberia and performs functions delegated by the MAH. Guidelines on Post-Authorization Safety Studies 13
Marketing Authorization Holder (MAH) A person or company authorized by LMHRA to manufacture, import, receive as donation, distribute or sell a medicinal product/ device in Liberia. Missing information information about the safety of a medicinal product which is not available at the time of submission of a particular risk management plan and which represents a limitation of the safety data with respect to predicting the safety of the product in the marketplace. examples of missing information include populations not studied (e.g. pregnant women or patients with severe renal impairment) or where there is a high likelihood of off-label use period. Medicinal product Any substance or combination of substances * presented as having properties for treating or preventing disease in human beings; or ¢ which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. This definition is from EU GVP Annex I -Definitions (Rev 4). This includes vaccines and biomedical products (blood products etc). Periodic Safety Update Report (PSUR) A regular update of the world-wide safety experience of a medicinal product at defined times during post-registration period. Pharmacovigilance (PV) The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug- related problem. Post Authorisation Safety Studies (PASS) Any study relating to an authorized medicinal product conducted with the aim of identifying, characterizing or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures. A PASS may be interventional or non-interventional. Potential Risk An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed. An example is toxicological findings seen in non-clinical safety studies which have not been observed or resolved in clinical studies. An important potential risk is a potential risk that could have an impact on the benefit-risk of the product or have implications for public health. What constitutes an important risk will depend upon several factors, including the impact on the individual, the seriousness of the risk and the impact on public health. Normally any risk that is likely to be included in the contraindications or precautions section of the product information should be considered important. Quality of a Pharmacovigilance System All characteristics of the pharmacovigilance system which are considered to produce, according to estimated likelihoods, outcomes relevant to the objectives of pharmacovigilance. Qualified Person Responsible for Pharmacovigilance (QPPV) An individual named by the Marketing Authorization Holder (MAH) and approved by LMHRA as the person responsible for ensuring that the MAH meets its legal obligation in accordance with LMHRA PV regulatory obligations in Liberia. Quality System Requirements Those characteristics of a system that is likely to produce the desired outcome, or quality objectives. Guidelines on Post-Authorization Safety Studies 14
Quality Management System of a Pharmacovigilance System The organisational structure, responsibilities, procedures, processes and resources of the pharmacovigilance system as well as appropriate resource management, compliance management and_ record management. Risk Management Plan A systematic approach and set of pharmacovigilance activities and (RMP) interventions designed to identify, characterize, prevent or minimize risks relating to medicinal products, and the assessment of effectiveness of those intervention and how these risks will be communicated to LMHRA and the general population. Safety Concern An important identified risk, important potential risk, or important missing information. Serious adverse reaction Serious adverse reaction is an adverse drug experience that — (A) results in: - death; - an adverse drug experience that places the patient at immediate risk of death from the adverse drug experience as it occurred (not including an adverse drug experience that might have caused death had it occurred in a more severe form); - inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or a congenital anomaly or birth defect; or (B) based on appropriate medical judgment, may jeopardize the patient and may require a medical or surgical intervention to prevent an outcome described under subparagraph (A). Substantial amendment to the study protocol Amendment to the protocol likely to have an impact on the safety, physical or mental well-being of the study participants or that may affect the study results and their interpretation, such as changes to the primary or secondary objectives of the study, the study population, the sample size, the study design, the data sources, the method of data collection, the definitions of the main exposure, outcome and confounding variables or the statistical analytical plan as described in the study protocol. Guidelines on Post-Authorization Safety Studies IS
Appendices Legislations and guidelines used to develop this guideline This guideline was developed by LMHRA in line with the country legislation for pharmacovigilance (PV) Medicines & Health Products Regulatory Authority (LMRHA) Act of 2010 and the Guideline on Pharmacovigilance in Liberia Version #: 02 and Regulation On Pharmacovigilance In Liberia _ and other applicable legislations aligned with the legislation and the guidelines from the international organizations and standards developed by WHO, the European Union and other ICH documents with relevant information that include: Regulation (EC) No 726/2004 Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) Directive 2001/83/EC of the European Parliament and of the Council GVP Module VIII on Post-authorisation safety studies, EMA/813938/2011 Rev 3* EMA/623947/2012 - Guidance for the format and content of the protocol of non- interventional post-authorisation safety studies chrome- extension://efaidnbmnnnibpcajpeglclefindmkaj/https://www.ema.europa.eu/system/files/ documents/other/wc500133174_en.pdf EMA/699686/2015 Pharmacovigilance Risk Assessment Committee (PRAC) <PRAC> <Rapporteur> <preliminary> <updated> non-interventional imposed PASS final study report <and RMP> assessment report https://www.ema.europa.eu/system/files/documents/template-form/we500161089_en.pdf EMA/48663/2013 Guidance for the format and content of the final study report of non- interventional post-authorisation safety studies https://www.ema.europa.eu/system/files/documents/regulatory-procedural- guideline/wc500137939_en.pdf https://www.ema.europa.eu/en/human-regulatory-overview/post- authorisation/pharmacovigilance-post-authorisation/post-authorisation-safety-studies- pass Safety Monitoring of Medicinal Products: Guidelines for Setting Up and Running a Pharmacovigilance Centre. UMC, WHO, 2000, http://apps. who. int/medicinedocs/en/d/Jh2934e/ WHO Pharmacovigilance indicators: A practical manual for the assessment of pharmacovigilance systems. World Health Organization. 2015, (http://apps.who.int/medicinedocs/documents/s2 1970en/s21970en.pdf) WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems. World Health Organization; 2004, http://apps.who.int/medicinedocs/documents/s7 1 48e/s7 148e.pdf) The importance of Pharmacovigilance: safety monitoring of medicinal products. World Health Organization, 2002, (http://apps.who.int/medicinedocs/pdf/s4893e/s4893e.pdf) Guidelines on Post-Authorization Safety Studies 16
The guidelines on Post-Authorization Safety Studies is Hereby Promulgated and Approved by the Managing Director on this 13 Day of April A. D. 2026. Hon. Luke L Bawo- Managing Director / LMHRA a a Guidelines on Post-Authorization Safety Studies 17