Governance, Policy, Law, and Regulation
The national pharmacovigilance programs of Ethiopia, Kenya, Rwanda, and Tanzania were well supported by legal instruments such as acts, regulations, and policies (Table 1). These legal documents defined the role of the NMRAs and their mandate to monitor the quality, safety, and efficacy of medicinal products.
Regulations to enforce the pharmaceutical industries’ responsibilities to perform post-marketing safety surveillance (PMS) were available. It was mandatory for Marketing Authorization Holders (MAHs) to conduct PMS and report Individual Case Safety Reports (ICSRs) or medicine safety issues in Ethiopia, Rwanda, and Tanzania (Table 2). In Kenya, there was no legal provision that required MAHs to conduct post-marketing safety activities and report ADRs or medicine safety issues. However, these responsibilities were written in the pharmacovigilance guidelines. In Ethiopia and Tanzania, MAHs were required to regularly submit Periodic Safety Update Reports (PSURs) or Periodic Benefit–Risk Evaluation Reports (PBRERs), and the NMRAs had the mandate to require MAHs to submit pharmacovigilance plans, risk management plans, and/or risk minimization/mitigation plans. In Ethiopia, MAHs are expected to submit PSURs to the authority every 6 months during the first 2 years after marketing authorization and, after that, annually for 3 years.
The 2018 pharmacovigilance regulations and guidelines in Tanzania require manufacturers/MAHs to have a Qualified Person responsible for Pharmacovigilance (QPPV). The new pharmacovigilance guidelines in Kenya (recently approved) require MAHs to keep a pharmacovigilance master file and to employ a QPPV to be responsible for all product safety issues. Rwanda and Ethiopia were considering including these requirements in their new guidelines as stipulated in the draft EAC pharmacovigilance guidelines.
Systems, Structures, and Stakeholder Coordination
In Kenya and Rwanda, the national pharmacovigilance center was a unit of its own hosted by the PPB and Rwanda Food and Drugs Authority (Rwanda FDA), respectively. In both Ethiopia and Tanzania, the national pharmacovigilance program was managed under the Clinical Trials Control and Pharmacovigilance section of the EFDA and TFDA, respectively. In Tanzania, Ethiopia, Kenya, and Rwanda, the full-time equivalent staff working in the pharmacovigilance unit were 12 (five at the TDFA headquarters and seven pharmacovigilance focal persons at TFDA zonal offices), ten (six working on clinical trials and four on pharmacovigilance), five (three working on pharmacovigilance and two on PMS) and two, respectively. In Kenya and Tanzania, there were specific annual budgetary allocations for pharmacovigilance activities. In Ethiopia and Rwanda, there were no designated budgets allocated to pharmacovigilance activities, but the budget for such activities was included with other activities managed by the respective directorate/department where the pharmacovigilance unit is placed.
In Tanzania, there were established SOPs for receiving and processing ADR reports, reviewing and annotating ADR reports, and development and approval of the ADR bulletin, all reviewed in 2018. The national pharmacovigilance center in Kenya had SOPs for routine management and processing of ICSRs, last reviewed in 2016. Ethiopia had one SOP for receiving and processing ICSRs. In Rwanda, SOPs for routine operation of the pharmacovigilance center and its management and processing of reports of suspected ADRs were being developed for adoption.
A national medicine safety advisory committee provides technical advice on the safety of medicines to the regulatory authority. In Tanzania, there was a technical committee for pharmacovigilance and adverse events following immunization (AEFIs), supporting the national pharmacovigilance program. In Ethiopia and Kenya, the committees that supported the national pharmacovigilance programs on pharmacovigilance issues were the causality assessment of AEFI committee and the clinical trials committee, respectively. Kenya has plans to establish a separate Kenya Pharmacovigilance Risk Assessment and Advisory Committee (PRAAC), taking over the responsibilities for medicine safety issues from the previous committee. Ethiopia has transformed the AEFIs committee to a general safety advisory committee. Rwanda has not yet established a national medicine safety advisory committee.
The latest issue of the National List of Essential Medicines in Tanzania, Kenya, Ethiopia, and Rwanda was published in 2017, 2016, 2015, and 2015, respectively. All four countries had a process for development of the National List of Essential Medicines; the review was managed by the respective ministries responsible for health. In Kenya, Tanzania, and Ethiopia, the NMRAs were represented on the National List of Essential Medicines committee, and their role was to provide information on safety data for consideration; these data are rarely based on local experience, because of the low level of ICSRs in the respective countries. In Rwanda, a multi-stakeholder working group assigned by the ministry of health is tasked with this process, but the pharmacovigilance division is not part of the working group.
The submission of ICSRs from healthcare facilities was very low. In the last calendar year (2017/2018), the proportion of health facilities that reported suspected ICSRs to national pharmacovigilance systems in Ethiopia, Kenya, and Tanzania was ≤ 1% of the total number of health facilities per country. There was no pre-service pharmacovigilance training for healthcare professional students in Rwanda, Kenya, and Tanzania (Table 3). In 2013, the national pharmacovigilance center in Ethiopia in collaboration with universities in the country developed a harmonized training curriculum in pharmacovigilance for undergraduate courses in medical, pharmacy, and nursing schools. This was supported by the Ministry of Education, but not yet adopted or implemented. The national pharmacovigilance centers in Ethiopia, Kenya, and Tanzania provide in-service pharmacovigilance training to healthcare professionals:
In Ethiopia, 2–3 days training on ADRs and separate training for AEFIs (for 20–40 attendees per session) was given in the last calendar year (2017/2018). A total of 1300 health professionals and decision-makers were trained.
In Kenya, the national pharmacovigilance system provides three types of training: 5-day, 3-day, and 1-day training courses. The 1-day training course was updated in 2018; the other two training courses were last revised in 2012. In the last calendar year, 384 health professionals were trained throughout the country. In the last calendar year, the national pharmacovigilance system in Kenya participated in 12 training sessions; six were conducted by the pharmacovigilance system, and the other six were in collaboration with partners.
In Tanzania, they used a 5-day training-of-trainers (ToTs) model, and nine such training sessions were conducted in the last calendar year. Additionally, 1253 individuals were reached through 13 sensitization activities in the last calendar year.
There was no web-based training/continuing education for professional development facilities in any of the four countries.
None of the national pharmacovigilance systems had a source for statistics on the volume of sales, consumption, and/or prescription of medicines (Table 3). Ethiopia and Tanzania have a communication plan for pharmacovigilance. In Kenya, there is a general PPB communication plan, but it is not specific to pharmacovigilance. In Rwanda, the newly established Rwanda FDA did not have a communication plan for dissemination of safety information. The main dissemination mechanisms for pharmacovigilance information are drug safety bulletins/newsletters and websites in Ethiopia, Kenya, and Tanzania. In Ethiopia and Tanzania, the bulletin/newsletter is scheduled to be published four and two times a year, respectively, but during the last 12 months, only one issue was produced in each country. In Kenya, PPB issued an annual pharmacovigilance newsletter, and a quarterly summary report is available on the PPB website. All the national pharmacovigilance centers, except for the newly established Rwanda FDA had websites. The national pharmacovigilance centers in Ethiopia and Tanzania had a toll-free telephone number for use by the public for pharmacovigilance information. The public can make calls to the national pharmacovigilance center in Kenya, but the line is not toll-free. Reporters may also send SMS messages and will then be called back. The Rwanda Ministry of Health has a toll-free telephone number that is open to the public for asking questions, not specific to pharmacovigilance issues. Other channels used for dissemination of pharmacovigilance information are group emailing and communication applications like WhatsApp (not in Ethiopia, due to IT policy), radio, and television.
Signal Generation and Data Management
All the national pharmacovigilance centers had a national database for managing data, although the central database in Rwanda was not in use (Table 4). This is because at the time of the assessment, the internal human resource competence for operating the VigiFlow case management system was lost and no replacement had been recruited and/or trained. Infrastructure necessary for continuing the use of VigiFlow as the national ICSR management system is in place at the Rwanda FDA in terms of availability of computers and access to the internet.
All the four pharmacovigilance centers have AE reporting forms, mainly for healthcare professionals. Only Tanzania has one for consumers/patients, which is in the local language, Swahili. In Kenya and Tanzania, there is an electronic AE reporting system. The specific medicine-related problems that can be reported in the standard AE reporting forms in each of the four countries are shown in Table 5. In Kenya, Rwanda, and Tanzania, a separate reporting form was used for product quality issues. In Ethiopia and Kenya, there are separate reporting forms for AEFIs.
In Kenya and Rwanda, there was no reporting mechanism for problems associated with medical devices and diagnostics. In Tanzania, there was a separate form for medication errors or problems associated with medical devices and diagnostics. The national pharmacovigilance centers in Kenya, Tanzania, and Ethiopia have developed SOPs for data management and signal analysis. In Rwanda, there was no process in place for collection, recording, and analysis of ADR reports.
Risk Assessment and Evaluation
In Ethiopia, Rwanda, and Tanzania the number of registered products with a pharmacovigilance plan and/or a risk management strategy from MAHs was not recorded. In Kenya, Periodic Update Safety Reports (PUSRs) were submitted for all approximately 10,000 registered products, including innovator and generics. The national pharmacovigilance centers in Tanzania, Ethiopia, and Kenya have conducted three, one, and one cohort event monitoring (CEM) study, respectively, in the last 3 years (36 months). The CEM study initiated by the pharmacovigilance center in Ethiopia was later outsourced to another institute with better resources. No active pharmacovigilance studies have been carried out by the national pharmacovigilance center in Rwanda.
The national pharmacovigilance centers in Kenya, Tanzania, Ethiopia, and Rwanda have submitted 11,373, 1899, 1331, and 30 Individual Case Safety Reports (ICSRs) to VigiBase since joining the WHO PIDM to December 2018 (Table 6).
The rates of suspected ICSRs received during 2017/2018 in Kenya, Ethiopia, and Tanzania were 35, 6.7, and 4.1 per million, respectively, based on an estimated population of “Worldometers” in 2017 (Fig. 1) . In Tanzania, all the suspected ICSRs received were reports of suspected ADRs. The Rwanda FDA received no ICSRs in 2017/2018. Since 2014, the national pharmacovigilance center, initially under the Pharmacy Task Force unit of the Rwanda Ministry of Health, had only received five ICSRs.
In Ethiopia, 72% (n = 504) of ICSRs received referred to suspected ADRs, of which 47% (n = 235) came from the tuberculosis program (see Fig. 2). In Kenya, 85% (n = 1468) and 8% (n = 132) of all ICSR reports received were on ADRs and AEFIs, respectively; a majority, 76% (n = 1320), of the ICSRs that the national pharmacovigilance center received emanated from the national HIV/AIDS program. In Ethiopia and Kenya, 26% (n = 181) and 8% (n = 137) of the ICSRs received referred to product quality issues, respectively. In Tanzania, 90% of the ICSRs were on suspected ADRs; the remaining 10% were on medical devices and diagnostics.
None of the four countries received ICSRs from MAHs. The national pharmacovigilance systems in Kenya and Ethiopia received 142 and 118 reports from MAHs, respectively. In Kenya, most MAH reports used the Council for International Organizations of Medical Sciences (CIOMS) summary, and hence, the reports were not included in the PPB database. In Ethiopia, the reports from MAHs were in the form of PSURs.
In Tanzania, during the last calendar year, 97% (n = 228) of ICSRs were subjected to causality assessment. In Ethiopia and Kenya, in the last calendar year, the proportions of ICSRs that were subjected to causality assessment were 2.0% (n = 14) and 5.5% (n = 96), respectively. The VigiGrade completeness scores (a measure of the amount of information on ICSRs) of quarterly reports submitted to VigiBase in 2017/2018 for Ethiopia, Kenya, and Tanzania were 0.87, 0.72, and 0.57, respectively, out of a maximum score of 1.0 . In Rwanda and Ethiopia, none of the health facilities reported ten or more ICSRs. In Kenya and Tanzania, the number of health facilities that reported ten or more ICSRs was 15 and 3, respectively. The number of health facilities in Ethiopia, Kenya, Rwanda, and Tanzania was 20,298 (2015), 10,864, 7072, and 1140, respectively.
Risk Management and Communication
In the last calendar year, pharmacovigilance activities in Ethiopia, Kenya, and Tanzania have resulted in four product withdrawals, 13 product recalls (voluntary and regulatory), and two withdrawals, respectively. Most of the recalls were related to poor quality. In the last 8 years, 31 regulatory actions were documented relating to pharmacovigilance activities in Ethiopia. In most instances, actions were based on the poor quality of the product, identified through reports of adverse reactions. In Kenya, 30 signals relating to substandard quality of medicines were detected, and one medicine safety signal was identified during the past year. In Tanzania, on an average, five safety signals have been identified per year during the last 5 years, and regulatory actions were taken. The average time from first identification of a suspected problem until regulatory action varies between the four countries. In Ethiopia, it took 2–3 months, depending on the nature of the investigation needed. In Kenya, the average time was between 7 days and 3 months, depending on the nature of the case. For Tanzania, it took anywhere between days to weeks, depending on the severity. The Rwanda FDA was established in 2018, and its Division of Pharmacovigilance and Safety Monitoring had new staff. No ICSR reports were received during the last calendar year, and therefore no activities of signal detection and analysis took place.
Tanzania was the only country that recorded requests for information about medicine safety from professionals or the public. In the last year, the national pharmacovigilance center received 36 requests, and all were addressed. In Ethiopia, requests for information about medicines were managed by another department (the Health Regulatory Information Centre). No statistical records were kept at the pharmacovigilance center regarding the number or nature of such requests. In Kenya, information about medicine safety was received and addressed, but the number of requests was not recorded; hence, it is unknown.
The national pharmacovigilance systems in Kenya and Tanzania act upon medicine safety issues reported from abroad. In Kenya, five medicine safety issues reported from abroad were acted upon in the last year. The national pharmacovigilance system in Ethiopia has not initiated any regulatory action based on information about safety issues received from the WHO or individual countries. The newly established Rwanda FDA has no activities to report relating to safety communication with the pharmacovigilance stakeholders, and no relevant regulatory decisions have been taken, neither based on domestic nor data from abroad.
In Ethiopia, the national pharmacovigilance toll-free number was regularly promoted at 7.00 am on national morning radio broadcasting. There was no information provided on the number/type of awareness/sensitization activities related to medicine safety that have been targeted towards the public. In Kenya, public educational activities have been carried out via newspaper articles, television, or roadshows. In Tanzania, the national pharmacovigilance system engaged in public education related to medicines and their safety, such as through broadcast media (television and radio) on about five channels.