Special Section: Pharmacovigilance

scientist pointing to graphics of scientific icons
Smart Safety Surveillance (3S): Proven Approach to Building Functional LMIC Pharmacovigilance Systems
Shyam Bhaskaran, Charles Preston, Raj Long
Bill & Melinda Gates Foundation
@gatesfoundation
S

mart Safety Surveillance (3S) is a product-focused, principles-based approach to building functional LMIC (low- and middle-income countries) pharmacovigilance (PV) systems that has been validated across multiple products and geographies. The lessons learned and key success factors enabling this work have been shared with interested country regulators and public health decision makers tasked with protecting the safety of their populations, funders, and multilateral organizations partnering with these countries, and to product developers developing global product launch plans.

What is the Need?

Safety is an increasing concern for regulators and public health decision makers as more global health products are being targeted directly to LMICs (e.g., RTS S malaria vaccine) or launched in both LMICs and HICs (high-income countries) at the same time (e.g., COVID-19 vaccines), many with limited safety data packages (e.g., bedaquiline for multi-drug-resistant TB was approved with pooled safety data from only 335 treated patients across three studies). Moreover, although progress has been made, PV systems in many LMICs are still evolving, with low adverse event reporting rates, data trapped in paper forms not being available for downstream analysis, digital tools not fit for purpose or not interoperable, data not fully shared between siloed public health programs (PHPs) and national regulatory authorities (NRAs), safety analysis limited to causality determination of serious cases, minimal signal detection from aggregate data, and limited technical expertise to support evidence-based decision-making.

Figure 1 illustrates a functional PV system. Adverse events are captured in electronic formats and through interoperable systems become available in real time to PHPs and NRAs. These decision makers should have the ability to interrogate the data for causality and signal detection, as well as the expertise to make evidence-based decisions that link back to the patient and healthcare provider, such as changed treatment guidelines, labeling changes, or product withdrawal. Data should also flow transparently beyond the national level into regional and global databases and be continually analyzed for new signals that may become apparent as datasets are enhanced.

(This discussion focuses on in-country PV systems covering products once launched and not specific post-authorization studies required of product developers as part of their risk management plans.)

Schematic of a functional LMIC pharmacovigilance system
Figure 1: Schematic of a functional LMIC pharmacovigilance system, with an action-based feedback loop to patients and HCPs (healthcare providers).

What is Smart Safety Surveillance (3S)?

Spurred by the growing safety need in LMICs highlighted by our country partners, the Bill and Melinda Gates Foundation (BMGF) convened a Safety and Surveillance Working Group (SSWG) comprised of NRAs from LMICs and HICs, multilateral organizations, product developers, and academia. The SSWG was tasked with developing a heat map (based on product launch date, product safety profile, and existing PV capacity in targeted countries) to identify geographies with patients at high safety risk, as well as recommendations for interventions that might work in these resource-limited settings to mitigate that risk. Based on the output of this SSWG and other internal discussions, the BMGF created the 3S strategy in 2015 to inform our PV strengthening work in LMICs.

The 3S approach is to use priority products relevant to the target country as the vehicle for PV systems strengthening. This allows often limited resources to be utilized in a focused way rather than attempting everything at once. By subsequently confirming or adding to the product’s safety profile, PHPs and NRAs can immediately show their public health impact to their patients and the value of the system strengthening to their stakeholders. PV systems can then be scaled in a sustainable way to other products and geographies of interest.

The first partnership in our 3S strategy was with the World Health Organization (WHO) and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) to validate the initial 3S principles. Three new products (one vaccine, two medicines) with known safety concerns were chosen, as well as six target countries based on disease burden and some existing PV capability to build on: bedaquiline in Armenia, Brazil, Ethiopia, and Peru; rotavirus vaccine in India; and tafenoquine in Brazil, Ethiopia, Peru, and Thailand (due to tafenoquine launch delays, primaquine was used as a surrogate in some cases). Each country went through a baseline assessment using the PV module of WHO’s Global Benchmarking Tool (GBT) and then developed a customized strengthening plan for their specific gaps. Impact was measured based on reporting rates and level of structural indicators measured pre- and post-intervention, as well as whether the data analyses confirmed or added to the product’s known safety profile.

Within the nine- to 18-month pilot period (depending on the country), it was clear that the 3S approach sustained systems strengthening and positive public health impact (as detailed in a recent publication). Armenia, for example, took an end-to-end strengthening approach, including training for PHP and NRA professionals, rolling out the Med Safety app for electronic data collection, breaking siloes between PHPs and NRAs (bedaquiline safety data was not previously shared with the regulator), and creating a national pharmacovigilance committee to analyze and if needed act upon this data.

In contrast, India primarily focused on creating a process for integrating and analyzing data already being collected across multiple siloed safety programs (regulator, manufacturer, immunization program, sentinel sites, and academic studies), with an analysis of more than 1,500 cases of intussusception concluding that there was no added risk from the rotavirus vaccines used in the country’s immunization program. In both cases, the systems created were then scalable to other products.

Following this successful proof of concept, 3S has informed and become embedded in all BMGF PV strengthening partnerships in Central America, the Caribbean, Southeast Asia, China, and Africa. It was also chosen as the main theme of the 18th ICDRA (International Conference of Drug Regulatory Authorities).

Case Study: African-Union Smart Safety Surveillance (AU-3S)

Our AU-3S partnership began in early 2020 with AUDA-NEPAD (African Union Development Agency) as the grantee and MHRA as a technical partner. It is a 10-year program to develop a centralized PV system for Africa: improving the safety of priority products over their whole lifecycle, enabling African ownership of their own data, piloting and scaling tools fit for their unique setting, end-to-end strengthening of safety expertise and decision-making capability, and collaborating with other continental initiatives such as AVAREF (African Vaccine Regulatory Forum), AMRH (African Medicines Regulatory Harmonization), and AMA (African Medicines Agency).

The COVID-19 crisis provided an opportunity to accelerate this program and address an urgent new need: the imminent arrival of vaccines with limited to no safety data in African populations. In late 2020, AU-3S shifted its short-term strategy to help four pilot countries (Ethiopia, Ghana, Nigeria, and South Africa, initially targeted as COVAX entry countries and covering 30 percent of the African population) with their COVID-19 vaccine safety response. MHRA continues to be the main technical partner, with WHO AfRO (Africa Regional Office), WHO EMRO (Eastern Mediterranean Regional Office), and US FDA (US Food and Drug Administration) added as advisors.

Within nine months, working with each country’s NRAs and PHPs, AU-3S was able to roll out targeted in- and cross-country solutions that:

  • Developed a digital health ecosystem for safety data collection (covering ~400M people)
  • Strengthened safety capability end-to-end across both NRAs and PHPs
  • Created an African-owned cross-country safety data integration and signal detection platform
  • Created a cross-country Joint Signal Management group that reviews and acts on any signals seen in the integrated data.

The public health impact of the AU-3S COVID-19 vaccine pilot has been immediate and significant. Based on data collected so far (detailed further here, with more than 20,000 reports across four vaccines, and more than 1,600 vaccine-event combinations analyzed), African regulators and public health decision makers from the four pilot countries were able to confirm through their own analyses that these vaccines have similar safety profiles in their own populations as in HICs, and that the benefits of vaccination clearly outweigh the risks. As the continent receives more supplies (currently at less than 10 percent of estimated need) and the amount and diversity of available safety data continues to grow, the end-to-end system that has been created is ready and capable of responding to any potential new signals. AU-3S is now looking to scale this vaccine pilot to other countries, as well as potentially leverage the system for anticipated COVID-19 therapeutics. Moreover, other regions could use the approach taken by the African Union as a model to build their own accelerated pandemic safety response.

Moving Forward

Other stakeholders interested in strengthening LMIC PV systems can build on the lessons learned from the 3S work and embed its principles and key success factors (see Figure 2) into their own funding strategies and implementation plans: using pilot products as the mechanism for systems strengthening and to show value to stakeholders, creating high levels of in-country buy-in and engagement before scaling in a sustainable way; working with peer regulators as technical partners; creating fit-for-purpose and interoperable digital health tools; and leveraging existing platforms (for significantly less investment). Protecting patient safety will continue to be an urgent concern in LMICs, particularly with the accelerated pace of product development in pandemic situations, and there remains need for additional funders and partners to invest in this space. 3S provides them with a proven approach to utilize limited resources in a value-added way to achieve this goal and will continue to be embedded in all of our global safety partnerships.
Schematic of a functional LMIC pharmacovigilance system
Figure 2: Common themes enabling successful 3S implementation by our partners across multiple products and geographies.
Back to Issue