Agnostic Toolkit for Introduction of a New Product for Children

Children have been left behind when it comes to introduction of new medicines or even diagnostics for better clinical management and improved prognoses for children. It has been suggested that pharmaceutical companies are reluctant to study new drugs and formulations in children due to financial, regulatory, and ethical complexities as well as operational challenges ^a. This is despite most regulatory bodies requiring all relevant drugs to be studied in children. The Pediatric Research Equity Act (PREA) launched in 2003 in the US and the European Paediatric Regulation (EPR) launched in 2006 have made paediatric drug development mandatory ^b,c.

The Global Accelerator for Paediatric Formulations (GAP-f) network was established by the World Health Organisation (WHO) to address the paediatric treatment gap^d. The collaboration platform works across different sectors developing a prioritization framework for optimal drugs/formulations for children and helps across the entire lifecycle of a new drug/formulation introduction for children from clinical trial design, implementation, evaluation, regulation, adoption, procurement, rollout, and monitoring of the impact.

Process of Adoption of a New Product

Prior to the introduction of a new product in the country, there needs to be a process of evaluation and agreement that the product is needed. CHAI has put together a valuable ‘5’ lenses approach to assist in the decision-making process:

1. Patient Level
   • Clinical benefit
   • Convenience
2. Program Level
   • Cost
   • Availability
   • Program complexity

International disease management guidelines, regulatory approvals, clinical trial data, WHO prequalification are critical in the decision-making process.

Evaluating the benefits of the new product in comparison to existing standard of care of treatment in the country in terms of prognosis, side effects, type of formulation, adherence to treatment and quality of life is most important.

If the new product is superior to the current standard of care, long term benefits vs. cost of the medication should be reviewed. In spite of the cost of the new product, if the benefits in terms of disease prognosis, quality of life and mortality outweigh current standard of care, a rights based approach should be used whereby LMICs should be supported to develop a phased transition plan and opportunities to reduce the cost through generic manufacturers and pooled procurement should be explored so that any child who needs the new product should be able to access it.

Why an 'Agnostic' Toolkit?

While a few excellent toolkits are available for specific diseases e.g. CHAI’s ‘New HIV drug introduction toolkit’, there is no generic toolkit that can be adapted for any disease for introduction of new products in children^e.

Introduction of a new product requires significant investments in advocacy, engagement and planning which includes logistic, financial, monitoring and evaluation.

The purpose of this disease agnostic toolkit is to support the countries and interested stakeholders to develop an implementation plan for introducing a new product for children in their country so that it can be financially viable, sustainable, and readily accessible to all those who need it.

Audience

It is meant to serve as a guide for the GAP-f partner network, ministry of health, health care advocates, civil society, non-governmental organisations, donor agencies and implementers with key recommendations/steps that could be adjusted as per the country requirements.

When To Use The Toolkit?

The toolkit comes in once the product has been approved by WHO/Stringent regulatory authority (SRAs) for global use and is included in the global recommendations for treatment or diagnosis of the disease in children.

It assumes that paediatric indications, dosing guidance and safety data for use in children will be available.

How The Toolkit Should Be Used?

The resources in this “agnostic” toolkit should be used to develop a product specific rollout plan. Elements of that plan could include:

• Disease specific burden in country (age group/gender); prognosis; treatment options etc.
• Product specific: Classification; safety and efficacy; FDA/EMEA/SRA/NDRA approval with any specific clauses for children – weight bands and age groups.
• Product specific tools for each step of the rollout developed from the resources provided.
• Any specific country nuances.

A Living Document

We envisage this evolving as additional tools and resources become available and propose it will be a living document that can be updated. The toolkit defines a series of steps which can be initiated concurrently or consecutively as felt appropriate by the country leadership and team.

Proposed Steps

1. Community and other Stakeholder Engagement
2. In Country Registration
3. Revision of National Guidelines
4. Planning and Budgeting
5. Quantification
6. Procurement and Supply Chain
7. Health care provider capacitation
8. Demand Creation
9. Pharmacovigilance
10. Tracking and Impact

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References

• a. Conroy S, McIntyre J, Choonara I, Stephenson T. Drug trials in children: problems and the way forward. Br J Clin Pharmacol. 2000 Feb;49(2):93-7. doi: 10.1046/j.1365-2125.2000.00125.x. PMID: 10671901; PMCID: PMC2014901
• b. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review - US Food & Drug Administration
• c. Guideline on pharmaceutical development of medicines for paediatric use - European Medicine Agency
• d. Global Accelerator for Paediatric Formulations Network (GAP-f) - WHO
• e. HIV New Product Introduction Toolkit - Clinto Global Health Initiavie

Stakeholder engagement is an essential part of the approval and regulatory process in country and could be started even prior to the regulatory process. Engagement of political leadership, civil society, technical experts, program managers, donors and the community can provide the much-needed momentum for paediatric products to get approval.

In many chronic diseases affecting children, there are unacceptable delays of up to 7-10 years from approval of medications for adults to approval of the same medication for children. This has resulted in some clinicians needing to resort to off label use for lifesaving conditions.

1.1.1 Objective of the Engagement

There needs to be clear stated objective/s for the engagement. This would include increasing awareness and creating advocacy for the new product; adoption of the new product in the national management guidelines; rollout and possible funding opportunities to support the country to procure the product, train the health care providers, support the transition to the new product, etc.

1.1.2 Community Engagement

Parents, caregivers, and patients themselves are strong advocates for better medicines and management for their illness. Hoos et al. have outlined in their comprehensive overview on partnering with patients in the development of medicines that we need to move from ‘engagement’ to ‘involvement’ of patients, caregivers and patients as their involvement can streamline drug development globally and approvals in country, ensure the time taken from regulatory approval to registration is shortened, create demand, and inform on the post marketing surveillance^a.

Involving communities early in the discussions for a new product introduction is essential. In most countries, patients, parents, caregivers, and patient advocacy groups are pro-active and engaged in finding better management options for their disease. Amongst the communities, it is also important to engage community and traditional leaders who have influence over the community. It will help to increase awareness on the new product as well as validate the use.

Amongst the communities, it is also important to engage community and traditional leaders who have influence over the community. It will help to increase awareness on the new product as well as validate the use.

1.1.3 Mapping of Stakeholders

For each product under consideration, before starting with stakeholder engagement, there is a need map out the interested parties. These could include relevant colleagues from:

• Ministry of Health
• Clinical specialists
• Health care institutions- clinics and hospitals
• Health care researchers and academic institutions
• Technical working groups
• Professional associations
• Health care industry representatives
• Health policy makers
• Funders
• Community advisory boards
• Patients, parents, caregivers, patient advocacy organisations

1.1.4 Stakeholder engagement plan

A stakeholder engagement plan will help identify priorities for each stakeholder to support advocacy, adoption, and demand generation for the new product.

1.1.5 Process of engagement

The process should include informing the stakeholders, consulting with them on the next steps and ascertaining that the new product is needed, involving them in the decisions and collaborating with them to ensure the process is sustainable. The engagement could be broken down by groups of stakeholders where the discussion could vary from being very technical to semi-technical.

The key points to note regardless of the group being engaged is to use the same process, be inclusive, maintain good communication, transparency, be respectful of priorities and expectation of outcomes. This will help the continued engagement and feedback post registration and usage of the new product for post market surveillance.

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1.1.6 References

• a. Hoos A, Anderson J, Boutin M, Dewulf L, Geissler J, Johnston G, et al. Partnering With Patients in the Development and Lifecycle of Medicines: A Call for Action. Ther Innov Regul Sci. 2015 Nov;49(6):929-939. doi: 10.1177/2168479015580384. PMID: 26539338; PMCID: PMC4616907.

To enable a product to be available and accessible for clinical management of a disease, it needs to be registered by the national regulatory authority (NRA) in the country. Each NRA has their own requirements in terms of forms and supporting documentation that needs to be appropriately filled and submitted. However, in some low- and middle-income countries (LMICs), the national capacity to perform this function is not there in terms of human resources, this results in some depending on the stringent regulatory authority (SRA) to perform this function ^a,b.

2.1.1 Stringent Regulatory Authority

The national regulatory authorities that participated in the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) until 2015 are considered Stringent regulatory authorities by the Global Fund and WHO. These are considered to apply stringent standards for quality, safety and efficacy during their regulatory review of drugs and vaccines for marketing authorization^c.

2.1.2 Collaborative Registration Procedure

WHO introduced a collaborative procedure (CRP) for accelerating registration of prequalified finished pharmaceutical products (FPPs) in 2013 through information sharing between the WHO prequalification and the National regulatory authorities^d. Countries could speed up registration of products in country by utilizing some of the assessments and inspection outputs already produced by WHO^d.

In 2016, this was revised to include products that had been approved by an SRA, after a successful pilot study conducted in 2014 to allow confidential sharing of a detailed assessment of the product by an SRA with the NRA. It was found to reduce the time taken for approval in the country, promote collaboration, allow regulatory convergence and build capacity in the country^c. An evaluation of the SRA CRP conducted by WHO and European Medicines Agency (EMA), found that since its establishment in 2015, 59 approvals were granted to 16 medicines in 23 countries through this process^e. This reaffirmed that the SRA CRP was producing the results needed in terms of quicker timelines for approval of medications in countries, however the recommendation was to further improve the collaboration between the regulatory authorities, expand the usage of the procedure and provide guidance on management of post-approval changes^ec.

2.1.3 Pre-requisites for the registration of a new product^b

• The pharmaceutical manufacturer needs to have filed a dossier with the National Drug regulatory authority.
• Clinical trial data on safety, efficacy, dosing for drugs/formulation (age/sex bands)
• FDA/EMEA/SRA approval
• Inclusion in WHO/other global guidance for management
• WHO pre-qualification
• CPP- Certificate of Pharmaceutical Product issued by a country’s regulatory authority at the request of a product owner or sponsor to support the registration process of a pharmaceutical product of another regulatory authority (speeds up the process).
• Product sample
• Manufacturer dossier on quality assurance for each raw product and capacity to meet demand.
• Fees

Generally, for a donor agency to be able to support procurement of a product in country, it needs to have WHO pre-qualification and have FDA/EMEA/SRA approval. Despite the submission of the above, the MOH and other stakeholders need to check in to ensure any bottlenecks are addressed in a timely manner otherwise the process can be delayed leading to children not being able to access the treatment on time.

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2.1.4 References

• a. Moran M, Guzman J, McDonald A, Wu L, Omune B. Registering new drugs: the African context. London: Health Policy Division, The George Institute for International Health. 2010
• b. Hill S, Johnson K (2004). Emerging Challenges and Opportunities in Drug Registration and Regulation in Developing Countries. DFID Health Systems Resource Centre.
• c. World Health Organization & WHO Expert Committee on Specifications for Pharmaceutical Preparations (2018). Fifty-second report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (PDF). Geneva, Switzerland: World Health Organization. p. 355–6. ISBN 978-92-4-121019-5. OCLC 1039407367
• d. Collaborative Procedure for Accelerated Registration - WHO
• e. Vaz A, Roldão Santos M, Gwaza L, Mezquita González E, Pajewska Lewandowska M, Azatyan S, Saint-Raymond A. WHO collaborative registration procedure using stringent regulatory authorities' medicine evaluation: reliance in action? Expert Rev Clin Pharmacol. 2022 Jan;15(1):11-17. doi: 10.1080/17512433.2022.2037419. Epub 2022 Feb 12. PMID: 35130803.
• f. Davidson, A., Grace, A.J., Schwarz, E.W. et al. The Value of the Certificate of Pharmaceutical Product in Registration of Medicinal Products. Ther Innov Regul Sci 36, 163–167 (2002).

To validate the usage of a new product in country, the product needs to be included in the national clinical management guidelines for the disease. This needs to be done in collaboration with the MoH, specified program and technical specialists, academia, researchers and civil society.

A thorough review of current guidelines needs to be undertaken before a revision is undertaken to understand the specific areas needing to be revised. There are various tools to support the development and assessment of clinical practice guidelines. Vlayen et al. did a systematic review of twenty four appraisal tools that they found in literature and found that none of the tools scored the evidence on which the clinical content of the guidelines were based^a. The Cluzeau’s ‘Appraisal Instrument’ on which the ‘AGREE’ tool was based is the only one which was validated^a.

3.1.1 Planning

The decision-making process should be inclusive with the Ministry of Health inviting participation of stakeholders representing the community, technical specialists, program managers, implementing partners, non-governmental organisations working in the field, academia and researchers to agree on the process.

There needs to be agreement on the following:

• Chair of the guidelines committee needs to be elected
• Scope of the revision of the guidelines
  • Adoption of new product as per global recommendations
  • If the national guidelines for the clinical management of the disease is to be revised or a circular with the revised recommendation will be issued
  • Agreement on style and format of the guidelines
• Budget for revision, training, and dissemination of new guidelines
• Revision of essential drugs list as applicable

3.1.2 Process of revision

A writing committee should be formed through representatives from the stakeholders. The process followed can include:

• Formulation of review questions
• Identify and review the evidence
  • Review of the literature on the new product which includes clinical trial data and any experience from other countries
  • FDA/EMEA/SRA approval, check for any clauses
  • WHO and other global recommendations
  • Comparison with current treatment: benefits, side-effects, palatability, adherence, resistance profile etc.
  • Quality of the data
• Review current national guidelines to identify areas that need to be updated; once a review is undertaken, the guideline should be reviewed in entirety, so that if other areas need to be updated, that could be also done.
• Develop recommendations
  • Alignment with National Strategic plan
  • Clinical guidelines for implementation
  • Cost effectiveness of new treatment
  • Research recommendations (expansion of evidence database)
  • Monitoring and evaluation plan
• The revised guidelines are then sent for comments to the various academic institutions, technical working groups, civil society and patient advocacy groups, implementers, and funders for comments.
• Alternatively, if a circular is being issued, the wording and phrasing of the circular should be reviewed by the team to ensure that there is no ambiguity in the understanding
• Revisions or clarifications are made as per the review to ensure that the guideline or circular developed is clear and in keeping with the global guidance
• Final version of the guideline is prepared and sent for the authorizing signature/s.
• Launch the guideline
• Plan a schedule for next review and update

3.1.3 Training and Dissemination

Discuss the timing of the training, logistics, budget and the dissemination process- the information, education, and communication (IEC) material that needs to be developed. Responsibility for the training and development of materials needs to be laid out.

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4.1.4 References

• a. Vlayen J, Aertgeerts B, Hannes K, Sermeus W, Ramaekers D. A systematic review of appraisal tools for clinical practice guidelines: multiple similarities and one common deficit, International Journal for Quality in Health Care, Volume 17, Issue 3, June 2005, Pages 235-242

In preparation for the rollout of the new product, a transition/implementation plan needs to be developed.

The Implementation Plan needs to specify the following:

• Priority population groups for the rollout
• If the transition would be phased with an estimated time frame
• Estimated volume of product with associated budget by year
• Source of financing
  • MoH meeting with treasury on the required budget
  • Cost-benefit ratio
  • Alternative source of financing (donors, patient interest groups, philanthropic organisations etc.)

4.1.1 Prioritisation Matrix and Transition plan

There may be current products in use for the clinical management of the disease. To limit wastage of resources, most LMICs prefer to use what is currently available unless the old product is ineffective.

Depending on the status and stock of the old product, and budget available, program managers will work with the technical specialists, technical working group and MoH officials to develop a prioritisation matrix highlighting patients/population groups who would have access to the new product first followed by the others with an associated time frame by which all patients will have access to the new product.The plan would include planned coverage of the patients by the new product by quarter and year.

4.1.2 Budget

Volume of the new product needed by quarter and year needs to be estimated considering the planned coverage, disease burden and incidence of the disease.

An estimated annual budget is then calculated for the time frame of the transition.

4.1.3 Financing

MoH needs to meet with the Treasury to discuss the budget needed. They need to communicate the following:

• Advantages of the new product
• Cost-benefit ratio (consider in the long term)
• Difference in costs between the old and new product
• Associated reduced morbidity and mortality
• Reduced cost to the government due to reduced hospitalisation and disability adjusted life year (DALYs)

The treasury will have to advise the MoH if the transition to the new product is possible in the current financial year or if provision needs to be made to apply for funding through other sources e.g., donors- PEPFAR, Global Fund etc., other governments, philanthropic organisations, non-governmental organisations, disease advocacy groups, etc.

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4.1.4 References

• a. Gupta A, Juneja S, Vitoria M, Habiyambere V, Nguimfack BD, Doherty M, Low-Beer D. Projected Uptake of New Antiretroviral (ARV) Medicines in Adults in Low- and Middle-Income Countries: A Forecast Analysis 2015-2025. PLoS One. 2016 Oct 13;11(10):e0164619. doi: 10.1371/journal.pone.0164619. PMID: 27736953; PMCID: PMC5063297.
• b. Wettermark, Bjorn & Persson, Marie & Wilking, Nils & Kalin, Mats & Korkmaz, Seher & Hjemdahl, Paul & Godman, Brian & Petzold, Max & Gustafsson, Lars. (2010). Forecasting drug use and expenditures in a metropolitan health region. BMC health services research. 10. 128. 10.1186/1472-6963-10-128.

Forecasting is the procedure of estimating the quantity of new product that is needed or will be used within a specified timeframe^a,b. Quantification is the process to estimate the volume or quantity of the new product needed within a specified timeframe and when it should be delivered to ascertain that the transition of the new product is sustainable and there are no shortages^a,b. It is often calculated with an associated budget. Hence, quantification uses both forecasting and supply planning.

5.1.1 Forecasting

To forecast accurately, the following need to be evaluated:

• Demographics
• Historical use of the current product by year
• Current product stock in hand, procurement pipeline, and estimated usage
• Burden of unmet need
• Expected program performance (improved diagnosis, etc.)

In addition, the inclusion of the following would be useful:

• Expected rate of roll out/uptake- demand creation
• Calculation of quantity by age band for medications- adjusting for aging out and weight changes
• Expected duration of the new treatment for medication
• Number of tests needed routinely using the old product in case of diagnostic kits
• Assumptions may be needed where data is unavailable or unreliable

5.1.2 Supply Planning

For the transition of the new product to be sustainable and for health care providers to be confident that they don’t need to revert to the old product due to stock and supply chain issues, it is important to have a supply plan in place.

The plan needs to include calculation of adequate quantities of the new product and budget required considering the following^a,b:

5.1.3 Engaging the right people

To ensure that the results from the quantification can be used purposefully, it is important to engage the right people^a. At a minimum, the technical specialists, program managers, procurement managers, logistics team should be engaged. Depending on the product, pharmacists, laboratory specialists/advisors and clinicians may need to be engaged. To do the forecasting and analytics, statisticians, epidemiologists can be invited to provide support. In certain countries, international organisations and donors provide additional support for this exercise, however we need to ascertain that in-country capacity is built as quantification is not a once off exercise and needs to be ongoing to ensure that there is no break in the procurement and supply of the new product.

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5.1.4 References

• a. John Snow, Inc. 2017. Quantification of Health Commodities: A Guide to Forecasting and Supply Planning for Procurement. Arlington, Va.: John Snow, Inc
• b. Quantification - USAID
• c. Reflection paper on forecasting demand for medicinal products in the EU/EEA

The procurement process and supply chain need to be robust for sustainability of the rollout of the new product and to ensure that there is equitable distribution of the product across the country especially where the need is.

In particular, the following need to be considered:

• Manufacturer/s- number and if any are generic
• Capacity of the manufacturer/s
• Raw material for the product- availability, pipeline
• Manufacturing and Marketing License
• Quality assurance of the product

There is a need to implement the World Health Assembly resolution WHA72.8 to improve equitable access to fair pricing and increase collaboration between countries for improved access to health products.

WHO/Europe with the Norwegian Ministry of Health and Care services and the Norwegian Medicines Agency have developed the ‘Oslo Medicines Initiative’^a. “This provides a neutral platform where the public and private entities can jointly outline a vision for equitable and sustainable access to effective, innovative and affordable medicines^a.”

6.1.1 Procurement

Procurement systems need to be robust to ensure that the new product is of good quality, can reach the people who need it, is affordable and sustainable. Effective procurement systems need capacitated individuals in the country who can monitor regulatory compliance and quality assurance of the product. There is also a need to work with multiple stakeholders to ensure that there is no stock out of essential medical products including test kits, medicines, vaccines etc.

Various international organisations are working to support countries globally through different mechanisms:

• Launch of the Oslo Medicines initiative
• Strengthening of in country capacity
• Pooling of resources for joint procurement

6.1.2 Supply Chain

The supply chain needs to be reviewed periodically due to the various conflicts around the world to ensure that the raw material for the medication is in adequate supply and there is no stockout of the final product. This can be supported through the ‘Oslo Medicines initiative’.

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6.1.3 References

• a. Supporting the development and strengthening of procurement and supply management systems
• b. Health product procurement and supply chain management - UNDP
• c. John Snow, Inc. 2017. Quantification of Health Commodities: A Guide to Forecasting and Supply Planning for Procurement. Arlington, Va.: John Snow, Inc
• d. Procurement Tools - The Global Fund

Once the guidelines have been revised or a circular has been issued informing the health care providers about the new product, the Ministry of Health supported by technical specialists, working group members, academia, implementing partners, international organizations, and/or donors need to develop a training plan to capacitate the health care providers. The type of training being offered is often country specific and could be in multiple formats to ensure that the health provider can access the format/s that are most suitable to them in terms of logistics.

7.1.1 Training of trainers

Most LMICs opt for training of master trainers from each region due to cost, space, and time constraints. These master trainers then take the responsibility to disseminate the training at the health district and sub-district level in smaller groups. This is additionally supported by MoH program managers, implementing partners, academic institutions and non-governmental organisations working in those communities.

7.1.2 Virtual Training

Online training through virtual platforms such as Zoom and Microsoft Teams became necessary during the SARS-CoV-2 pandemic and remain a critical format for training on and dissemination of guidelines. It has allowed the MoH program managers and technical specialists to reach a wider audience allowing health care providers from remote sites to attend the sessions and participate. These sessions can be recorded and made available to health care providers to watch/listen in their own time. This however comes with a few challenges such as data usage, bandwidth, and connectivity issues which need to be addressed.

7.1.3 Self-learning platforms

Self-learning platforms are increasingly becoming popular among those health care providers who are unable to attend virtual or in person sessions due to time constraints and are willing to or prefer attending the recorded sessions or reading the guidelines in their own time.

7.1.4 Additional Support

1. Job Aids:In short-staffed clinics or in clinics employing the ‘Super-Market’ approach, primary health care clinicians provide care and treatment for all diseases in one place, hence it may sometimes be challenging to remember all the updates and nuances in the different disease specific treatment guidelines and associated medicine dosages for children. Job Aids can play an important role after the training has been completed to support adherence to the guidelines and serve as a reminder to health care providers of the process flow in the guidelines, timing of laboratory tests as well as more importantly dosages for children. These job aids can be in the form of desk reference tools e.g., flow charts, check lists, abridged guidelines, posters, dosage charts etc.
2. Ongoing Mentorship, Training and File Audits:All trainings should be accompanied by ongoing mentorship at the site level. File audits can be conducted periodically to identify any gaps in adherence to or interpretation of the national guidelines and should be addressed through targeted mentorship and retraining where needed.
3. Helplines and Online support:Toll-free and WhatsApp helplines, email, and online platforms where challenges, questions and clarifications can be discussed and responded to by technical experts have been shown to be useful and should be encouraged as it will improve the understanding of the guidelines. The questions, clarifications and responses can be used to update the guideline and improve future trainings and guideline development.

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Demand creation is defined as the process to increase demand for a product or service using marketing techniques^a. This is usually used to attract consumers to products or services that are unknown to them. In the health care setting, involving communities early in the discussions for a new product introduction is essential. Empowered patients, parents, caregivers, and patient advocacy groups are usually pro-active and engaged in finding better management options for their disease.

To improve involvement of all the communities regardless of their educational and economic status and as a result advocacy, there is a need to improve health literacy. This will help not only with demand creation to ascertain better patient outcomes and sustain the use of the new product but also help to inform research and policy. When engaging communities, it is important to initiate discussions with community and traditional leaders who have influence over the community as their ‘buy in’ will help to increase community awareness on the new product as well as validate the use.

8.1.1 Health Literacy

This is the extent to which an individual, parent/caregiver can access or understand health information, treatment options and services available to make an informed decision about their own health or for a child/family member that is being cared for by them.

Treatment literacy is health literacy but specific to a disease condition. Patient advocacy groups often criticize the health care providers that they do not take the time or have enough time to discuss the disease, investigations, and treatment options with the patients.

It is crucial for health care providers to engage with the communities including patients, parents and caregivers as increasing health literacy in the community will improve transparency of health procedures and processes, information sharing, health seeking behaviour, adherence to preventative measures and treatment, build trust, and generally improve the health of the community.

8.1.2 Health Literacy Strategies

It is important to develop communication strategies for our patients/caregivers that are in acceptable format which is easy to understand and retain. The ‘P Process’ is a tool that is used for planning social and behaviour change communication (SBCC) programs, it was developed in 1982 and is still used today to design, implement, monitor and evaluate communication strategies.

It has five steps: Inquire; Design your strategy; Create and test; Mobilize and monitor; and Evaluate and evolve^b. It is based on three cross-cutting concepts: SBCC theory, Stakeholder participation and Continuous capacity strengthening^b. The authors caution the reader not to assume they know the audience and to engage stakeholders as much as possible when developing the communication material. It is also critical to have a monitoring and evaluation plan so that the program can be strengthened continuously along the way.

The following methods are commonly used to provide Health Literacy:

• In facility: Health care provider health talks, group sessions, one on one sessions
• In the community: group sessions, community health days
• Mass media: radio, television
• Information, education, and communication (IEC) material: pamphlets, videos, etc.
• Social media: WhatsApp messages, Facebook platform
• Edutainment: Using plays and games

An excellent example of using lived experiences to generate demand generation is that from ICAP who have developed a video series ‘ The Power of PrEP’ of testimonials from individuals in the Democratic Republic of Congo, Kenya and Nigeria who have used PrEP and benefitted from it. These are being shared by different countries in facility waiting rooms to help with demand creation for PrEP as well as to train health care providers.

8.1.3 Community led Monitoring

This is a collaborative method where the members of the community collect, analyse and use information from health care facilities and elsewhere so that they can improve their understanding of the program and any gaps. They then use this data to advocate for better management and/or resources.

Community led monitoring can assist the country in identifying facilities where the new product is not yet available or is available but not being dispensed for e.g., due to a gap in training or understanding of the guidelines. They can also assist in identifying facilities with drug stock out or facilities where the patients are not being educated and empowered on all available treatment for their condition. It has been used often in the HIV treatment space to identify facilities which have drug stockouts, staff shortage, lack of consulting space and need better management skills, training for stigma and discrimination, key population sensitisation, differentiated service delivery options, etc. MoH can use these reports to improve the program and service delivery and focus on making the program client centred.

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8.1.4 References

• a. 7 Examples of Demand Creation
• b. Health Communication Capacity Collaborative (November 2013). The P Process. Five Steps to Strategic Communication. Baltimore: Johns Hopkins Bloomberg School of Public Health Center for Communication Programs
• c. What is Community-Led Monitoring & Why is it Important?
• d. Demand Creation - ITECH
• e. The Power of PrEP Video Series - ICAP at Columbia University

While randomised clinical trials (RCTs) are the gold standard for collection of information on efficacy, safety, and risks of a new medical product, they are unable to provide information of drug usage in a real-world setting. The safety data collected through clinical trials has certain limitations due to sample size, population studied, inclusion/exclusion criteria for study enrolment, geographical region/s where the study was conducted, controlled environment, etc.

There have also been some changes in regulation to ascertain that new treatments can be rapidly accessed by patients e.g., the 21st Century Cures Act signed into law on December 13,2016, supports the acceleration of medical product development and brings new innovations and advances to patients who need them^a. Hence, ongoing pharmacovigilance and post marketing surveillance are critical not only in country but globally to strengthen the safety and efficacy data on the new product and to support its continued use.

It is also in the country’s interest and part of its ethical and legal responsibility to continue to monitor and evaluate any new medical product after it has been launched in the country.

9.1.1 Safety and Toxicity monitoring

It is only when the product is in use by the general public, that some of the safety and toxicity concerns are identified^b. It would be judicious to perform ongoing safety and toxicity monitoring pro-actively for new and previously approved medical products. These fall under post-market surveillance.

Post Market surveillance is defined as “active, systematic and scientifically valid collection, analysis and interpretation of data or other information about a marketed device”^c.

9.1.2 Real World Evidence

The FDA collects real world data (RWD) from different sources including electronic medical records, medical claims data, data from product and disease registries etc., to create real world evidence (RWE) which includes usage, safety, and risk information to support regulatory oversight of medical products after they have been registered as well as to advance the development of better treatment^d.

Since the passing of the Cares Act, the FDA established a framework in December 2018, to strengthen the evaluation of RWE to support additional indications for the already approved product as well as to support the ongoing monitoring and evaluation of the new product’s usage, side effects and risk profile^e.

Pharmacovigilance is defined by WHO as ‘the science and activities related to detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems’^f. WHO recommends that every country should have a pharmacovigilance system which allows them to conduct these activities at a local and national level and collate the information for reporting into a global platform. There are many success stories from the adverse event reporting for immunization and global collaboration that we can learn from and apply to other products^f.

It is therefore crucial that there is in country capacitation and development of electronic pharmacovigilance systems. Training and ongoing mentorship should be provided to health care providers to support the reporting of any adverse events associated with the new product. National regulatory authorities should be capacitated to evaluate the reported adverse events to determine causality and inform the global database on the new product usage, safety and risk profile.Health care providers need to be capacitated to perform routine pro-active ongoing safety and toxicity monitoring of both new and previously approved medical products as this will improve the quality of care provided to our patients.

The European union requires every new medicinal product to have a risk management plan (RMP) as part of its licensing and approval process^c. RMPs contain the product’s safety profile, measures to minimise and prevent risk in patients, measurement of the effectiveness of risk minimisation procedures as well as plans to collect additional data for safety and effiicacy of the medication^c. They need to updated throughout the lifetime of the product and submitted to the EMA whenever the risk management profile is altered due to new information^c.

There is a move to collecting more real world information outside of the randomized control trial setting which despite being the ‘gold standard’, does not allow collection of data among routine clinic and hospital patients. Post-authorization safety studies (PASS) can be designed to allow prospective collection of additional safety and risk information and help plan for risk minimising management and prove the effectiveness of such measures.

The specialist cohort event monitoring (SCEM) methods used in the UK and EU are an excellent example of how routine use of such methods in clinical practice can help inform safety and risk information for new and existing products^e.

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9.1.3 References

• a. 21st Century Cures Act - US Food & Drug Administration
• b. Rodrigues D, Silvestre S, Monteiro C, Duarte AP. Medication and the Risk of Falls: An Analysis of Adverse Drug Reactions Reported to the Portuguese Pharmacovigilance System. J Clin Med. 2023 Nov 23;12(23):7268. doi: 10.3390/jcm12237268. PMID: 38068320; PMCID: PMC10707262.
• c. Title 21 - eCFR System
• d. Real-World Evidence - US Food & Drug Administration
• e. Framework for FDA’s Real-World Evidence Program - FDA 2018
• f. Tools and Innovations in Pharmacovigilance - WHO
• g. Guidance for post-market surveillance and market surveillance of medical devices, including in vitro diagnostics - WHO
• h. Risk management plans - European Medicines Agency
• i. Post-authorisation safety studies (PASS) - European Medicines Agency
• j. Layton D, Shakir SA. Specialist Cohort Event Monitoring studies: a new study method for risk management in pharmacovigilance. Drug Saf. 2015 Feb;38(2):153-63. doi: 10.1007/s40264-014-0260-x. PMID: 25564333; PMCID: PMC4328122.

New clinical products can enhance the quality of life through reducing morbidity and mortality while also reducing costs for the individual and health system and workdays lost^a. Lichtenburg conducted an econometric analysis of the impact of new drug launches on longevity in 52 countries from 1982-2001, and found that the launch of new chemical entities accounted for nearly 2 years increase in life expectancy across the 52 countries from 1986-2000^b.

Once a new product has been rolled out, it is important to not only assess the robustness of the procurement and supply chain processes but also to ensure there is demand for the new product and uptake. This should be followed by an assessment of the impact of the product in the management of the disease- early diagnostics, impact on disease prognosis and eventually the disease burden in the region.

In a retrospective cohort analysis in South Africa between July 2014 and March 2016, it was noted that the introduction of Bedaquiline reduced all-cause mortality among patients with multi drug resistant TB or rifampicin resistant TB (hazard ratio 0.35; 95%CI 0.28-0.46) and with extensively drug resistant TB (hazard ratio 0.26; 95% CI 0.18-0.38) compared with standard regimens^c.

Amongst 9419 HIV positive children and adolescents 0-19 years of age (CALHIV) on treatment in six Eastern and Southern African countries, it was noted in a retrospective analysis that 93.4% of the CALHIV using Dolutegravir (DTG) were virally suppressed, and among those who were previously unsuppressed, 79.8% achieved viral suppression once transitioned to DTG^d.

The impact of prevention of mother to child transmission of HIV (PMTCT) programs with the implementation of “treat all” on the burden of disease among children has been well established. Despite South Africa having the largest HIV burden among children globally, and sub-optimal treatment coverage, it has seen the among the largest declines in both mother to child transmission of HIV and AIDS deaths from 2017-2018 ^e.

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10.1.2 References

• a. Lichtenberg FR.The economic and human impact of new drugs. J Clin Psychiatry. 2003;64 Suppl 17:15-8. PMID: 14680422
• b. Lichtenburg FR. The impact of new drug launches on longevity: evidence from longitudinal, disease-level data from 52 countries, 1982-2001. NBER Working Paper No. 9754 June 2003 JEL No. I12, F00, L65, O3, O4
• c. Schnippel K, Ndjeka N, Maartens G, Meintjes G, Master I, Ismail N, et al. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. Lancet Respir Med. 2018 Sep;6(9):699-706. doi: 10.1016/S2213-2600(18)30235-2. Epub 2018 Jul 11. PMID: 30001994
• d. Bacha JM, Dlamini S, Anabwani F, Gwimile J, Kanywa JB, Farirai J, et al. Realizing the Promise of Dolutegravir in Effectively Treating Children and Adolescents Living With HIV in Real-world Settings in 6 Countries in Eastern and Southern Africa. Pediatr Infect Dis J. 2023 Jul 1;42(7):576-581. doi: 10.1097/INF.0000000000003878. Epub 2023 Feb 14. PMID: 36795586; PMCID: PMC10259212
• e. Johnson LF, Patrick M, Stephen C, Patten G, Dorrington RE, Maskew M, et al. Steep Declines in Pediatric AIDS Mortality in South Africa, Despite Poor Progress Toward Pediatric Diagnosis and Treatment Targets. Pediatr Infect Dis J. 2020 Sep;39(9):843-848. doi: 10.1097/INF.0000000000002680. PMID: 32433224; PMCID: PMC7958302