Agnostic Toolkit for Introduction of a New Product for Children

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. Clinical benefit
2. Convenience
3. Cost
4. Availability
5. rogram 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 a child who needs the new product should be able to access it.

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.

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.

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

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.

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.

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.

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.

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.

Malawi Treatment CAB Case Study

Problem:Children were not getting appropriate antiretroviral therapy due to firstly the bitterness of the Kaletra (Lopinavir/ritonavir) solution and secondly the need to refrigerate Kaletra and many people not having access to electricity in Malawi.WHO recommended transitioning all people living with HIV for whom a formulation was available to a Dolutegravir based regimen in 2018. A generic paediatric Dolutegravir (pDTG) 10mg dispersible tablet became available in 2021.

Methods:The African Community advisory board (AfroCab) engaged with multiple stakeholders including patients and their caregivers, MOH, CHAI, National and District AIDS commissions, health education unit, implementing partners, civil society organisations and civil society advocacy forum to create advocacy and awareness on pDTG in 2022. Engagement was done through in-person meetings, awareness and sensitisation meetings with caregivers, trainings with health care providers and caregivers, media interactions and development of IEC material.

Outcome:AfroCab played a key role working with communities and multiple stakeholders in Malawi to increase awareness and successful adoption and rollout of pDTG.AfroCab even developed a monitoring framework to identify challenges e.g. stockouts and lack of training among the health care providers at the facility level and worked closely with the MOH to address these issues. This resulted in a successful transition of almost all children living with HIV to pDTG as per the MOH.

https://clintonhealth.app.box.com/s/f5tw51eded1xeslf0cqnlgkajmn5yk6i

Successful community engagement through the Community Advisory Board (CAB) at KEMRI Centre for Global Health, Kenya

Objective:To successfully engage the community before introducing a new study drug Cabotegravir for PrEP (pre-exposure prophylaxis)-HPTN 084

Methods:The Community liaison lead for the KEMRI Centre developed a community entry plan, whereby he reached out to the community leaders and stakeholders first, followed by the community and then finally the clients themselves. They used patient educators to introduce the study concept, demonstrations using skits and storylines that related to their community.

Outcome:The introduction of Cabotegravir was acceptable to the community leaders and stakeholders which helped with the buy in at the community level and clients. The importance of going through the community leaders and building a relationship with them was critical in getting the approval to introduce the new study drug. The concerning observation was that despite high awareness about HIV in the community, people were still unaware of what it is and how to prevent it. This further drives the importance of health literacy and community empowerment.

https://www.hptn.org/news-and-events/featurestories/communityengagement

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.

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.

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 authoritiesd. Countries could speed up registration of products in country by utilizing some of the assessments and inspection outputs already produced by WHO.

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 countryc. 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 processe. 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 changese.

2.1.3 Pre-requisites for the registration of a new product

• 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.

Successful Registration of Dispersible Amoxicillin in Ghana

Problem:The MoH in Ghana in collaboration with UNICEF is implementing the SPRINT (Scaling Pneumonia Response Innovations) initiative. The objective is to reduce deaths from pneumonia among children through scaling up pneumonia treatment with amoxicillin dispersible tablets (DT) and oxygen through a health systems strengthening approach. To achieve these objectives, there was a need to get approval for and registration of Amoxicillin dispersible tablet by the Ghana Food and Drugs Authority (FDA).

Methods:As Amoxicillin capsule and powder were restricted for local pharmaceutical manufacturers, the MoH requested the Ghana FDA to allow registration of the new product using WHO guidance and the evidence that the dispersible tablets would improve adherence to treatment and completion of the course. In addition, to reduce the financial impact on the local manufacturers, there were discussions held between the UNICEF prequalified suppliers of Amoxicillin DT and the local manufacturers for technology transfer. The MoH had review meetings with the Ghana FDA and the Ghana Health service to review the evidence and form a case to approve Amoxicillin DT. They also held advocacy meetings with them and submitted the required documentation and literature.

Outcome:The MoH received Ghana FDA approval for the need for Amoxicillin DT to be made available in Ghana and regulatory approval for registration of the drug. It has since been included in the essential medicines list and in the standard treatment guidelines.