Janssen Pilot Speeds Up African Approvals As Harmonization Project Expands

A recent pilot involving Janssen Pharmaceutica has shown that drug approval times were reduced from a median of 20 months to seven months in a set of sub-Saharan African countries using a new “collaborative registration procedure” as part of the African Medicines Regulatory Harmonization initiative. In part 2 of this article on the AMRH, we look at the results of the pilot, how the initiative is being expanded to include more countries and to cover clinical trials and pharmacovigilance, and how far efforts to set up an African Medicines Agency by 2018 might bear fruit.

In 2014, Janssen Pharmaceutica Inc., part of Johnson & Johnson, took part in a pilot run of a new “collaborative registration procedure” intended to encourage regulators in a number of African countries to rely on assessments already conducted by what are termed “stringent regulatory authorities” (SRAs), such as the European Medicines Agency and the US Food and Drug Administration, when reviewing products submitted for approval.

The pilot, which succeeded in shortening regulatory timelines from a median of 20 months to around seven months with one product in a number of African countries, is part of the African Medicines Regulatory Harmonization (AMRH) initiative (see box), which has been under way since 2009 and has also produced encouraging results with a regional joint assessment pilot carried out in the East Africa Community (EAC). (Also see "African Regulatory Harmonization Project Cuts Drug Approval Times And Saves Scarce Resources" - Pink Sheet, 30 Jan, 2017.)

The collaborative registration procedure (CRP) began in 2012 with a World Health Organization initiative that sought to facilitate national drug approvals by sharing data from the WHO’s prequalification of a particular drug with an African national regulatory authorities (NRA) that was reviewing an approval application for that product. Prequalification is a service provided by the WHO whereby it determines whether a drug complies with quality, safety and efficacy standards.

According to a briefing paper published last year by Mercè Caturla, Janssen’s global access regulatory lead for Africa and the WHO, the WHO CRP reduced registration timelines “significantly”, with more than half of all registrations completed within the 90-day target.

Then in 2014, the WHO began piloting a similar procedure for SRA-approved drugs, with support from the International Federation of Pharmaceutical Manufacturers and Associations, under which companies were to share detailed assessment and inspection data produced by an SRA so that the African NRA in question could use the data when assessing a product submitted for approval in their country.

Janssen’s Pilot

This procedure was first tested in a number of African countries by the EMA and Janssen Pharmaceutica, using a pediatric formulation of the company’s antiretroviral drug Intelence (etravirine) 25mg oral tablets. The results, said Caturla, were “very encouraging.”

“We started with WHO’s support on some collaborative registration procedure pilots of SRA-approved products. In this case the SRA was the EMA, and we also set up a kind of adapted dossier so we have fewer and more aligned requirements which includes the EMA assessment report and inspection report, and we ask them to rely on what the EMA has done so as to accelerate the regulatory approval. We have the results of the first pilot, they were very encouraging, and we are trying to improve the process.”

The pilot ran in two waves in a total of 11 African countries including the ZaZiBoNa nations (Zambia, Zimbabwe, Botswana and Namibia), which are part of the Southern African Development Community (SADC).

The dossier submitted to these countries was aligned to the initial EMA submission, and was well accepted by the NRAs, Caturla said. Some countries asked for additional documents (such as a price certificate or a power of attorney), with most accepting the provision of such documentation during the review, not at the point of the initial dossier submission.

The target review time was 90 days; this was achieved in Namibia (86 days) but took longer in others (10.5 months in Zimbabwe for instance, and about a year in Cameroon). It showed that “we can reduce timelines, which is great because before the median for approval was about 20 months according to a Bill and Melinda Gates Foundation (BMGF) survey, but we got a median of seven months in nine out of 11 countries,” said Caturla, who is also chair of the IFPMA’s African Regulatory Network.

The initiative showed that an accelerated registration process for drugs already approved by an SRA is possible, and that having the same dossier resulted in time and resource savings, according to Caturla, who said that a second pilot has been run with another Janssen antiretroviral, Prezista (darunavir), in the ZaZiBoNa countries. Submissions for this product began in November 2015, and the drug’s first approval was granted under the collaborative procedure in August 2016.

A third product, the TB drug Sirturo (bedaquiline), is undergoing a similar exercise, with the first submissions having been made in February 2016.

Getting all the regulators to trust each other isn’t all plain sailing though. “It will be a challenge,” Caturla said. “The countries have to understand that they have to rely on stringent regulatory authorities and not to duplicate an assessment if one has already been done.”

The AMRH itself conceded last year that “more work is required to encourage Regional Economic Communities, member states and cooperating partners and agencies to realize the medicines regulatory agenda in Africa.”

Expansion Under Way

Based on the successful results to date, the AMRH is now being expanded in terms of both geographical and regulatory reach.

It has been launched in the 15-country ECOWAS (Economic Community of West African States), where harmonization of technical standards and requirements is nearing completion, with joint dossier reviews and marketing authorizations to follow. Alignment of regulations in SADC has begun, starting with the ZaZiBoNa countries, while “modest” activities are under way in the Economic and Monetary Community of Central Africa (CEMAC) covering six countries, and the Intergovernmental Authority for Development (IGAD) in the Horn of Africa (eight).

Steps are also being taken to extend its scope to include clinical trials and pharmacovigilance. Strengthening oversight of clinical trials has for some time been the province of the African Vaccine Regulatory Forum (AVAREF), and its experience in vaccine trials is now being used to expand its activities to medicines and diagnostics, using funding from the Gates Foundation and other sources. The AMRH and AVAREF were leveraged for initiating trials of vaccine candidates during the Ebola outbreak in West Africa, and the regional economic communities (RECs) will make use of this experience and receive technical support from AVAREF for the clinical trials workstream, starting this year, the AMRH says.

New terms of reference for AVAREF were endorsed by heads of agencies at a meeting in Addis Ababa, Ethiopia, in June 2016, which also brought together the African Union, the REC secretariats, the World Bank, manufacturers, regulators from Europe and North America, and donors.

AVAREF’s remit now extends to the whole continent, and covers the clinical trials application package as well as trial approval by regulators and ethics committees working together. The collaboration part might be tricky, though, because regulators and ethics committees are not used to working together.

“They will have to look at harmonizing requirements and aligning ethics committees and health authorities because I don’t think there is much dialogue between the two of them,” says Caturla. “I guess they will also work on this theme of reliance in the review of the clinical trial protocol, I suppose it will be based on the same principle. But good to hear they are starting on that.”

Pharmacovigilance

Detecting, reporting and acting on adverse events with medicines is clearly a challenge in Africa, where pharmacovigilance is far from a well-established concept.

According to Paul Dearden, head of emerging markets at AbbVie in the UK, pharmacovigilance “is probably the biggest challenge. Regulation is relatively simple in a way, compared with pharmacovigilance.” Three years ago, he said, the Arab League produced a guideline on pharmacovigilance but it was not really appropriate for the situation in Africa. “It was based on the EU [pharmacovigilance] legislation, and there were implementation recommendations that African countries simply don’t have the resources to achieve,” Dearden told the Pink Sheet.

“It was issued in 2014 and we believe there is another revision due in 2017. It was coordinated by Egypt who, like other north African countries, are not part of the AMRH program. We hope that the work that the BMGF, AMRH and NEPAD [New Partnership for Africa’s Development] do will bring some sensible solutions for safety monitoring,” he said.

Once the revised guideline is out, “we will see if it has been tailored to what people can realistically do,” Dearden continued. “We hope that the work that the BMGF, AMRH and NEPAD do will bring some sensible solutions.”

He added: “It’s worth pointing out that regional harmonization in East Africa is further ahead. It is in the second phase of implementation, and is actively looking at pharmacovigilance, among other areas. The Bill and Melinda Gates Foundation is getting very involved in supporting pharmacovigilance for LMICs. The pharmacovigilance infrastructure in Africa is very limited and from the patient safety point of view it is important that there are good safety monitoring systems in place. We hope the BMGF will also be very active in helping agencies with practical solutions.”

Towards An African Agency?

A key aim of the AMRH efforts is to create an African Medicines Agency (AMA), which NEPAD says could be launched by the end of 2018. NEPAD, the African Union Commission and the WHO have been given responsibility for defining the scope of the products to be covered by the agency, and an AMA team has developed a legal and institutional framework and business plan, according to NEPAD’s 2016 annual report.

It’s not clear exactly what role such a body might eventually assume, and whether that timeline will be met. It is unlikely, though, to resemble a centralized drug assessment, approval and monitoring agency along the lines of bodies like the EMA and the FDA.

The AMA will probably have a role in coordinating national and regional regulatory systems and promoting cooperation and mutual recognition of regulatory decisions. “As I see it the aspiration is to have a legal entity by 2018,” Caturla said. “They are very positive on that but it’s not clear what the functions of this agency would be – they want to centralize some activities but not everything, so it would be supporting the regions.” One possibility, she suggested, is that the AMA might take on a centralized role for some global activities, for example in specialized areas like vaccines and biotech products.

“It is open to anyone’s interpretation,” said Vincent Ahonkhai, senior regulatory officer for global health delivery at the Gates Foundation. “It makes sense to think that if you have a network of regional bodies that function on a par with each other and are generally similar in their scope of work and how they work, you have the beginnings of an African agency. Is it realistic? Yes. Is it going to happen tomorrow? No.”

Challenges And Risks

While the AMRH is producing results, there are challenges in sustaining the momentum gained so far. The initiative is receiving finance from donors, but over the longer term the regions will need to look at how to maintain their growing regulatory activity when they can no longer rely on donor funding.

“The Bill & Melinda Gates Foundation strategy is to go where no one else seems to be going and then attract others in and step back,” Ahonkhai told the Pink Sheet. “Part of our funding typically involves research that goes into the scoping of various approaches that will allow you to find your own resources and become self-sustaining. That is being conducted in the EAC as we speak, and the goal is that within a certain period of time a certain percentage of funding will be coming from sources other than ourselves, and eventually we will have to exit and go elsewhere.”

The five EAC countries have recruited new staff to strengthen capacity, and they will gradually increase their own financial resource contributions over time to ensure the sustainability of the AMRH, according to a progress report from the AMRH partners drafted in December.

The World Bank Trust Fund is supporting a management consulting firm that is working with the EAC countries on sustainable financing of their NRAs and the regional harmonization initiative, and the AMRH would like to see the same level of commitment from the other regions, particularly ECOWAS and SADC, the report says.

But it cautions that a “major risk” to the success of the regional initiatives is “the ability to sustain the political will and financial commitment that is critical to continue the AMRH initiative in the absence of external donor support.” This risk is currently being mitigated by the sustainable financing mentioned above, but it will also be necessary to integrate harmonization activities into the agencies’ routine work processes.

Unless this is done, it says, “the resources of NRAs will become strained as harmonization is expanded. It is worth noting here that the vision of AMRH is to leverage reliance, and remove redundancies – therefore, a successful AMRH effort will bring tremendous efficiencies to all NRAs involved.”

The African Medicines Regulatory Harmonization initiative

The African Medicines Regulatory Harmonization (AMRH) initiative is based on strengthening regulatory capacity and encouraging the harmonization of regulatory requirements and practices with a view to improving patient access to safe, effective and quality medicines in a continent where they are often in short supply.

Coordinated by the African Union’s technical body, the New Partnership for Africa’s Development (NEPAD), the focus of the AMRH is on the countries of sub-Saharan Africa. Partners in the venture include the World Health Organization (WHO), the African Union Commission (AUC), the Bill and Melinda Gates Foundation (BMGF), the World Bank, the UK Department for International Development (DFID), the US government, and the Global Alliance for Vaccines and Immunization (GAVI).

Industry is represented by the International Federation of Pharmaceutical Industry Associations (IFPMA), which has set up an African Regulatory Network (ARN) to work with regulatory bodies and other stakeholders.

The creation of the AMRH was driven by the need to remove the barriers that hinder patient access to healthcare products, a problem that afflicts many low- and middle-income countries (LMICs) but is particularly pressing in sub-Saharan Africa.

ICDRA Conference

The AMRH and the AMA were on the agenda of the International Conference of Drug Regulatory Authorities (ICDRA) conference, and the public pre-ICDRA event that preceded it, which were held in Cape Town, South Africa, at the end of 2016. Caturla said the event was very fruitful and enabled industry to increase its interactions with regulatory bodies in Africa.

“We are happy now that we have the communication with the regulators,” she said. “Our main concern is that they harmonize at regional level, but also ideally we would like to be able to submit one dossier in Africa and get approval everywhere. Harmonization has to be at both regional and continental level, and this is why the regions need to talk to each other and rely on what has been done elsewhere with regard to dossier assessment and inspections. If our drugs have been approved by a stringent regulatory authority like the EMA, please rely on this and fast-track. So that is what we would like to see happening. It is happening faster and faster.”

Ahonkhai too was pleased with the conference. “Virtually every session” mentioned collaboration, harmonization and so on, he said, “which tells me it is resonating in a very real way with countries and stakeholders.”

From the editors of Scrip Regulatory Affairs.