EU eyes revamp of policy to speed drug approvals in developing countries

A revamp has been proposed because it is underused – just a handful of products have gone through the Article 58 process since its launch in 2004. The most recent is an antiseptic chlorhexidine gel that prevents new-born umbilical cord infections in developing countries. A joint project between GSK and Save the Children, it was approved late last month [26 April].

Possible improvements include financial incentives, borrowing from other schemes including the European orphan drug designation and the priority review voucher system used in the US, and even rebranding Article 58 altogether.

If it goes ahead, the revamp could be applicable to around 30 products currently under development.

Article 58 allows stringent regulatory assessments of drugs to be carried out by the European Medicines Agency (EMA) and World Health Organization. Together they issue positive (or negative) opinions on medicines and vaccines for human use that are intended exclusively for markets outside the European Union.

Regulators from developing countries can use these assessments, or so-called positive opinions, when deciding whether to approve new drugs in their own countries.

These regulators may not have the resources or in-depth expertise to undertake such scientific assessments themselves – certainly in the amount of detail routinely carried out by well-resourced regulators such as the EMA, the United States Food and Drug Administration (FDA), or Swissmedic, the Swiss medicines regulator. Many are more experienced at assessing and approving generic drugs rather new molecular entities that require more detailed safety profiles and data for analysis.

Usually they rely on Northern regulators for novel drugs approvals. But for drugs that have been designed specifically for conditions that disproportionately affect poorer countries, Northern regulators have little experience in what are often tropical diseases and epidemiology. Decisions on drugs are made in the interests of European or US patients, and do not necessarily take into account the needs and safety of, for example, target African patients.

For instance, a US or European approval won’t necessarily require data for safe large-scale use in Africa. That has meant at least one TB drug registered under the US orphan drug scheme could not be used in African TB patients, despite being approved by the FDA, because the trial design had excluded HIV positive patients.

That is why the process brings disease experts from the WHO together with the EMA’s committee for medicinal products for human use (CHMP) that routinely carries out assessments for drugs to be registered in the European Union.

“It’s very unique. It’s really trying to bridge the context gaps that Europe has with the scientific gaps that the regulators in these countries have,” said Nathalie Strub Wourgaft, medical director at product development partnership Drugs for Neglected Diseases initiative (DNDi), which has assessed the process.

And that’s why only certain drugs are eligible for Article 58; vaccines on the WHO expanded programme to countries immunisation, public health priority diseases, and WHO target diseases such as HIV/AIDS, malaria and tuberculosis.

The procedure has been lauded by global health experts including public development partnership, Medicines for Malaria Venture (MMV). With its Korean manufacturing partner Shin Poong Pharmaceutical, it submitted a child-friendly fixed-dose artemisinin combination therapy (ACT) of pyronaridine and artesunate, Pyramax Granules, to Article 58. Theirs was the first paediatric antimalarial to be granted a positive scientific opinion. With it, they say they were able to seek national approvals in several endemic countries, and importantly, WHO prequalification. With prequalification, the drug can be procured by United Nations agencies including UNAIDS and UNICEF.

“We benefited from excellent collaboration and scientific advice from the rapporteurs throughout the procedure as well as the involvement of the WHO – their joint assessment of the dossier resulted in a quicker prequalification process,” said a spokesperson for MMV.

Article 58 has been welcomed by several manufacturers who have found it helpful in shaping their clinical plans, according to a report jointly compiled by the European Commission, Bill and Melinda Gates Foundation and EMA. That includes UK manufacturer GSK, which has sought scientific advice under Article 58 for its forthcoming malaria vaccine, RTS,S (also known as Mosquirix).

And there have been proposals to expand it. The Global Health Technology Coalition, a group of around 27 non-government organisations interested in public health, said in a report published last month [19 April] that the US FDA should begin a similar approval process.

Despite this, Article 58 is poorly used by endemic country regulators and manufacturers alike.

There are several reasons. Firstly, although EMA publishes a scientific opinion, it does not result in a European approval. “One drawback of Article 58 today is the perception that it is somehow inferior to a full EMA dossier review,” said the spokesperson from MMV.

In addition, manufacturers have little incentive to use it, because there is little proof that the process speeds up approvals in developing countries (EMA says it did not collect this information).

So, the process of revamping is underway according to Dr Marie-Hélène Pinheiro, industry stakeholder liaison at EMA. She says increasing the use of Article 58 will be, in part, about making sure everybody understands more clearly how it works.

For instance, manufacturers need to understand that there is more flexibility now to submit their dossiers for assessment under the standard EMA pathway at the same time as via Article 58. (They may see the market potential of a product in the EU and apply through EMA’s central pathway to gain an EU marketing authorisation.)

A priority, however, is to get national regulators more involved in the process, she said. That way they might better understand that positive opinions are identical to a standard EMA regulatory review; that they require submission of the full regulatory dossier as any other product submitted to the EMA and are analysed by the same assessors in the same way as standard EMA products.

Developing country regulators should be helped to attend more meetings during which discussions over dossiers are held. That way they would get more of an idea of the rigour involved she says.

DNDi, which has also sought scientific advice using the Article 58 process for its forthcoming sleeping sickness drug fexinidazole, agrees more regulator involvement in dossier discussions could probably speed up national approvals. They have often not been involved, and often for logistical reasons and it has been frustrating. “[Article 58] needs a bit of tweaking here and there. We have experienced advice meetings with EMA and WHO and we get we really get a very thorough and complete feedback on our questions that we could share with the regulators of the endemic countries. We would have liked them to be there but they couldn’t make it,” said Strub Wourgaft.

DNDi thinks there should also be an automatic system to invite regulators to meet with EMA and WHO directly after a positive opinion so that the country-level approvals process can be kick-started in a more systematic way.

Another way to promote Article 58 amongst regulators, according to EMA’s Pinheiro, is to allow any medicine that receives a positive opinion from EMA, to be automatically WHO prequalified.

That might reinforce the idea that a scientific opinion from EMA is just as robust a process as prequalification because endemic countries recognise that as a badge of quality. Closer collaboration with WHO’s prequalification department might lead to much simpler country-level registration with the potential to speed-up registrations by up to a year, says MMV. The move to automatically prequalify is almost complete, says Pinheiro.

More substantive incentives to use Article 58 are on the cards too, although final decisions have not been made; under consideration are possible fee waivers, research funding, if rebranding is necessary and market exclusivity clauses. Manufacturers are reportedly keen on an orphan Article 58 designation so that they could borrow market exclusivity provisions from the EU’s orphan drug scheme (an orphan drug designation carries 10 years of market exclusivity across the EU countries).

However, market exclusivity might be difficult to achieve in practice. That’s because it would mean seeking agreement from individual developing country regulators. They would then have to amend their legislation accordingly.

Also under discussion, is the priority review voucher system. That would entitle a drug manufacturer to a voucher for an expedited review of another drug of its choice. Proponents say they welcome any incentives, while others say more discussion is necessary to decide what is appropriate for Europe.

Meanwhile, there has been a change in attitudes to Article 58 and a rise in applications to use the procedure, according to Pinheiro. “There is a change in the environment since it was launched. We are seeing more interest from both industry and regulators,” she said.

Source: Intellectual Property Watch