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EMA Orphan Chief On Smart Strategies For Companies

This article was originally published in Scrip

Executive Summary

15 years ago there was very little for patients in the way of treatments for rare diseases, but since Europe enacted its Orphan Regulation and set up the European Medicines Agency's Committee for Orphan Medicinal Products (COMP) in 2000, a lot has changed. Now, more than 1,500 products have orphan designation and the committee is turning its attention to ensuring more orphan medicines get to patients, says Bruno Sepodes, the committee's chair. He talked to Scrip Intelligence about the fruits of transparency, how the COMP pioneered patient involvement at the agency, and why companies need to think beyond orphan designation.

Bruno Sepodes

As of July this year the committee had received more than 2,273 submissions for orphan designation, of which 1,546 had translated into positive opinions for designations. And to date the European Commission has approved a total of 123 orphan drugs. "The numbers speak for themselves," says Sepodes, who has just been re-elected chair of the committee for another three years. "There was next to nothing in this area, so I think the scientific work of the committee is running smoothly," he says. He points to J&J/Pharmacyclics' Imbruvica (ibrutinib) in cancer treatment and Roche's Esbriet (pirfenidone) for idiopathic pulmonary fibrosis as important breakthroughs for patients.

Much of the success is down to the incentives on offer, particularly the 10-year period of market exclusivity after marketing authorization when similar medicines for the same indication cannot be placed on the market. Interestingly, Sepodes says that moves to increase transparency at the EMA have had a positive effect in attracting attention. "When you designate something for the first time there is a spark of interest and the outside world wants to know more. We've been seeing it more since we've been publishing the meeting minutes."

Traditionally orphan drug developers have been most interested in rare cancers, but this is starting to change and the committee is seeing an increasing number of submissions for orphan designations for treatments for eye conditions, like retinitis pigmentosa, and skin conditions such as epidermolysis bullosa, as well as for conditions related to premature birth in newborns. The shift could be down to the increase in prevalence of some cancers as patients live longer thanks to advances in treatment. For example, the committee no longer views renal cancer as a rare disease. "Companies that want to make use of the incentives may be moving to other conditions," he says. For the most part, big pharma has the biggest interest in oncology and is particularly focused on hematological cancers, while the organizations behind other designations tend to be SMEs or academics, he adds.

Now Sepodes believes it is time to try and shift the focus from orphan designation further downstream to help companies bring these products to market. The COMP effectively operates as a "gate opener" at the time of designation and makes sure that the developer's proposals are on course to fulfil all the right criteria for developing a medicine that treats or prevents a rare disease. The committee also steps in when the developer is going for marketing authorization to check whether it has made good on fulfilling those criteria. According to Sepodes, more needs to be done to encourage developers to think about their "post-designation strategies". He urges companies to take advantage of incentives other than market exclusivity, chiefly free protocol assistance. This could help companies design the best possible trial to ensure an effective medicine gets to patients. "We can help check the significant benefit is there, that the disease prevalence is maintained and that the design of the trial will support the claims being made." Sepodes is surprised that more companies don't go for the assistance, and the reasons why they don't aren't clear, he says. The number of requests for protocol assistance rose only from 79 in 2011 to 113 in 2014.

He also reminds developers that they can go for conditional approval, rather than full approval, for their orphan drug. "Far from being a lesser option, conditional approval is an opportunity to gain more knowledge and support development." This would give companies a better shot at getting full development further down the line, he adds.

Meanwhile. the adaptive pathways initiative, which aims to bring new medicines to market at an earlier stage to an initially small pool of patients, is likely to be good news for orphan drugs. "Here we have the chance to do phased development and shape that development according to the results: it's something I really want to highlight to companies." A number of orphans have been selected as pilots for the initiative, and as these move forward Sepodes expects the committee will be increasingly involved in progressing the initiative. Already two COMP members have been heavily involved in designing the "conceptual phase" and Sepodes says he is excited about the possibilities ahead for orphans.

Another opportunity for the orphan community to help move drug development forward is patient reported outcomes, which he says have in the past been overlooked by regulators and companies. This is now beginning to change and both are recognizing the importance of patient reported outcomes. "Orphans offer a very nice way to test this concept, we're talking about very small populations, highly difficult trial designs and it is, especially for significant benefit, very important to have patient related outcomes," he says.

Indeed, the committee was the agency's guinea pig in terms of developing patient involvement and should be seen as a reference for other committees, according to Sepodes. Among its members are three patient representatives selected by the commission who help find patient experts able to offer input on whether a product may offer significant benefit or a major contribution to patient care. "We have to look at what is really meaningful to the patient, and no one is a better expert on the disease than the patient," said Sepodes. He adds that patients are invited to discussions with companies, which he describes as a "very, very fruitful interaction". Sepodes believes that the patient voice is getting louder and says companies are not only bringing their own patient representatives to meetings, but also starting to put more stock into gathering patient reported outcomes.

Meanwhile, change is afoot that could improve prospects for companies hoping to win orphan designations and to clear up some confusion in the orphan legislation that has at times ended in the courts. The commission is reviewing how both "significant benefit" and "similar product" should be defined. Significant benefit determines whether the size of a new drug's benefit constitutes an important enough advance compared with that of existing treatments. "Similar product" ensures that no product that is deemed to be "similar" to an existing orphan drug is approved for the same indication during the 10-year exclusivity period.

However, the terms are now somewhat dated and the lack of clarity has led some companies to take legal action against EMA decisions rejecting orphan designation. Sepodes is pleased that the definitions are to be amended. "They need to be updated. Back in 2000, they made sense – we didn't know what was coming in terms of scientific developments and progress. They no longer reflect what is state of the art or the problems that developers face." He would like to see the definition of significant benefit more clearly identify what a major contribution to patient care might be.

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