In a recent interview with Dr. Evangeline Wassmer, Paediatric neurology consultant at Birmingham Children’s Hospital, Proventa discussed the problems with rare disease clinical research. Dr. Wassmer has extensive experience in paedatric rare diseases –  paediatric Multiple Sclerosis, neurometabolic and neurodegenerative in particular. In this article, she addresses the key problems in rare disease research, including study design and factors that impact drug development for paediatric conditions.

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According to Dr. Wassmer: “Both the FDA and EMA have really changed the way they look at things. Drug companies are now allowed to extend their patency for a number of years if they do a paediatric study, so the drug companies are now much more motivated. The patency isn’t just for paediatrics, but for adults too. So you can imagine: for MS drugs which have a huge market in the adult world, an extra five years is a large financial incentive to do a paediatric study. As a result, drug companies are very keen to do these studies now, but there are still problems. 

“For example, the problem with MS drugs is that there are a lot of new drugs in development and the way they design these are akin to in adult studies. To do a conventional randomised controlled study you need a large number of patients. You can reduce the number by using placebo, which is probably unethical because you shouldn’t really not treat patients. However, if you use a placebo you can reduce the number of patients you need to power the study. But if you use a comparative study, you need much larger numbers – so we’re talking about 400 to 500 in each arm as a minimum. If you look internationally, you probably would be able to recruit around 200 paediatric MS patients every year. So as you can imagine, it takes an awful long time for a new drug to do a randomised controlled trial (RCT) – around four or five years.”

Unfortunately randomised controlled clinical trials can be subject to problems in the face of rare diseases including unclear hypotheses, insufficient sample size and poor selection of endpoints.

“One reason a long duration of a RCT is problematic is you never get to see the MRI scans as a clinician, so you don’t know if the drug is working. Also, the patient doesn’t know which drug they are on until at least the end of the study which can take up to five, or six years. So that’s quite hard to be taking a placebo injection for up to five, or six years to know if you are taking the active drug or not.”

Challenges with ultra-rare diseases

The complex issues that arise with rare diseases in clinical research are amplified with ultra-rare diseases. Poor understanding of the pathology and very small patient cohorts make it difficult to test therapeutic treatment of drugs for ultra-rare diseases. We discussed some of these challenges with Dr. Wassmer and their impact on clinical trials. 

“Now there’s a lot of even rarer diseases in which there are very few patients in the country, or even the world. So, those much rarer diseases are harder [to recruit for]. Firstly, these rarer diseases don’t have treatment, so any treatment you are using or trying out, you can pretty much only do phase I or phase II studies – so safety studies; and then in a small group you can try and test some efficacy. It is very hard to get to do a feasible phase III or even randomised studies because the numbers are just too small. What they often do are natural cohort studies. So, run a baseline and then compare the treated patients to the natural history. There are a lot of natural history studies going on. It’s a shame we didn’t start collecting that data years ago in anticipation for treatments, but for natural history studies you really must have long-term outcome data, not just two years.”

The impact of poor FDA/EMA collaboration 

Achieving FDA and EMA approval is the final goal for drug development programmes. Unfortunately, the differing regulations between the two bodies often result in problems for rare disease research. 

“Ideally you would have a surrogate biomarker, like an MRI scan or a blood marker, but the FDA prefers clinical outcome. The EMA is more amenable to using surrogate biomarkers.”

Unfortunately, drug companies are now creating two different drug designs – one for the FDA and one for the EMA. Which is a disaster really, because we then only have small numbers of patients as there are two studies which divide the small numbers. For example, in paediatric MS,  a drug company had three different study designs with the same drug and that’s a headache, because that means you can only recruit a very small number of people. This means that all three studies are set up to fail. 

“We did a meeting around five years ago, where we got the EMA and FDA in the same room and also included people from the university in Birmingham who discussed potential study designs. In terms of study designs, oncologists have done this much better. They have developed their network and multiple treatment options in factorial designs. The people from the university discussed  adaptive designs that aimed to reduce the number of patients you need. This needs further work and discussions with FDA and EMA.”

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Charlotte Di Salvo, Junior Medical Writer
Proventa International