Patient-led Clinical Trials

May 8, 2017 - May 9, 2017, London

Where patients and pharma join forces to deliver empowered trials

Turning Clinical Trial Recruitment on its Head

Oliver Timmis, AKU Society on how input from patient advocacy groups can lead to dramatic successes in trial recruitment & retention.

Heretofore, pharmaceutical companies have found recruiting for clinical trial participation to be one of the most burdensome and often unachievable parts of clinical trial research. So what about if it wasn’t the job of the pharmaceutical companies? What if patient advocacy groups, with their vast swathes of knowledge of disease area and patient population, did the job for them?

The answer is that while this is still rare, what few examples there are have been remarkably successful.

The truth is that it is becoming increasingly clear that pharma cannot recruit alone. Linking with patient advocacy groups is critical to working in collaboration with patients and gaining their trust.

The AKU Society is the first organization of its kind to develop and implement a clinical trial based on a scientist/patient model funded by the European Union. The Society’s CEO, Oliver Timmis explains that it primarily offers support to patients and forms scientific partnerships, with the aim of finding a cure for alkaptonuria (AKU).

A rare genetic condition, AKU affects more than 64 patients in the UK and 950 worldwide. Known colloquially as black bone disease, it involves a build-up of homogentisic acid in cartilage; bones and cartilage turn black and become brittle, eventually causing osteoarthritis in about 50 per cent of older adults with AKU.

“For the patients that usually means that in their twenties, they start to get quite a lot of joint and back pain, and by their thirties they require a number of replacement operations, and then by the end of their lives they often have had up to ten operations replacing every major joint in the body,” Timmis explains.

An early failure

For patients, this is an incredibly destructive and painful disease, for which there is no known cure –patients generally manage their AKU with a combination of pain control, joint replacements and light exercise.

The drug nitisinone, however, has shown considerable promise as the world’s first treatment for AKU. Already licensed for another rare disease, tyrosinemia type 1, the compound was first investigated as a potential treatment for AKU in the 1990s by the National Institute for Health in the US. Although Phase I, II, and III studies were carried out, the phase III trial was inconclusive – it showed that while the drug had a positive trend, this wasn’t statistically significant.

According to Timmis, this was largely due to poor trial design; the primary endpoint of hip rotation was fundamentally flawed, as a large number of patients had to take leave of the trial to avail of hip replacements.

“In hindsight, it was an obvious problem with the trial design; starting off with too few patients, they then lost quite a few of the patients they did have. So in the end, there just wasn’t enough to show if the drug was definitively having an effect.”

Patient demand

The positive trend identified, however, was also backed up by patient-reported outcomes; patients said they felt better while taking the drug, and had significantly reduced the pain medication, for example. Publication of the data from the failed study led to demand for the drug among the AKU community, with demands for a new trial that would be designed appropriately.

From this, the AKU Society was born in 2003. Timmis explains that the Society spent the next seven years focusing on research, collaborating with the University of Liverpool in the UK. They worked to collect some basic data; for example, testing nitisonone in an animal model. The organization’s researchers also carried out observational studies at the Royal Liverpool University Hospital.

These observational studies were key, leading to the development of a validated severity score index for AKU, meaning that for the first time, a numerical value could be applied to the condition. Timmis explains that this finally allowed any improvements or disimprovements in the patient condition to be tracked more easily; for example, that their severity score had improved by two points in a year.

“That’s really important for clinical trials as it means that it takes into account all aspects of AKU, not just hip rotation like the original American trial. This is a much more flexible scale, because it can be used even if patients have operations to replace joints, but it also gives it that numerical value which makes outcomes more obvious.”

Trial 2.0

At this point, the AKU Society felt there was enough data to carry out a clinical trial again and approached Swedish Orphan Biovitrum (Sobi), the makers of nitisinone.

“As the trial had failed in the US, they were hesitant about carrying out another trial, but we showed them that we had the data, and the patient population too. Eventually, they came around to the idea and now they fully support us.”

In 2011, the AKU Society, Sobi, and three hospital investigative sites applied to the European Commission for funding; in 2012 the consortium were awarded €6 million euro. With Sobi providing the drug for free, and other in-kind contributions being made available, the DevelopAKUre trials could begin. The consortium is now made up of 13 hospitals, pharmaceutical companies and consultancies, universities, biotech companies and national AKU patient groups and Timmis says this is unique in its evolution.

“We see it as that the AKU Society initiated the clinical trial and that we are now equal partners. This is quite unusual, because more often than not, the initiative for a clinical trial comes from a pharmaceutical company and patient groups are lucky to be involved at all. With us, it’s very much the other way around – we started the trials and now we have an active role in them.”

This reverse approach also means that patients have a much stronger voice in how the trial progresses; any patient-reported outcomes are taken into account, and patient wishes can be incorporated into the design of the trial from the outset.

Leading on recruitment

Ensuring the patient voice is heard within trials means that recruitment is targeted, informative and engaging. This approach significantly aided in trial recruitment with DevelopAKUre, says Timmis; by nature of the AKU Society’s involvement, patients could see immediately that it was a patient-centric trial and that they would have a much bigger role to play.

If you told a pharmaceutical company that you were aiming to recruit half the patient population of a rare disease, they would say it is impossible to do. We also did it within a timeframe of nine months which they might also say is impossible.

“This certainly made recruitment easier at the start. It also meant that we led on recruitment, as we already had existing databases of patients.”

The AKU Society recruited 140 patients across Europe to partake in the trial, a number that represents half the eligible adult patients in the region. This one-in-two success rate is unheard of in the clinical trials space.

“If you told a pharmaceutical company that you were aiming to recruit half the patient population of a rare disease, they would say it is impossible to do. We also did it within a timeframe of nine months which they might also say is impossible; but we already had those relationships and the databases. For me, it makes a lot of sense to have a patient group leading on something like that, where it relies on patient contact; we can have a more open discussion, because there is a trust there as we know so many of them already.”

This established relationship also aids in trial retention; thus far, there have been minimal dropouts and mainly for unavoidable reasons, such as a patient becoming pregnant.

“No one has dropped out because the trial isn’t working, or because it’s too much hassle for them, and that’s something we are quite proud of. As we have only 140 patients to begin with, we can’t afford to lose too many,” Timmis admits.

This may also be because of the Society’s desire to minimize inconvenience for the patients; among other efforts, they provide transport to and from trial sites.

“We respect that patients have to give up time from work, and holiday leave, and may have to travel to a country they’ve never been to before, even one where they can’t necessarily speak the language. That can be quite intimidating and scary and our efforts to make it easy as possible for them recognise all that.”


Timmis also admits that the nature of the condition may partly explain the willingness of patients to become involved in the clinical trial.

“It is quite common in rare diseases, that patients see the clinical trial as their only chance as they realize there is such little research maybe going on in their own rare disease that this could be the only opportunity to get involved in something like this.”

But discussions with patients on why they become involved have elicited a wide range of responses; some wish to help the next generation of AKU patients, or feel that a few years’ inconvenience may ultimately provide them with a lifetime of efficacious treatment.

The SONIA 2 trial is now ongoing and is not due to finish until 2019. Meanwhile, the next trial in the DevelopAKUre stable is now recruiting; SOFIA, an observational study, aims to elucidate the timeline of AKU development. Doing this will answer a crucial question about when to begin any potential treatment.

“We need to find out if it is better to give the treatment at 16 years of age, or 25 years when the symptoms have developed. It is an unknown as with back pain and joint pain, you cannot see what’s happening inside the body, so it is uncertain whether the pain is the start of disease, or whether there has been a few years of build up to that point,” says Timmis.

The new blueprint

The DevelopAKUre success story should serve as a blueprint for a reversal in clinical trial instigation. Timmis says that with some encouragement, many patient advocacy groups and patient organizations may find that they have exactly what a pharmaceutical company with a pipeline drug is seeking –for example, having an active patient database is incredibly valuable, particularly in rare diseases.

Indeed, a promise of rapid recruitment and high rates of retention is highly attractive for pharmaceutical companies usually plagued with problems in these areas.

“In our case, it could not have been done without patient group involvement as it helped tremendously in trial recruitment and retention. It has been well-documented that in clinical trials where patient groups have been involved, they tend to run more smoothly and efficiently.”

Timmis believes that patient groups must recognize their special assets and attributes and come forward with their patient data and insights; these provide a significant opportunity for companies fearful of inadequate recruitment and retention in their proposed trials.

“Pharmaceutical companies must recognize that patient groups have a role, but also patient groups need to recognize that they can be useful in clinical research; many are surprised at our success and say that they wouldn’t know how to get involved in this manner. We need to give patient groups the confidence to know that they can play an important role in vital clinical trials”. 

Patient-led Clinical Trials

May 8, 2017 - May 9, 2017, London

Where patients and pharma join forces to deliver empowered trials