The research clinic. Ready 4 research

The development of new drugs also takes long, because clinical trials are difficult to perform – partly because enrolment of patients is slow. This is not because patients are unwilling to participate. CHDR regularly approaches patients with a certain disorder directly, through advertisements in newspapers and on the internet. Often, literally hundreds of interested patients respond to a single campaign. In fact, the direct approach of patients is much more efficient than recruitment via doctors or hospitals. However, usually only a minority of the respondents qualify for the study.

Whereas self-management of diagnostics and therapeutics changes rapidly, patient involvement in clinical trials is lagging behind. Many studies fail because recruitment targets are not met. Multicenter trials where each center contributes a small number of patients hugely increases costs and complexity, and thwarts more sophisticated research. CHDR has therefore started another initiative to facilitate clinical trials: our first Ready-For-Research clinic in psychiatry will open this month, clinics in rheumatology and diabetes will follow soon. CHDR has a good overview which drugs  are developed by pharmaceutical industries. We invite patients with matching diseases who are willing to participate in clinical trials to come to our Ready-For-Research outpatient clinic, not for a concrete protocol but for a full medical screen and inclusion in our research database. With hundreds of respondents to advertisement campaigns, it shouldn’t take long to gather enough patients. The features of this particular group are used to approach pharmaceutical industries, which then allows the design of a protocol that suits the patients who are ready for research. This is more naturalistic than most predefined selection criteria, which often fit only a few percent of the population. Obviously, a patient’s decision to participate is still completely voluntary, and not all individuals will be eligible. But getting patients Ready-For-Research before the study is designed, will be much more efficient than trying to find them only after ethics approval of a protocol that excludes most patients.

CHDR is sharing this initiative with organizations for patients and medical professionals. Some diseases don’t attract much attention from the pharmaceutical industry, because they are rare and studies are considered difficult – even if the industry has a potentially effective drug in development. This may change when enough of those patients are ready to participate in a trial. Drugs that are primarily developed for a more prevalent condition, can then also be effectively studied in a rare disease where they may also have beneficial effects. It may not always be possible to find a study that matches the unmet medical needs of patients with a certain disease. But together we have a much larger chance of accelerating drug development. When patients get Ready-For-Research, investigators can design more efficient protocols. Patient empowerment should also focus on their contributions to clinical research.

The end of the multicenter phase II trial starts in Leiden

Clinical 03A- MQ

When performing clinical trials with novel compounds in patients there is always one major challenge. How can we enroll all 50 patients within a couple of months? Whenever CHDR gets this question we have a solid answer. Collaboration.

In 2014 we performed a proof-of-concept phase 2 trial in moderate to severe psoriasis patients. Not an easy population to recruit, especially not in summer when psoriasis tends to be better. Performing such a trial in normal circumstances involves one coordinating CRO and 15-20 hospitals. The enrollment of the 44 patients would take 7-8 months and an estimated 25 dermatologists would be co-investigators assessing the diseased skin of 1-2 patients each. Many of the centers will not recruit a single patient but require full initiation.

We chose a different path. Before start of the trial we approached all dermatologists of Western Netherlands. Although not the biggest country, we reached more than 180 dermatologists of which many were enthusiastic to help identifying potential patients in order to carry out high-quality research. At the same time we reached patients directly using an advertising campaign. And something extraordinary happened. Together with our dermatology partners we were able to enroll a total of 46 patients in 6 months. All assessments were performed by two dermatologists from the Erasmus MC at CHDR. With only two assessors we derived very consistent data, without large variability due to inter-observer variance. The logistics, execution and study handling was much less complicated since all was done at one site. And, most importantly, the patient experienced a professional and fully dedicated research atmosphere instead of a very busy outward patient clinic with long waiting times and bad coffee.

In dermatology this is a record-breaking performance in terms of speed. For the dermatological community in the Netherlands this first proof-of-concept study within the Dutch Trial Network Dermatology means a very important success on the road to more collaborative projects. After this kick off there are many projects evolving.

Obviously, this approach is also taken for other indications and other research fields. For the landscape of drug development this is an important change. Phase 2 trials can be efficiently executed at a single site with multicenter recruitment using both doctors but also direct-to-patient advertising. Data-rich early clinical phase trials with sophisticated and expensive methodology become feasible, e.g. taking advanced skin photographs, fMRI, PET etc. What do you need to engage these research communities? Again, the answer is strong collaboration between researchers, practicing physicians and above all the patients. The Netherlands is perhaps the ideal place for this, with a well-educated patient population who want to be involved in the scientific aspects of their disease and a tightly knit clinical research community. However, one questions remains. Why do we still need to perform multicenter trials in the way we did?

By: Robert Rissmann, Senior Clinical Scientist Dermatology

Clinical trials now and then: 1983 vs 2014

Clinical 04- MQIn 1983 I administered my first new medicine to a human being in the department of clinical pharmacology at the Wellcome Research laboratories in Beckenham, UK. It was the antiepileptic lamotrigine (Lamictal) and it eventually reached a turnover of more than a billion pounds, but we were not so sure then. Lamotrigine killed dogs (due to a metabolite that we later found was only formed in the dog) and did nasty things to the kidneys of a certain species of rat.  After internal discussion we went ahead anyway probably to the benefit of many patients with epilepsy and depression, who are currently being treated with lamotrigine. This first in human study was also one of the first with an approval of an ethics committee. Before this we just went ahead after approval by one of the directors.

So the study went ahead. My boss came down from a meeting, had an iv cannula inserted and took the first capsule, returned to his meeting and occasionally walked down for an ECG and a blood sample. The second subject was the chemist who invented the molecule and was rather nervous about causing problems for ‘his’ molecule. This almost inevitably induced a nasty migraine attack. “Don’t winge Dave”, we said as he lay there with a bad headache and we injected anti vomiting drugs in him. The rest is history.

This story may cause severe distress in the modern quality assurance officer, trial monitor, or an attentive regulator. However it is real and by describing the past tries to highlight the contrast with the present.

When we started CHDR in 1987 we very quickly started to do studies for industry and our maiden first-in-human study was with an antiarrhythmic that prolonged the QT interval in the ECG. This cost about 80.000 Dutch Guilders and this would be in today’s terms about the same amount in euros. The protocol had 20 pages and the whole submission dossier to the ethics committee about 30.  The study was completed very quickly after the protocol was written and monitoring was done by one of the employees of the company. She visited us once or twice from Belgium and as a rule brought Belgian chocolates.

The real cost of such a study today is a factor 10 higher, the dossier would be about 20 times more pages and the staff involved in such a study is about tenfold. Of course this is excluding the internal cost of the company. Most likely they will employ an IT company for the study database, an ECG company to read the ECG’s, a central lab company to study the clinical chemistry and a monitoring company to meticulously go over all the blood pressures and side effects. Rules against conflict of interest have done away with the Belgian chocolates. Many of this is global so there is quite a CO2 footprint associated with such a study.

Some of this is good and I would not suggest that we go back to the informal studies of the last century. However, we have a duty to keep new medicines affordable to the whole world. The cost of current drug development is without a doubt unsustainable and the efficiency of the process must be increased. Innovating drug development and its methodology can do this. This is what we have been doing at CHDR for the past 27 years. This new blog series will be written by all our staff members and tell you about our views on this innovation and what we do about it. We hope you are going to read them and share your comments.

By: Adam Cohen