It is always interesting to see a sponsor’s reaction when we describe the Dutch directive related to publication of trial results. It either ranges from nonchalant shrugging of shoulders to raised eyebrows to utter panic. In the Netherlands, the Competent Authority has issued a directive that the clinical trial agreement cannot include unreasonable restrictions on publication of trial results. Many small biotech companies are very open to publishing their trial’s results. On the other hand, there is an unfounded fear amongst some pharma (or at least their lawyers) that their confidential, proprietary data will be published without their consent. Of course, there are safe-guards in the directive preventing this kind of recklessness. And unsurprisingly, in a collaborative setting this is never the case.
The merits of publishing (and the perils and biases of not publishing) are well known and are not simply restricted to increasing academic knowledge but indirectly benefits subjects, patients and the community as well. Nonetheless, for a niche CRO such as CHDR, publication of peer-reviewed articles is one of the ways we establish our expertise in an particular field. And many of our sponsors initially become familiar with us by finding research we have (co-)authored in the literature or as poster presentations at conferences.
Also CHDR is somewhat unique in that the clinical scientists and research physicians who work as project managers are also PhD candidates. With the goal that within 3 to 5 years they have completed their degree, this also includes publishing 4 to 7 articles. This construct of having PhD candidates working in early phase clinical research unit has the benefit of educating them in the fundamentals of clinical pharmacology and at the same time they gain experience in how pharma and academia works (or doesn’t). This also enables us to address the knowledge gap between academia and industry.
Besides, all of our senior clinical scientists are encouraged to participate in peer-review of manuscripts in their respective fields. With some of our research directors and CEO, being Executive Editors and Editor-in-Chief of the British Journal of Clinical Pharmacology, respectively. This allows our management team to keep up to date with the latest, cutting edge, clinical pharmacology research.
It is motivating to see that even at a regulatory level there is a push for greater transparency. Since the beginning of 2015, the EMA will proactively publish the clinical reports submitted as part of marketing-authorization applications for human medicines, no doubt including many early phase studies. Similarly, it will be interesting to see how the new European Clinical Trial Regulation will be implemented. The regulation includes the requirement for Phase 1 trials to be registered and summary reports and lay summaries published within one year from the end of the clinical trial. No doubt we will see in due course if this forces the disclosure of commercially confidential information or sets out to do what it intended to do and provide information on innovative (and not-so-innovative) clinical research.
In 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.