How to test subjects at home

Tuesday morning, 8.55 hours: monthly scientific advisory board meeting at CHDR.

I was one of the first to arrive at CHDR’s auditorium this morning as I will be presenting the new study that I and Christophe, the elective student who is working with me on the project, are preparing. As the auditorium is filling up and most of the regular attendees find a seat my heartbeat slightly increases in anticipation of giving the presentation. It is not that I am not capable of giving an oral presentation, only this time we have incorporated an extra feature into the presentation that will give a live insight into the study that I will be presenting.

While Christophe is checking the functionality of our surprise feature for the last time Piet Hein van der Graaf opens the meeting by welcoming everybody. Four session are on the menu this month: three introductions on new projects and one presentation on the results of a project that was already finished. According to the agenda Christophe and I are up for the second talk so we are still relaxed. However, the presenter of the first study is experiencing some familiar problems with the national railway and will not make it in time for the first talk.

This means that we are up to kick off the meeting. While I gather my papers and find my way to the microphone I start to wonder what effect this unexpected change will have on the surprise feature.

After the general introduction to the topic of the study, at home monitoring of two patient groups using a wearable biosensor, Christophe takes the microphone to address the technical aspects of this so-called healthpatch, which is able to continuously monitor the user’s heart function, respiratory rate and body position.

Another feature present on this biosensor is stress-level detection. And this is where our presentation becomes very interesting. What nobody but Christophe and me knows is that I am wearing the biosensor on my chest and in the next slide the audience will be able to look at my live vital signs during the presentation. The thought of everybody studying my stress level already causes slight stress. As the next slide appears, revealing my live ECG, heart and respiration rate and my stress level and the audience realizes what they are actually looking at people start making jokes about my rising stress level, which is indeed the case. One person even wonders if an ambulance should be called as my heartbeat keeps on rising. Next to the feeling of exposing myself in front of the whole advisory board this nicely reflects the increased stress that many will recognize when standing in front of an audience that is eyeballing you.

An interesting phenomenon is also seen at the end of my talk, during the questions: everybody can see that my heart and respiratory rate increase when a question is asked and just before I answer these vital signs quickly decrease again, a reflection of my initial insecurity on my ability to answer the question and the subsequent relieve of knowing the answer.

Using this device to monitor patients in the comfort of their own homes will reduce burden and costs of clinical trials, as well as provide more naturalistic data as they did for us in a way hitherto impossible. Watch out for my next blog where I hope to be able to share the first results of our trials@home project!

Ellen ‘t Hart

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.

Publication: we all benefit

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.

Justin Hay, Senior Clinical Scientist

Translational biomarkers: towards a better understanding of modern drugs

New medicinal compounds are proteins. These biopharmaceuticals can trigger immune responses causing side effects such as rash, fever, and fall in blood pressure. As long as these responses do not interfere with the effectiveness of the compound (e.g. via formation of anti-drug antibodies), or seriously hamper the patient’s well-being, the occurrence of these immune responses may be accepted by patients and pharmaceutical companies and regulatory bodies; the clinical development of the compound is not necessarily halted or terminated. For example, a monoclonal antibody like Herceptin, commonly used for the treatment of metastatic breast cancer, induces fever and inflammatory symptoms in 40-60% of all treated patients. As long as the benefit-risk balance for a drug is favorable, clinical use of the compound is defendable. However, it is remarkable from a scientific point-of-view that we administer compounds to humans when these inflammatory effects are poorly understood.

Some intravenously administered biopharmaceuticals reach a maximal plasma concentration at a time beyond the infusion duration. This phenomenon cannot be explained by conventional pharmacokinetic rules, and potential causes and consequences have only be speculated on so far.

These are examples of uncritical acceptance that certain drugs may behave ‘odd’. At CHDR we aim to optimally understand the behavior and effects of drugs, even if it concerns long-term marketed drugs. CHDR invests in the investigation of insufficiently understood drug behavior/effects. For example, we have recently demonstrated that therapeutic proteins non-specifically stick to the endothelium, which translates into delayed maximal plasma concentrations. Furthermore, we are relating inflammatory effects of biopharmaceuticals in vivo to drug responses observed in cell-based systems, aiming to develop in vitro methodology that better predicts drug effects in vivo. Importantly, a more extensive exploration of drug effects may exceed the level ‘nice to know’, as demonstrated by the first-in-human trial with anti-CD28 antibody TGN1412. All 6 healthy volunteers receiving this investigational compound experienced cytokine release syndrome, resulting in a potentially long-term disruption of the immune system. Evaluation of the TeGenero case by key opinion leaders led to the conclusion that the problems resulted from unforeseen biological drug action in humans, rather than from clinical misconduct. This case shows that drugs affecting previously unexplored pathophysiological pathways require careful exploration in tailored early phase clinical studies, with biomarkers that are fit-to-purpose.

CHDR advocates that recent evolutions in drug development require a more direct approach to monitor intended and unintended drug effects. For biopharmaceuticals and compounds with new mechanisms-of-action, biomarkers reflecting early/direct drug effects on cells or tissues should be selected. This will allow a more efficient, more rational, and safer translation between different stages in drug development: from animals to humans, from in vitro experiments on human cells to clinical studies, and from healthy volunteers to the targeted patient population. Such ‘translational biomarkers’ will play an increasingly important role in future drug development.

Matthijs Moerland

Research Director Translational Biomarkers