What being an intern is all about…

For the past 4 weeks I have been an intern at the Leiden University Medical Centre, at the department of Pediatrics, a part of my training as clinical pharmacologist. And let me tell you that from senior clinical scientist at CHDR to intern at the hospital is a world of difference…

On Monday my internship would start at 8.15 in a room that is of course very well hidden in the many hallways of the hospital. An extra handicap here was that my supervisor (and the only person I knew from the whole department) was still away on holiday, but she had assured me that there would be a colleague who would know of me starting as an intern that day. So the challenge of finding that person (of which of course nobody that I met in the many hallways knew anything about) began. In the end I found someone who could guide me to the room where I had to be present that morning, and the secretary had been able to find a document with the specifics (supervisors, meetings and rooms per week) of my internship. And so the 4 weeks commenced.

In this period I noticed that some of the supervisors tend to underestimate you as you are ‘just an intern’. They are surprised to hear that I was not a student, but an experienced researcher with a PhD. And that is a funny thing, that you tend to put people in a box, and if that box is labelled ‘intern’, that there are specific presumptions about your level of experience. I on the other hand, was eagerly consuming new information and integrating that into my own knowledge. Because I have a somewhat different background than my supervisors (I am not an MD) and because working at CHDR is different from working in the hospital, I was of course curious about certain procedures and the reasons why things are being done in a certain way. And I noticed that in some cases the questions that I posed made people wonder why a procedure is as it is, and if it is still the correct or most logical way.

And I recognize that from my own experience as a supervisor of interns. At CHDR the roles are opposite; I have been the supervisor of a number of students, guiding them in clinical projects and overseeing the writing process of their master thesis. And when they are fresh in, they pose questions. Good interns tend to challenge existing procedures and make you think about things you do routinely and possibly without good reason or thought. And this makes interns valuable assets to a company; they are (hopefully) eager to learn, but they also possess a healthy portion of critical thinking. They are new to the company, see it from a different perspective and, let’s not forget, are fresh out of college and have a lot of textbook knowledge readily available.

Being able to do a clinical rotation at the Pediatrics department has been an interesting experience, and it made me be aware of what being an intern is all about. But even more importantly, it also renewed my critical thinking!

So, value your interns, and it wouldn’t be bad idea to once in a while be an intern in your own company to renew your own critical view…. And, keep on learning!

Ellen ‘t Hart

Gene therapy studies @ CHDR, how to get started?

In the past 9 years as senior clinical scientist, I have been challenged many times by working with new and innovative drugs. Sometimes, unraveling the best study design to study novel drugs is not the only challenge I encounter.

Last year I got the opportunity to work with GMO’s (genetically modified organisms). More specifically: genetically modified vaccines and a gene therapeutic. For this type of interventions there is – next to the regular guidelines for clinical trials – additional legislation. As it is likely that we will encounter more of these types of interventions in the future, I find it worthwhile to use this blog as the opportunity to share my experiences with overcoming some of the legal and administrative hurdles associated with GMO’s in early phase clinical development.

In short, for the evaluation of clinical gene therapy research different aspects come together;

1) genetic modification,

2) environmental aspects and

3) clinical research.

As a result, also a whole bunch of different legal regimes based on European directives, come together. Unfortunately, the implementation of the directives into Dutch legislation contain aspects that still are not converged sufficiently.

Generally in the Netherlands, besides ethical approval, the institute that wants to work with the GMO needs a license from the Ministry of Environment. This implicates that next to the CCMO as reviewing committee and the Ministry of Health as competent authority (laid down by The Medicines Evaluation Board), the Ministry of Environment is involved as well. Furthermore, COGEM (the Netherlands Commission on Genetic Modification; http:// www. cogem.net) acts as advisory committee for obtaining the environmental license and bureau GGO (Bureau of genetically modified organisms; http://www.ggo-vergunningverlening.nl/) is involved for all administration regarding the license. Thus, there are many legal instances that the researcher need to involve and provide with the right documentation. However, the researcher can always get help from “Loket Gentherapie” that streamlines the processes and communication between the different bodies and is always of help when a researcher is lost in legislation.

There are only some minor differences for the clinical trial application for gene therapy studies to the EC/CA compared to a ‘regular’ clinical trial application. It is the application for the environmental license that makes the process complicated, or more accurately: lengthy.

For the license, the Ministry of Environment focuses in particular on the environmental aspects and the environmental risk analysis of the application. Just like a normal permit for installing for example your roof top terrace, the permit is available for public inspection (2 times, 6 weeks). The whole process takes at least 120 days, with clock stops for addressing the public objections. In practice, it takes months before you have the permission to start your clinical trial.

I’m puzzled by the idea that the general public would be able to judge the environmental risks of applying gene therapeutics in a clinical trial. These risk analyses are complicated matter and not common practice, even for the researchers involved. In my opinion, this makes the procedure unnecessarily lengthy and it does not automatically make the studies any safer. Do not get me wrong; of course, these clinical studies should only be executed if they are safe for both the volunteer and the environment. However, I do not understand why the environmental risk assessment cannot be incorporated in the CCMO assessment. COGEM/ministry of health experts could be additionally be involved if deemed necessary. This could make the whole process much shorter and further build on the reputation of the Netherlands as an attractive country for the innovative pharmaceutical industry to perform their gene therapy studies.

Anyway, I am happy that I have had this challenge and that I was able to scrutinize Dutch law regarding gene therapy studies. And now we have adapted all applicable CHDR SOPS according the current legislation we are ready to start our first clinical gene therapy studies!


by Ingrid de Visser, Senior Clinical Scientist

Understanding your materials and methods

Imagine you’d perform a clinical study in healthy volunteers to assess the activity of a new anti-inflammatory drug. How to demonstrate the compound’s anti-inflammatory effect in healthy subjects? These subjects don’t have chronic inflammation; they’re healthy so there’s nothing to treat. A solution is to induce inflammation outside the body. This is done by exposing blood from volunteers that received the drug to a foreign trigger. The theory is simple: if the drug has the intended pharmacological activity, it reduces the trigger-induced inflammatory response.

Obviously, this inflammatory response should be completely controlled in terms of magnitude (what’s the cytokine level?) and nature (what is the pathway producing cytokines?). No unintended inflammation may be present in the test tube. For this reason, only blood collection tubes are used that are endotoxin-free. Endotoxin is a bacterial component that is everywhere, contaminating everything that is handled by human hands. This is certainly not something that you’d want to be in your test tubes!

The clinical trial is executed, cytokine analyses are run, and data are reported. Data analysis reveals that the anti-inflammatory drug did not inhibit inflammation at any dose level tested. Moreover, even the blank conditions (without any inflammatory trigger added) show massive cytokine release! A failed clinical study, who to blame?

This is a hypothetical case, but not inconceivable to happen. We discovered that immune cells collected in heparin tubes may become activated, even though the tubes were tested to be endotoxin-free. This activation differed per manufacturer and even per tube batch. Apparently, heparin tubes may contain an unknown trigger activating the immune system. Luckily, we discovered this before the blood collection tubes were used in a clinical study. Hence, we decided to always test each future tube batch for undesired immune stimulation prior to clinical use. Thereby we avoided a failed clinical trial.

The verification of materials and methods may not be the sexiest topic to blog about. However, above example demonstrates the importance of control and understanding of all experimental details in clinical research. Following the text books, the manufacturer’s specifications, or PubMed is not sufficient. Artifacts may be introduced at different levels: preanalytical, analytical and postanalytical variables play a role. An unsuitable blood collection method may activate platelets and interfere in your readouts, a delay in sample handling may result in reduced responsiveness of the cells in your bioassay, your primary readout measure may be subject to diurnal fluctuations, etcetera. Just imagine that we’d not have tested the blood collection tubes preceding our clinical study. The loss of information, time and money would have been enormous!

Matthijs Moerland

Don’t forget to check out CHDR’s new Annual Report! Click here to download the book.

Humans are the best model for human disease

blog 7



One of the cool things about being a medical scientist is going to international conferences in places all over the world. I’m not saying it’s a good reason to become one, but when you end up in this line of work, conferences abroad are certainly the cherries on the pie (or the “raisins in the porridge” as we would say in the Netherlands). Just now, I’m flying back from San Diego where I attended the annual meeting of the American Society for Clinical Pharmacology and Therapeutics. There was a keynote lecture by dr Allen Shuldiner, professor of medicine and physiology at the University of Maryland, Baltimore and Vice President of Regeneron Genetics, a biotech company that aims to find new disease targets based on extensive genome wide screens in large populations before developing targeted therapies. Dr. Shuldiner started his talk by saying that humans are the best model for human disease, which was his way to make it clear that we should rather study the genetic factors contributing to disease in humans than to do animal studies, if we want to learn more about the etiology. I couldn’t agree more and I would even go further and argue that we should also rather use humans than animals as models for human disease when we test our new drugs. My own PhD research was focused on finding new treatments for amyotrophic lateral sclerosis (ALS) and included several animal experiments using the G93A SOD1 mouse model for ALS. Some of the experiments were positive, some were negative, but that’s not the issue. The problem is that the predictive value of a positive G93A SOD1 mouse experiment is nearing zero! There has only been one drug that had a positive effect in this animal model that also worked in humans -causing a very modest but statistically significant prolongation of life expectancy of several months- while the number of drugs that worked in the diseased mice that didn’t work in humans is steadily increasing to probably over 100 by now, and counting. Thinking about the waste of time and money is already discouraging, but if you consider that the reverse might also be true, that there will be ample compounds that tested negative in animal experiments, which might have worked in humans, should really make you feel utterly depressed!

And that is only considering efficacy issues. The recent disaster in France with the FAAH inhibitor of Bial has again shown that the safety of drugs can also not be guaranteed or predicted based on animal experiments. While the real problem with that particular study might have been related to the unnecessary urge of companies to elevate dose levels to what is maximally tolerated in humans instead of to the levels where the pharmacodynamic effects no longer increase -a different issue that that I may decide to cover in a future blog- , it does also point out that animal drug studies are far removed from human reality.

And why not use humans as models for human disease? We have developed a wide array of pharmacological and non-pharmacological challenges that will lead to temporary states resembling human disease in healthy subjects. Anti-muscarinic and anti-nicotinic challenges cause temporary cognitive disturbances and can be used to show effects of compounds that enhance cognition, inhaled Δ9-tetrahydrocannabinol or low doses of iv ketamine lead to symptoms reminiscent of psychosis and can be used to show effects of antipsychotics, electrical, heat, cold or pressure stimuli lead to diverse types of pain and are used to show effects of analgesics and we even infuse very low quantities of lipopolysaccharide derived from bacteria to induce symptoms related to systemic inflammation to show effects of anti-inflammatory drugs. Positive studies with new compounds that affect these symptoms, occurring in humans and not in animal models, have a very high predictive value of success in patients and can even predict the correct dose levels. In our experience, therefore, real live humans are indeed the best model for human disease, which is why we will remain the Centre for Human Drug Research and will advocate the use of our highly predictive human disease models in early phase drug development.

Dr Geert Jan Groeneveld

“And the dose for the next cohort will be…

“And the dose for the next cohort will be…”

Interim analysis for CNS first in human single ascending dose studies at CHDR

Being member of the interim safety committees is one of the most enjoyable parts of my work as the determination of the next dose level in a clinical trial unites both science and clinical operations at its best. The speed with which such ascending dose trails are performed, the close operations with colleagues and sponsor, and the excitement to find out details of the interim report content are a good recipe for pleasure.

Routinely, as single ascending dose phase 1 studies have a limited cohort size (e.g. 8-12 healthy volunteers), the clinical phase of a single cohort is often performed in one or two days, and subsequent cohorts are commonly carried out with one week intervals1. This allows 3-4 working days or so to produce the interim report, although we recently applied even shorter time lines during a frog leap designed study for which 2 cohorts were dosed each weak requiring the production of the interim report during the weekends.

In order to prevent possible delay in the production of the study medication at the LUMC pharmacy, we tend to predict a range for the most likely dose levels for the next two cohorts, allowing the pharmacy to prepare the medication well in advance.

For CNS studies, the interim report not only contains information on subject characteristics, adverse events and graphs for safety parameters. Pharmacodynamic (PD) parameters, we often use the most sensitive tests on our CNS test battery, have proven to be an indispensible part of interim analysis as information of the compound’s penetration of the brain often predicts side effects.

Often the dose escalation steps are provided in the protocol, but deviating from these predefined dose levels, but within regulatory limitations, is not uncommon. Sound determination of the first dose level is the most delicate step is in my opinion. In addition to FDA’s NOAEL conversion table for animal to human equivalence doses2, we routinely prepare a structured overview of all preclinical data available and use this as a tool for dose escalation as it has proven to predict safety and pharmacodynamics in many trials.

However, sometimes the compound behaves differently from what was predicted, e.g. unexpected nonlinear pharmacokinetics due to slow absorption, or side effects emerge before a clear efficacy-related CNS effect is observed. Therefore, in addition to clinical common sense, strategies for early stopping are essential. These stopping rules, e.g. occurrence of severe adverse events, are typically described in protocol as well as the highest allowed dose level. If no formal stopping events are encountered during the study, the pharmacodynamic effects can still provide sound reasons to stop dose escalation, for instance if the effects seem to max out with the highest two or three doses.

This PD-based approach towards dose escalation studies is appreciated by sponsors for its speed, accuracy and concomitant scientific advice. An approach to be proud off.

Rob Zuiker

ar 2016 dummy 2


1 Zuiker RG, Chen X, Østerberg O, Mirza NR, Muglia P, de Kam M, Klaassen ES, van Gerven JM. NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects. J Psychopahramcol. 2016 Mar;30(3): 253-62.

2 Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2005




CHDR on the interface between clinical pharmacology and psychiatry

Central nervous system (CNS) drugs are the mainstay of treatment for many patients with psychiatric disorders. However, the pathophysiology of psychiatric disorders in terms of brain function still remains poorly understood, receptor pharmacology of CNS drugs insufficiently explains their effects in psychiatric disease and reliable response- and treatment biomarkers of CNS function for use in psychiatric drug development and -treatment are lacking. In addition, a sizeable proportion of patients only respond partially or do not respond at all to currently registered drugs. Although the reasons for individual differences in drug response in psychiatry remain speculative, heterogeneity of populations with the same psychiatric diagnosis, interindividual variation in terms of neurotransmitter system function and differences in pharmacokinetics (PK) due to comorbid medical illness, age and polypharmacy probably play an important role.

As a psychiatrist I examine individuals with unusual perceptions, frightening or overly rigid ideas, uncontrollable urges and/or extreme emotions on a daily basis. Psychiatrists are trained to identify psychiatric symptoms and to consider them in the context of psychological-, general medical-, epidemiological and social factors. Symptoms that cluster together and are associated with common predisposing factors and/or a specific clinical course, are classified into clinical syndromes as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM), resulting in psychiatric diagnoses such as schizophrenia or generalized anxiety disorder. In contrast to other medical specialties, psychiatric diagnoses do not require the application of objective diagnostic methodologies like blood tests, a lumbar puncture or neuroimaging of the brain since no putative/experimental biomarkers yet reliably discriminate individuals who display a certain psychiatric symptom from healthy individuals. Diagnoses in psychiatry are therefore symptom-based and arguably depend on the psychiatrist’s professional interpretation of additional contextual information. Nonetheless, psychiatrists like other physicians, ultimately want reduce suffering and improve general well-being of patients, and are trained to apply both evidence-based psychotherapy and drug treatments for this purpose. Thus, the modern-day psychiatrist is 1) forced to make diagnoses that lack an objectifiable neurobiological basis, 2) constrained to prescribe drugs without knowing whether they influence a brain mechanism that is relevant to the patient’s disease, 3) not able to measure drug effects reliably, and at the same time, 3) obliged to consider PK factors that may influence drug response. This is a daunting task that often ends in advising patients to take CNS drugs in order to “restore a chemical imbalance”, while most psychiatrists would agree that although paracetamol is effective in treating headache, its therapeutic effect does not reflect the restoration of a paracetamol imbalance in the human brain. A puzzling phenomen that probably reflects a Freudian defence mechanism in the form of avoidance to cope with feelings of professional doubt or even incapacity.

When oncology was faced with similar challenges in the 60’s and 70’s of the previous century, academia did not concede and pressurized government until president Nixon and the US National Cancer Institute declared “the war on cancer” in 1971.  Billions of dollars were subsequently invested in cancer research, resulting in the elucidation of the pathophysiological pathways of many types of cancer, and culminating in state-of-the-art 21st century “personalized medicine” in terms of diagnosis and treatment. Clearly, psychiatry could benefit by taking an example from oncology, abandoning the Freudian “black box” approach to the brain and move forward by applying a mechanistic rather than a phenomenological approach. In this context, CHDR has an established history in innovative CNS drug development and has hitherto focused on developing reliable functional CNS biomarkers to quantify the pharmacodynamics (PD) effects of novel CNS compounds in healthy volunteers. Currently, we are expanding our activities to routinely perform trials with compounds that display innovative PD mechanisms in different psychiatric patient populations, and to include drug-sensitive biomarkers that are translatable from preclinical data to healthy volunteers and patients in such trials. By doing this, we aim to stimulate collaboration between pharma, academia, mental health institutions and patient organizations, and to provide an impetus for mechanism-based, innovative drug research in psychiatry in the Netherlands. At the same time, CHDR is involved in neurology and psychiatry residency teaching programmes where it provides clinical pharmacology as a basis for pharmacotherapy by specialists in the near future. Developing reliable biomarkers and innovative, effective drugs for brain disorders is time-consuming, but in the meantime, sound knowledge of the principles of clinical pharmacology could render current psychopharmacotherapy in psychiatry more effective.

Author: Gabriel Jacobs

Twitter: @psychCHDR

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