What being an intern is all about…

Presentation

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?

Clinical 13- LQ

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

Office

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

gj blog

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

The research clinic. Ready 4 research

Clinical 06- LQ

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.

How CHDR improves and changes the clinical trial

Clinical 05A- LQ

Naturalistic drug effect studies. Trial@Home

Traditional relationships between doctors and patients have changed. Patients are better educated than ever before, and want to take responsibility for their own lives. Although most patients value the relationship with their doctor, many now want to be informed and coached about health issues, rather than ‘treated’ by a benevolent and knowledgeable, yet somewhat paternalising physician. These changes will also affect clinical research.

Many patients with untreatable conditions are looking for alternative therapies. From the patient’s perspective, the risks associated with an unproven treatment understandably become less important if the disease is severe enough. The internet is a ready source of all types of compounds, often of dubious origin and quality. Access to experimental therapies is subject to strict regulations, and it is still difficult for a patient to be entered into a trial. Some patients now claim their right to decide for themselves, how much (unknown) risk they are willing to take with new unproven treatments. Organizations like MyTomorrows offer experimental drugs to patients who cannot be helped with regular treatments – outside of a clinical trial. Unfortunately  it is not in the patients’ benefit if new therapies are used in practice, without first being properly studied. Nonetheless, it is understandable that patients are looking for ways to accelerate the availability of new treatments – and researchers will have to respond.

Patients and healthy people are also taking responsibility for monitoring of their own health. An increasing number of genetic screens and laboratory diagnostics are offered to patients, often with medical advice. Miniature medical applications are increasingly sensitive, and large companies like Apple already offer apps and portable devices, which are able to constantly monitor physiological or behavioural indicators of healthy and performance in daily life. Unfortunately, the reliability of many of these applications is still unclear.

Over the decades, CHDR has devoted much of its time and resources to the development of tests for drug effects and disease. We use this experience in the collaboration with a number of technical parties in the joint development and validation of applications that patients can use at home, during the conduct of a clinical trial. Some examples include smartphone apps to photograph skin lesions, for new drugs in dermatology; small portable devices that continuously measure vital functions, like the Vital Connec®; and the Mini-NeuroCart®, which is based on CHDR’s drug-sensitive multimodal CNS test battery, made suitable for studies ‘in the field’. In addition, CHDR also develops tablet-based apps for ambulant patient instructions and effect measurements. And this is just part of our Trial@Home initiative, which aims to perform highly informative, data intensive studies under naturalistic conditions – during attacks of recurrent diseases, or for chronic drug effects in the comfort of the patient’s home, in their own bed at night, in the office, or any other situation that is affected by the compound – not just in the clinical research unit. The time has come that patients and researchers can team up to improve clinical research.

by Joop van Gerven

Publication: we all benefit

Office 07- LQ small

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

Why people matter for organisations and their clients. A personal view.

Office 11- MQ resized

In other blogs you can read about CHDR’s knowledge and expertise in early clinical drug development. In this blog I will share my view on how it happens that CHDR evolved from a business with a handful of scientists into one of world’s most innovative independent CRO’s, in less than 30 years. As a longstanding employee who experienced this growth I am convinced it is mainly due to the fact that CHDR attracts competent and dedicated staff. However – next to this – CHDR creates a work environment in which the best is brought out of people. It is the combination of hiring the right people and taking good care of them that brings a company further, no matter what the business is.

I started at CHDR right after my graduation as a medical biologist in 1999. CHDR gave me the freedom and responsibility to explore the role of motiline in upper and lower gastrointestinal discomfort. Johnson & Johnson had developed a motiline receptor antagonist and it was my duty to find a possible clinical target for this potentially new drug. It was mainly due to CHDR’s support and confidence in me that the research resulted in a thesis 4 years later. I really think that when you give people the confidence and freedom, it boosts their creativity and that they feel the responsibility to bring it to a success.

Besides supporting its personnel, CHDR puts effort in providing a pleasant and flexible work environment. The current custom designed building creates a spacious, flexible and enjoyable working space. And – if they wish – personnel can be equipped with an iPad to log in to the network from any location, either in- or outside the CHDR building. For me, this flexibility implies that I can continue my work from home in case of one of my children is ill or when I need work other hours, for example to catch a deadline. Even after they have left, CHDR still cares for its personnel. Many of our colleagues continue to get further medical specialist training but continue work for their PhD thesis. They can continue their research from home via the portal or at a desk in CHDR and they can always count on scientific and technical support. A good example is my ex- colleague and friend Marloes van Dongen. She accomplished to finish her PhD thesis “The role of glucagon in glucose homeostasis” while she was in training for medical specialist, being a mom and – last but not least – being pregnant. An excellent achievement.

Perhaps because of these arrangements people return like a boomerang back to CHDR. Both Martijn van Doorn and Gabriel Jacobs enjoy being hired again for their expertise in dermatology and psychiatry respectively, several years after they had completed their theses at CHDR. The creation of a community beyond the constraints of being an employee adds greatly to the services CHDR can provide to its clients.

All too often nowadays we hear from companies and universities that see their employees more as a cost item rather than an asset. In early drug development there is an enormous value in experience and commitment. Finding, developing and importantly retaining people is the key.

Ingrid de Visser – Kamerling

Innovative drugs need innovative methodology!

Figure_CHDR_Study_Setup_myelin_breakdown

In drug development it is important to try to answer as many questions as possible in as few drug studies as possible. If you expose humans –or other animals for that matter- to new and potentially harmful compounds, then not getting everything you can out of it, seems a waste. After a new drug has successfully passed the stage of animal studies, a “first in human” study is planned in which  -traditionally- pharmacokinetics of the new drug and potential side effects of the compound are determined. In this phase, however, it is likely that humans will be exposed to a broader range of drug doses than ever thereafter. An ideal opportunity to also try to determine the intended pharmacological effects of the new compound. To do that you need the correct methodology and this is often unavailable.

Luckily, more and more pharmaceutical and biotechnology companies are seeing the added value of this approach. CHDR’s self-funded research is focused on the development of new biomarkers and methodology to show pharmacological effects of new drugs in the earliest stages of clinical drug development. There is a new trend: co-funding of this type of research by a pharmaceutical company with a particular interest in the new method rather than just the new medicine.

Multiple Sclerosis is caused by inflammation that leads to demyelination -loss of the myelin sheath around neurons- in the brain and spinal cord. Existing therapies target inflammation and thus lead to inhibition of demyelination. However, new MS drugs are being developed, that target enhancement of the formation of new myelin and hence improvement of the function of demyelinated neurons. These targets are completely new and methods to quantify the effects of these innovative drugs therefore don’t yet exist. In collaboration with a biotechnology company, we developed and validated a method that uses labeling with deuterated water to estimate the speed at which new myelin is formed in the central nervous system. Healthy subjects drank 120 mL of “heavy water” per day for a period of 10 weeks and we performed repeated lumbar punctures to obtain cerebrospinal fluid over a period of almost half a year. We then extracted myelin breakdown products from the CSF and measured the rate of weight increase of the molecules, which was caused by incorporation of deuterium instead of hydrogen in newly formed molecules. These measurements, in combination with mathematical modeling, allowed us to estimate the rate of myelin formation.

Being able to quantify the rate of myelin formation will be essential in the process of developing a drug that is expected to positively influence remyelination. This may ultimately lead to a new treatment for patients with MS, which is much needed. But the method by which metabolic processes that occur within the confined space of the brain can be quantified using something as innocuous as water, may in turn contribute to the rational drug development of many other future CNS drugs.

Geert Jan Groeneveld

Cars & Clinical trials: driving simulators Vs. on-the-road-driving-tests

BvkYjb5IMAER8ow

For many of us, driving a car represents freedom and independence and economical power. What has this to do with CHDR, you might ask? Well, many pharmacological agents that affect the central nervous system are of concern when it comes to driving safety. Those medications (and also drugs of abuse) can induce fatigue, impair vision and reduce vigilance leading to periods of inattention. This poses a risk for the operation of dangerous equipment like a car. Although those risks are often already known at a drug-group level, for clinical pharmacologists like us, it is important to estimate the dose response relationship for an individual investigative drug early in its development. Additionally there may be certain groups, like the elderly or the young drivers, which are much more at risk when impaired by medicines, alcohol or drugs.

The effect of investigative drugs on driving performances is often assessed by using a standardized on-the-road-driving-test, which was developed in the 1980s and has been applied extensively in over 50 studies since. In short, subjects are instructed to drive a car over a 100 km highway. The car is equipped with two camera’s that constantly monitor the position of the car within the traffic lane. The outcome is mainly measured by the alterations in the standard deviation of lateral position (SDLP), which has proven to be a suitable parameter for vehicle control and traffic safety.

However, the on-the-road-driving-test is inflexible, labor intensive and therefore costly, it may take weeks to complete a full study while testing a single dose only, making the test less suitable for the assessment of dose response effects and certainly not suitable for a quick adaption in the study design. Nevertheless, the on-the-road-driving-test is often required for registration purposes, but a negative study outcome may cause a significant restriction in its indication as specified in the SMPC. Therefore, an on-the-road-driving-test may not be the single most suitable tool for drug-induced driving risks.

Luckily, the SDLP can also be measured in an in- house driving simulator in a much more practical and reproducible manner. Other parameters that are of importance in driving a car safely -, i.e. alertness, memory, coordination amongst others – can be added effortlessly. Also, driving simulation makes it possible to study the temporal relationship between medication and driving performance and work out the pharmacokinetic dynamic relationships. Of course all tests are surrogate endpoints for the occurrence of accidents but this ‘real’ endpoint can never be assessed. The current generation of driving simulators have, however, been validated positively against real driving behavior.

At CHDR we are currently studying the sensitivity of a driving simulator test battery to the effects of ethanol and a benzodiazepine, trying to compare these results with those of the NeuroCart™, a validated and established test battery developed by CHDR that quantifies a large range of drug-sensitive CNS-functions that are also relevant for every-day performance. Results from this study will allow us to determine whether a driving simulator is suitable to assess impairment in performance due to investigative drugs in a laboratory setting. This will set the standard for future studies in the important area of drug effects on real life performance.

Rob Zuiker

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