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.

How CHDR improves and changes the clinical trial

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

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.

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

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

Forgotten players in glucose homeostasis?

It is highly likely that you learned at secondary school that the pancreatic hormones insulin and glucagon are important in the regulation of glucose metabolism. However, it is equally likely that during your further education more attention was given to insulin compared to glucagon, which at best got the role of bystander. Funnily enough both hormones were discovered around the same time (insulin in 1921 and glucagon in 1923) as was their role in glucose homeostasis. Insulin got all attention as new revolutionary medicine, possibly because Insulin Dependent Diabetes Mellitus (Type I DM) was such a lethal disease that could now be properly treated. In contrast, glucagon-deficiency was not recognized as a clinical entity let alone as a disease. This is all very understandable, but it remains enigmatic why insulin-based therapies also dominated the treatment of Non-Insulin Dependent Diabetes Mellitus (Type II DM). Especially in view of the observations in the 1960’s that Type II DM is not a disease of insulin deficiency, but a condition of insulin resistance which cannot be overcome by increased endogenous insulin release. Whatever the explanation for this enigma may be, we are currently witnessing a revival in glucagon-based therapies for the treatment of Type II DM.

At CHDR we have adapted and validated existing techniques to investigate the role of glucagon in glucose homeostasis and to evaluate glucagon-based therapies in humans. The development of these tools with our colleagues in industry and academia was and will be a hallmark of CHDR’s philosophy. This also regards the development of mathematical models that try to capture the complex interplay between insulin, glucagon and glucose. We are proud that all this work is now integral available as PhD thesis, which our colleague Marloes van Dongen will publicly defend on January 7, 2015 in the historical Academiegebouw of Leiden University.

An important role of the specialty of clinical pharmacology is to develop the tools of the drug development trade. We sometimes define new (and untested) medicines as extremely sophisticated technological innovation after evaluation with rather primitive methodology. The ongoing drug innovation wave has to be matched with equally sophisticated methodology to see the potential effects. These techniques have to be developed preferably ahead of a new innovation wave in a certain field[1].

Renewed interest in glucagon as one of the ‘forgotten’ players in glucose homeostasis, of which there are more[2], will lead to a potential wave of new products and devices. We are happy that our work is now available to support this, and make a difference in the attack on the Type II DM epidemic.

Koos Burggraaf

[1] Cohen et al. Annu Rev Pharmacol Toxicol. 2014 Oct 6. [Epub ahead of print]; PMID: 25292425

[2] ‘certain factors produced by the intestinal mucosa in response to nutrient ingestion that are capable of stimulating the release of substances from the endocrine pancreas and thereby reducing blood glucose levels’; see for instance Bayliss WM, Starling EH. Proceedings of the Royal Society of London[Biol] 1902;69:352-353 / Moore B, Edie ES, Abram JH. Biochem J 1906;1:28-38) and La Barre J. Bull Acad R Med Belg 1932;12:620-634.

Innovative drugs need innovative methodology!

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