annual report 2010 the netherlands...annual report 2010 research involving human subjects 2006...
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Annual Report 2010
the Netherlands
The Central Committee
on Research Involving
Human Subjects (CCMO)
ensures the protection
of research subjects who
participate in medical
research by reviewing
such research based on
applicable legislation
and taking into account
the progress of medical
science.
Annual Report 2010
Research involving human subjects 2006 –2010 Central Committee on Research Involving Human Subjects
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Contents
Foreword
Summary
Interview ‘ the CCmo cannot permit itself to give a superficial judgement’
Frame: Withdrawal of accreditation for the steg/metc
Part 1. Research involving human subjects
Research involving human subjects
Interview ‘Soft when possible, hard when necessary’
Figures 2010
– Rejected research
– Minor and incapacitated subjects
– Gametes, embryos and the foetus
– Centrally reviewed research
Case study: Assessment of a Duchenne study in the eu
Transparency in research
– Government Information (Public Access) Act (Wob) requests
Interview ‘ It is the interpretation of regulations that is particularly important’
Frame: Injury insurance or compensation fund for Dutch research subjects?
Part 2. Legislation and regulations
– State of affairs regarding changes to the Medical Research Involving Human Subjects Act (wmo)
– Changes to the Embryos Act
– Independent Governmental Bodies Framework Act
– Human Tissue Bill
– vws regulation on cell transplantation
– Modification of directive for Expertise Requirements for (wmo) members of mrecs
– Evaluation of ccmo directive Assessment of Clinical Trial Agreement
Interview ‘A strictly legalistic approach does not work by definition’
Frame: Training of committee members and secretarial staff of the accredited mrecs.
Part 3. Review system
Review committees
Transparency of the review system
Interview ‘Oversight by the CCMO and the IGZ must go hand in hand’
Frame: Chair meeting
Frame: Secretary working group
Digitisation
Central Committee on Research Involving Human Subjects
Frame: Quality control within the mrec and the ccmo oversight system
Abbreviations used
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2010 was a busy year for the ccmo, particularly due to the supervisory interventions. Thanks to the additional efforts of many individuals, the ccmo was able to adequately fulfil this labour intensive task.
Gerard Koëterccmo Chair
performed its statutory tasks and/or insufficiently safeguarded the protection of research subjects. For these mrecs, the result was that they could no longer review any new research files. Suspension provides an mrec with the time to work on the required improvements. However, the current wmo does not provide the ccmo with the formal authority to give an accredited mrec an official warning or temporarily suspend its activities.
This year, the ccmo temporarily suspended the activities of two mrecs. Ultimately, the accredi-tation for one of these review committees was withdrawn. The mrec filed an objection to the decision, and requested a temporary injunction from the court. The judge did not honour the request. In the opinion of the judge, the fact the ccmo first issues a warning, without immediately moving to withdrawing accreditation, fell within the scope of the ccmo’s authority as an oversight body.Upon withdrawal of accreditation, the ccmo temporarily took on the review tasks of this mrec and secured the mrec archive. The ccmo also worked to transfer research files for ongoing studies to other accredited mrecs. Thanks to the cooperation of many review committees, this was successful. These events did demonstrate, however, that the law does not take into account the practical consequences that withdrawing accreditation entails.
Thanks to the expansion of its secretariat, the ccmo was also able to initiate continuous over-sight of accredited mrecs, with a primary focus on quality and content review. The chosen method – continuous oversight – was discussed with actors in the field. Currently, the nvmrec is working on a voluntary intervisitation system for accredited mrecs within its membership. The first intervisitations are scheduled to begin in 2011.
One of the ccmo’s mandates is to oversee accredited mrecs. The ccmo does this in part based on incident reports, incidents or negative outcomes of clinical scientific research. For the ccmo, the year 2010 was explicitly dedicated to this task.
The ccmo aims to improve the workings of the mrec in question through a supervisory inter-vention. Upon completion of the intervention, the mrec receives a report of the findings. The ccmo will also forward the results to all other accredited mrecs, so that they too can learn from them and make improvements to their committees where required.
For the ccmo, oversight is one of the instruments used to improve quality and harmonise the work-ing methods of mrecs. This oversight is focused primarily on reviewing the content, but also includes procedural and administrative aspects of the review process. During the drafting of the Medical Research Involving Human Subjects Act (wmo), the measures the ccmo may take if it notes negative findings with an mrec are not defined in detail. At the time, the legislator confined the ccmo to the inclusion of only one repressive sanction: withdrawal of accreditation. Now, more than ten years after the wmo was passed, the time seems ripe to reassess oversight options. What measures are available should the ccmo identify imperfections or errors in an mrec? And what aspects must be legislated?
The ccmo has developed two oversight instru-ments in the past years: a warning (‘yellow card’) and temporarily suspending an mrec’s activities. Only in one instance did an mrec receive a so-called yellow card, and in a few instances the activities of an mrec were temporarily suspended. In all cases in which the ccmo moved to suspend activities, this occurred after it had been determined that an mrec inadequately
Foreword
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The reviewing committee can then process them simply in ToetsingOnline. Finally, the ccmo presented the first results of a study into the feasibility of an it aid for investigators to put together a simple and structured informed consent form which complies with the present laws and regulations.
The basic principle of the quality of the reviewing process is the committees’ own responsibility in monitoring and improving it. The ccmo contributes through training and by providing information when and where possible. In the year under review the ccmo contributed to a course set up by the medical centre of the vu medical centre Amsterdam for reviewing committees.
In this annual report the ccmo introduces a new section: the case report. For the year 2010 a Duchenne study was chosen, and we will present an analysis of the reviewing process of this inter-national study in several eu member states. The case report gives insight into the review of the content of this particular research file. The analysis shows that the reviewing committees and competent authorities of the eu member states, with the exception of the Netherlands, asked hardly any questions regarding content on the risks and burden to the minor research participants.
With regards to the service provided by the secretariats of the reviewing committees, steps have been made toward collectively determining a service level to be provided to committee members and applicants of research files, and in defining a best practice service level. Part of the improved service is the digital distribution of committee meeting documents and research files to the committee members. Following the example set by the ccmo, one other reviewing committee made the switch to digital distribution in 2010. It is expected more will follow when digital submission of research files via Toetsing-Online is made possible. The submission of large piles of paper research files will then be a thing of the past. In 2010 attention was also given to a development which makes it possible for the reviewing committees to digitally report serious adverse events and reactions by way of a simple online form in ToetsingOnline. Furthermore, ToetsingOnline was developed with the module ‘Toegang voor derden’ (Access for third parties). This module makes it possible for applicants to issue viewing rights for their research file or sections thereof to participating co-investigators. It is also possible for the applicant to issue rights to these investigators to digitally report serious adverse events and reactions in ToetsingOnline directly to the reviewing committee.
In 2009 the ccmo presented her vision paper, entitled ‘Toetsing en toezicht in de toekomst’ (Assessment and Oversight in the Future). The objective of the report is to achieve an out-standing decentralised and transparent reviewing system in the Netherlands in the coming years. Three main themes are central to achieving this: excellent review regarding the content by the accredited medical reviewing ethics committees, optimal service provided by the secretariats of these committees, and transparency in the field of medical research and the reviewing thereof. A granted expansion of the ccmo secretariat in 2010 allowed for important developments to be made in all of these fields.
Transparency in the field of medical research saw a considerable improvement in the year under review. There was a substantial increase in the amount of core information from reviewed studies entered in the ccmo public trial register. In fact, in 2010 core information from nearly all studies reviewed (96%) was entered in the register. The biggest increase was seen in the pharmaceu-tical industry: in 2009 it provided core information on 48 percent of its studies. In 2010 this number had risen to 89 percent. The ccmo website now lists the rules and regula-tions, and complaint procedures of the accredited medical reviewing ethics committees. Applicants can now easily find information on the proce-dures in place at a reviewing committee and how they can submit a complaint to a committee or to the ccmo. As well as this, the ccmo publishes the annual reports of the reviewing committees of 2009 and beyond on its website. And in 2010 many committees registered their assessment of research files in the web portal ToetsingOnline. In 2011 the remaining reviewing committees will follow suit. Applicants can then follow the reviewing process of their submission via internet and can be alerted on the review timelines.
Summary
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Ruud van beest, mD psychiatrist and chair of the metigg
‘ oversight has worked in our favour’
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Interview
‘With accreditation comes oversight’, emphasises Van Beest, chair of the metigg. ‘As the first mrec to be evaluated following the new oversight method of the ccmo we could have been peeved but I believe it is important you consider the positive aspect of the criticism. I must admit in the beginning it is rather annoying, but then common sense takes over: it is necessary. The ccmo exists to monitor. When I looked at it from an integral point of view, I was quickly convinced of the necessity to improve our working methods.’
The metigg is a categorical committee for the psychiatric health care system. The foundation has seventeen members: mostly psychiatric institutions, but also for example the Trimbos institute. ‘We were set up more than 25 years ago. The predecessors of the present metigg were already active long before the Medical Research Involving Human Subjects Act (wmo) was passed’, says Van Beest. ‘Obviously, much has changed since then. We have grown from a committee which had ties to the institutes it repre-sented to the professional organisation it has become today. Oversight played a large part in this.’ The warning sign which the ccmo received in February 2009 concerned the quality of the methodological review of the research files. The ccmo requested research files from the South Chamber and then from the North Chamber of the metigg for review, including all correspondence, meeting documents, judgements and the accompanying adminis-tration. Conclusion: the quality of the reviewing was not up to scratch. The South Chamber was put on hold in January 2010, and the North Chamber followed one month later. ‘I had to laugh about that particular English term, Van Beest says. ‘As a psychiatrist I thought at the time, by using another language you are trying to cover something up’.
‘We have put a lot of time into the plan of approach and the improve-ment route’, says Van Beest. He sought contact with someone who had just ceased working for another accredited mrec. ‘That turned out to be of utmost importance. When you are writing you have an
idea of how it should turn out, but an outsider can offer you a lot of good input.’‘I believe the ccmo went through the assessments with a fine tooth comb. That is a form of oversight I’m not familiar with: going through the material so thoroughly. But if you consider it, it cannot be done any other way’, remarks Van Beest. ‘If Philips produces an electric shaving appliance it is the customer that reviews the quality of the product. The health care system and the medical research field are much too complex for that. It is not only impor-tant that you monitor your own working methods, but there also has to be an authority that is expert in the field of monitoring. Additionally, the ccmo cannot permit itself to pass superficial judgement. Not to researchers, but also not to the human research subjects, despite it being documented that they, given the nature of the reviewed researches, are not exposed to any great risks.’‘It was a very intense period,’ says Van Beest. ‘Everything was turned upside down. Our Standard Operating Procedures (sops) were rewritten, the minutes and the forms for judgements are now uniform, we have set up norms for the timelines and for the training of the committee members. Ultimately we have to say that the oversight has worked in our favour. It shook things up in an effective manner. In the past a negative judgement by the metigg was an extreme exception. In the last few months of 2010 a negative judgement was issued in eight instances. Awareness of how you operate and should operate as an mrec has been thoroughly ingrained in us. That is the legacy of the ccmo’s efforts, and for that I would like to offer my gratitude.’
The fact that the ccmo sent a slimmed-down version of the over-sight report to the other accredited mrecs is fine with Van Beest. ‘Please let us be transparent. At the moment I have no idea of how the other accredited mrecs operate, but I can imagine that in making this transparent more awareness will be the result with regards to quality requirements. If everything is found to be in order, they will once again be confirmed of the necessity of the oversight.’
‘ The CCMO cannot permit itself to give a superficial judgement’This year the Medical Ethical Reviewing Committee Psychiatric Health Care institutes (Medisch Ethische Toetsingscommissie instellingen Geestelijke Gezondheidszorg ‘METiGG’) was evaluated by the CCMO. This resulted in the activities of the MREC being temporary suspended. Ruud van Beest, MD, psychiatrist and chair of the METiGG: ‘Awareness of how you should operate has been thoroughly ingrained.’
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Withdrawal of accreditation for the STEG/METC
In its 2009 annual report, the CCmo reported on an analysis of phase I studies that were
reviewed by both accredited mReCs and the CCmo in that year (see CCmo annual report 2009,
page 18). the goal of this analysis was to gain insight into the precise nature of the phase
I research being conducted in the netherlands. the study showed that about three quarters
of the phase I studies are conducted with healthy volunteers. In 40 percent of cases, a new
medicinal product is administered to humans for the first time (first-in-man research).
During the analysis, one study drew particular attention due to the method of administration
of an experimental substance in healthy volunteers. they received a synthetic peptide intrathe-
cally (within the spinal canal). the sponsor for this study was a small foreign biotech company.
the study was only conducted in our country, by a Dutch establishment of a foreign Contract
Research Organisation (CRo). the research file was found to have been approved by the non-
institution-based accredited mReC of the Foundation for therapeutic assessment of medicinal
Products (Steg). the CCmo decided to request the full research file and underlying documents
from this mReC. the file was subsequently discussed during the plenary CCmo meeting in
early 2010.
the approval of the study by the Steg/mReC raised a great deal of questions with the CCmo.
For example, a previous clinical study involving the medicinal product in the uSa had been put
on hold by the FDa. this information was not included in the research protocol by the study
sponsor, and only came to light after examining the Investigator’s Brochure (Ib) and the Investigational
Medicinal Product File (ImPD). the CCmo felt the product information in the ImPD was
inadequate. the CCmo also had a large number of questions regarding the manufacture and
quality control of the medicinal product. It was discovered the product had not been developed
for intrathecal administration. the Steg/mReC had not asked the applicant of the research file
any questions on this issue. Furthermore, it was remarkable that the Steg/mReC approved the
administration of increasing doses of the substance to a subsequent group of healthy research
subjects based on relatively superficial safety information.
the provisional findings of the CCmo were such that it instructed the Steg/mReC to cease
review of any new files pending further investigations. the CCmo felt such a measure was
justified in order to protect research subjects in the netherlands. the Steg/mReC filed an
objection against this measure. at the same time, the CCmo requested five other reviewed
research files from the Steg/mReC for further analysis. the CCmo noted significant short-
comings in the review process for these studies as well, particularly with regard to the assessment
of their content. the conclusion of the CCmo was that the Steg/mReC had insufficient insight
into the limits of its competence and inadequately performed its statutory tasks.
the Steg/ mReC was informed of the findings of the analysis the CCmo conducted of the mReC
review process. Furthermore, the CCmo announced its intention to withdraw accreditation
and, in accordance with the applicable legal provision, gave the Steg/mReC the opportunity
to be heard. the Steg/ mReC chose not to make use of this opportunity. the Steg/mReC
did file a written response to the CCmo findings regarding the mReC review. this written
response was found not to have been drafted by the Steg/mReC itself. the committee had
left this to the sponsors of the research files in question. the written response was examined
by the CCmo, but did not lead to a reconsideration of the findings regarding the mReC review.
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Subsequently, taking into account the previous warnings it had issued to the Steg/mReC in
the past, the CCmo decided to withdraw the Steg/mReC’s accreditation on 8 july 2010.
the Steg/mReC filed an objection against this decision as well.
at the same time, it requested a temporary injunction from the administrative court with
the objective of suspending the decision to withdraw accreditation.
In the meanwhile, the Steg/mReC requested the documents that had led to withdrawal of
accreditation from the CCmo via the government Information (Public access) act (Wob).
In order to ensure a good and democratic operational process, the CCmo decided to provide
the requested information in such a manner that it could not be traced back to individuals and
in a (partially) objectified form.
Pending the objection against withdrawal, the CCmo retrieved the files for ongoing studies
from the dynamic Steg/ mReC archive. So as not to unnecessarily impede the performance
of these studies and to safeguard the protection of participating research subjects, the CCmo
temporarily took over the role of reviewing committee for these studies.
on 16 august 2010, the request for a temporary injunction was put before the court in Zwolle/
lelystad. the court denied the request by Steg/mReC. In the opinion of the administrative
judge, the fact the CCmo first issued a warning, without immediately moving to withdrawal of
the accreditation, fell within the scope the CCmo’s authority as an oversight body. Following
the judge’s ruling, the Steg/mReC withdrew both objections, and the withdrawal of accredi-
tation was final.
as the CCmo is not officially authorised to act as a reviewing committee for ongoing studies
which were approved by the Steg/mReC, it asked other accredited mReCs to each take over
one or more research files. thanks to the willingness of a number of mReCs, these files were
transferred relatively swiftly. additionally, the CCmo took action to ensure that the semi-static
archive of the Steg/mReC would be transferred to the ministry of Health, Welfare and Sport
(vWS). this transfer is expected to be completed in 2011.
the procedure regarding the withdrawal of accreditation of the Steg/mReC was discussed
with the chairs of the accredited mReCs and the CCmo during the autumn meeting. the topic
was also presented during consultation with the secretaries of the accredited mReCs and the
CCmo. the primary goal of these presentations was to provide clarity regarding the course
of the supervisory intervention and the withdrawal of accreditation. Secondly, the CCmo and
the accredited mReCs wanted to learn from the events. the CCmo also decided to publish
the withdrawal decision, leaving out a number of privacy-sensitive passages.
the withdrawal of accreditation based on the conclusion that an mReC insufficiently meets its
legal mandate is unique. the CCmo has never before felt it necessary to take such a drastic
measure to protect Dutch research subjects. the procedure showed that the current medical
Research Involving Human Subjects act (Wmo) insufficiently accounts for the consequences
a (planned) withdrawal entails. the CCmo would therefore like to see changes to certain
aspects of the act, so that the practical consequences of temporary suspension and potential
withdrawal of accreditation are clear to all parties.
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intervention. In observational research, no stimulus is administered. Only the existing situation is analysed. However, occasionally invasive actions such as collecting blood to determine normal values may be conducted.
As in previous years, in 2010 over half of all reviewed research files involved intervention research (58%). The remainder (42%) involved observational research. One third (31%) of all research files reviewed related to research with medicinal products. The pharmaceutical industry submitted 53 percent of these files itself. This research is focused primarily on the develop-ment of new medicinal products, with the final goal of obtaining marketing authorisation. The remaining 47 percent of medicinal product research is conducted by and on the initiative of (university) researchers. This research is primarily conducted to acquire scientific knowledge and optimise the use of existing medicinal products or expand the indications for their use.
Research subjects
Medical research requires the participation of research subjects. Even if all laboratory tests and possible animal studies showed good results, research with healthy research subjects and patients remains essential. Only in this manner can it be determined whether the new medicinal product or treatment is safe and effective in humans. The figures the ccmo collects annually provide insight into the number of research subjects that will be asked to take part in the assessed study. In the files assessed in 2010, researchers indicated they required a total of almost 520,000 research subjects in order to successfully complete their research. This figure is slightly higher than for the years prior to 2010. In the period 2005 – 2008, the numbers of required research subjects provided consistently lay between 300,000 and 500,000. Over 60,000 research subjects (12%) are involved in research
A great deal of medical research involving human subjects is performed in the Netherlands. Each year, about 1800 research files are submitted to an accredited medical research ethics committee (mrec) for review. In a small number of cases, review is conducted by the Central Committee on Research Involving Human Subjects (ccmo). Only after one of these committees has approved the research file can the proposed research can be initiated. This system of review by an independent committee of experts is mandated by the Medical Research Involving Human Subjects Act (wmo). The wmo also defines the requirements the study must meet. The review committee determines whether the study under review actually meets the requirements. The review of research with gametes and/or embryos remaining after in-vitro fertilisation (ivf) is regulated by the Embryos Act. This Act also requires a content assessment of the entire research, which must be conducted by the ccmo in this case.In this first part of the annual report, you will find figures and data on the research files reviewed by accredited mrecs and the ccmo within the context of the wmo and/or Embryos Act in 2010. Part 2 outlines the key changes to relevant legisla-tion and regulations. Part three details information about the review system in the Netherlands and the individual review committees, including the ccmo.
Types of research
Medical research consists of two main categories: intervention research and observational research. In intervention research, the research subject’s existing situation is modified on purpose. The research subject is exposed to a stimulus, and its effects on the body are studied. Examples of such stimuli include administration of a (new) medicinal product, testing of a new medical device or foods. There are also other forms of interven-tion research, such as research into new surgical techniques or research involving a psychosocial
Part 1. Research involving human subjects
533(31%)
712(42%)
457(27%)
research with medicinal products
other interventional research
observational research
97 phase I (18%)
129 phase II (24%)
171 phase III (32%)
52 phase Iv (10%)
75 other (14%)
9 na (2%)
282 industry (53%)
251 non-industry (47%)
Number of research files in 2010
total 1702 research files
of which
of which C
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Research involving human subjects
with medicinal products; about 70,000 (14%) in other intervention research. However, the vast majority of research subjects are involved in observational research: over 380,000 (74%).
The figures mentioned above are based on the numbers of research subjects that are expected to be asked to participate in research conducted in the Netherlands. These figures only provide a rough estimation. This is because a great deal of research is conducted in an international context. If the research begins elsewhere before it does in the Netherlands, fewer research subjects from our country will be asked to contribute. The reverse may also be true: if the research starts in our country before it does abroad, the percent-age of Dutch research subjects involved is larger.In most research studies, only adult, legally competent individuals are asked to take part (90%). In about 10% of the reviewed research files, the goal is to conduct research with children under the age of twelve. In 10 percent of cases, it involves minors in the age group between twelve and seventeen years old. Finally, in about 5% of the reviewed research files, the participation of incapacitated adults is required. Sometimes, research subjects are part in a study involving more than one of these target groups, for example a study involving children both over and under the age of 12 years. This means there may be duplicate counts for the percentages listed here in some cases, leading to a total of more than 100%.
1545 (91%)
78 (5%)
140 (8%)
26 (2%)
~63,000 (12%)
~70,000 (14%)~385,000
(74%)
172 (10%)
* For some studies more than one category of research
subjects are recruited.
Number of research subjects in 2010
research with medicinal products
other interventional research
observational research
total approx 520,000 research subjects in 2010
Most studies are with capacitated adults*
research with capacitated adults
research with incapacitated adults
research with capacitated minors (12-17 years)
research with incapacitated minors (12-17 years)
research with minors (< years)
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‘ effect is central to modern oversight, not compliance to the rules’marijn Colijn Senior advisor oversight development product safety non-food at the new Food and Commodities authority (nvWa)
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Interview
One of the most important themes at the moment is innovative monitoring’ says Colijn. ‘As regulator you can operate from a classic top-down hierarchy, whereby every organisation that does not comply with the regulations gets a rap on the knuckles. There is also another, more coordinated, approach. Willing organisations will find us on their side. You offer this group the necessary support and assistance in complying with regulations. Organisations that demonstrate bad or improper conduct find themselves coming face to face with the nvwa as enforcer. The basis principle is: soft where possible, hard where necessary.’
The goal of oversight and enforcement is promoting and improving the safety of non-food consumer products. Colijn: ‘It’s about thinking multidimensional: not only checking if the regulations are being complied with, but also operating in a problem solving manner in the wider sense of the term. Acute problems must be dealt with immediately, but in the case of less alarming risks structural oversight is more effective. In practice, we assess the products which carry the highest risks, such as toys for young children and electric appliances.’In the non-food consumer product sector there are estimated to be around 700,000 producers, importers and retailers active. ‘We never know exactly how many there are as accreditation is not necessary. For example, anyone can start importing from China as of tomorrow’, he says. ‘Also, the budget and capacity of the nvwa is somewhat stretched. Both developments mean we have to organise oversight in the most effective way possible.’
‘The central question is to what extent can you influence a change in conduct’, according to Colijn. ‘In the past we used to analyse compliance. That goes together with factors such as control pressure and the perceived risk of being caught in the act. But also knowledge of the legislation was taken into account. If there is little knowledge, then it is more effective to steer with increasing this knowledge in mind, than to purely aim at fining.An example: in 2007 the safety legislation for sun beds was tightened. Since then, exposure to uv-radiation must not exceed 0.3 Watt/m2. Sun beds can also not be used by persons under
the age of 18 years due to the risk of skin cancer at a later age. ‘Classic oversight would mean having to measure every sun bed studio which is barely achievable.’
The first step for the nvwa was to make an analysis of the knowledge of the regulations in place at the sun bed studios, combined with an information campaign in cooperation with the industry. Shortly after commencing the campaign a check of one hundred studios showed that just 18 percent complied with the new regulations. ‘It was then announced that in the case of non- compliance in the following year fines would be issued’, says Colijn. ‘The perception of the risk of being caught in the act increased as a result of this announcement: the realisation that the government just might pay you a visit hit home.’ In the second year the commu-nication campaign went even further. For example, specialist journals and the consumer television programme, Kassa, devoted attention to the regulations and the risks of high uv-radiation. And all the while, consumer pressure, pressure by the regulatory bodies and the media increased. During the second round of checks it emerged that the percentage of compliance had risen to 70; in 2010 this increased to 85 percent. ‘Over a period of three years and through the implementation of a number of oversight instru-ments a huge change in conduct had taken place. The use of enforcement communication meant a great saving in inspection capacity’, says Colijn. ‘And that is what oversight is all about: how can you ensure compliance through focussed oversight. This is a typical example of the Sparrow approach: managing by identifying risks applying and the most suitable instruments to achieve the best possible effect.
Since a few years the nvwa has also made use of the name & shame principle. ‘We do not explicitly publish black lists, however we do publish all control results, even those of organisations that do comply’, says Colijn. ‘the government has to be transparent. Not because this is the newest hype, but to demonstrate what you have achieved. In the days of classic oversight, you would concentrate on what you have done, the output, but with modern oversight it is the outcome that is central and its effect.
Marijn Colijn is senior advisor oversight development product safety non-food at the new Food and Commodities Authority (nVWA). The regulatory body focuses on effect management and is in this context continuously on the lookout for the most suitable instruments. ‘Applying maintenance communication means saving on inspection capacity.’
‘Soft when possible, hard when necessary’
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Figures 2010
In 2010, accredited mrecs and the ccmo reviewed fewer research files than in 2009. In that year (after correcting for forwarded judgements) 1,913 research files received a judgement; in 2010, the number was 1,702. The latter number will increase slightly once all forwarded mrec judgements from 2010 have been received and processed by the ccmo. The ccmo will report on them in its next annual report. Then it will also become clear whether fewer studies were in fact reviewed in 2010 than in previous years, as current figures suggest. The ratio of industry-financed medicinal products research to research submitted by researchers (53:47) remained roughly the same compared to previous years.Absolute figures say little about the type of research reviewed and conducted in the Netherlands. In its report ‘Toetsing en toezicht in de toekomst’ (Assessment and Oversight in the Future) (2009), the ccmo calls for the Netherlands to focus primarily on high-quality, innovative medical research. In other words, the emphasis should be on quality of research rather than on quantity.
Rejected research
In 2010, a total of 55 negative judgements were recorded. Compared to the total of 1,702 judge-ments, the overall rejection percentage is a good 3 percent. This is similar to 2009. The differences in rejection percentages among accredited medical research ethics committees remain large. Slightly more than half of the committees, fifteen to be precise, did not issue any negative judgements in the past year. The other twelve committees all rejected at least one study. In terms of percentages, the mrec metigg rejected the most studies in 2010, with a total of eight rejections (34%) (see page 9 for an interview with Ruud van Beest, chair of the metigg). Next in line is the vcmo with 11 negative judge-ments (27%). The mrec of the umc Utrecht rejected twelve studies in the past year (8%), and the mrec in the azm issued a negative ruling in five cases (4%). The committee in the umc Groningen issued two negative rulings (1%). The other mrecs each rejected one study. The ccmo issued ten negative judgements in 2010 (21%). A discussion of the research assigned to the ccmo may be found on page 22–26.
Appeals
Two administrative appeals were filed with the ccmo against a decision by an accredited mrec in 2010. This number is not significantly different from 2009, when the ccmo received three appeals. The number of appeals remains low.Of the two submitted appeals, one has yet to be settled by the ccmo. The other appeal was exam-ined in 2010 and declared unfounded. The appeal involved a proposed change to a (follow-up) study in pregnant women who were examined to determine whether they had a (subclinical) form of anxiety or depression. The discussion focused on the question of whether women who were only approached by mail for participation in follow-up research could be approached by telephone if they did not respond to the mail. The core of the mrec’s objection was approach by telephone.
Their opinion was that this could too easily be perceived as pressure.The ccmo feels it is not desirable to approach particularly this group of vulnerable research subjects by telephone for participation in (follow-up) research. Although such a telephone call may also be used to address the care these women may need, it is clear the goal of the discussion may not be inclusion in a study. The ccmo is of the opinion that requesting partici pation in a study during a conversation in the context of care may harm the carefulness of the care provided and is not desirable in the situation in question.Additionally, the ccmo completed one appeal filed in 2009 in 2010. This appeal related to an intervention study examining whether tinnitus could be reduced using manual therapy according to the Van der Bijl method. The conflict primarily involved the study design and the documentation, which the mrec had serious critical observations to. In addition to these issues concerning content, the question was whether the mrec could justly be accused of not observing due diligence in the review process. The ccmo shared the critical observations of the mrec regarding content. Although the scientific question may be interesting, the ccmo felt the design outlined in the research protocol was insufficient for properly answering this question. Regarding the procedural complaints, the ccmo is of the opinion that the mrec was unclear in its communication with the submitting party. Insofar as the appeal related to the latter diligence matters, the ccmo deemed it valid. The mrec judgement on content was upheld.
Objections
In 2010, the ccmo received six new objections against its decisions: four regarding a negative decision on a research proposal, and two within the context of a supervisory intervention on an accredited mrec. The first of the latter two
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2010
2009
2008
2007
2006
Proportion of multicentre studies
Proportion of studies with medicinal products
multicentre studies
monocentre studies
research with medicinal products
research with non-medicinal products
2010
2009
2008
2007
2006
628 / 1285
634 / 1264
614 / 1213
627 / 1224
533 / 1169
639 / 1063
719 / 1194
705 / 1193
687 / 1140
695 / 1156
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Sub
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628
634
614
627
533
126
113
119
127
129
73
78
65
65
67
68
70
53
59
75
190
199
172
206
186
186
69
42
12
29
1
0
0
14
19
2010
2009
2008
2007
2006
Type of interventional research
medicinal products
medical devices
psychosocial interventions
operations
other 2010
nutrients
physiotherapy
somatic cell therapy
radiotherapy
gene therapy
genetic modified organism (gmo)
animal components
vaccination
other
other
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130
135
124
127
97
145
133
133
122
129
171
203
183
210
171
70
68
67
57
52
103
81
90
84
75
9
14
17
26
9
Research with medicinal products per phase
phase I
phase II
phase III
phase Iv
other
na
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to a study into freezing egg cells for later use. This attracted the necessary media attention. The officially submitted objection was suspended in order to come to a solution in mutual consul-tation. A subsequently submitted new research protocol was again rejected in late 2010. The three other newly received objection were still being handled in late 2010.
targeted the ccmo decision to temporarily and partially suspend (place on hold) an accredited mrec. The underlying reason for this was to prevent the committee in question from receiving any new research files for review pending the outcome of the ccmo investigation into its activities. In the opinion of the ccmo, the pro-visional findings in the investigation were such that a measure of this nature was justified for the protection of Dutch research subjects. Upon completion of the supervisory intervention, the ccmo decided to withdraw accreditation. The mrec in question also filed an objection against this decision. At the same time, the committee in question requested a temporary injunction from the administrative court with the goal of immediately resuming their review activities. Upon rejection of this request for an injunction by the court, the mrec withdrew both letters of issue (see page 10 –11, Withdrawal of accreditation of the steg/mrec). In 2010, two letters of objection against negative ccmo decision from 2009 were handled. The first referred to a vaccine study that the ccmo felt had no added value for the National Vaccination Programme (rvp) in the design proposed. The objection its relevance was elaborated further. After modification of the research protocol, the study was approved. The second letter of objection also related to a vaccine study. This study looked into a potential new treatment for prostate cancer. The study was rejected because the radiation therapy to be administered to the tumour during the study could affect the measurements. During the objection procedure, the researchers were able to refute this objection with substantiation, so this study was also approved.
In 2010, the ccmo received four new letters of objection against negative rulings on research proposals. The first newly received letter of objection against a negative ruling pertained
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44(21%)
46(22%)
120(57%)
research with medicinal products
other interventional research
observational research
2 phase I (4%)
9 phase II (20%)
19 phase III (41%)
7 phase Iv (15%)
7 other (15%)
2 na (4%)
24 industry
(52%)
22 non-industry
(48%)
Studies with minors
total 210 studies with minors
of which
of which
Categorisation of research with minors and incapacitated subjects
total number of decisions in 2010
of which
decisions involving minors
and incapacitated adults
of which
decisions therapeutic research
decisions non-therapeutic research
of which
non-therapeutic observational research
non-therapeutic interventional research
1702
275
108
167
156
11
Minor and incapacitated subjects
Scientific research with minors and/or incapaci-tated adults is prohibited in the Netherlands, with two exceptions:– therapeutic research. This is the case if the
research may also benefit the research subject. The studies are reviewed by accredited mrecs;
– non-therapeutic group-specific research. This is the case if the research will not benefit the research subject, but can only be conducted with the cooperation of research subjects in the category to which the research subject belongs. The additional requirement set by the wmo for such research is that risks must be negligible and burden minimal.
275 of the total of 1,702 research files reviewed in 2010 involved minors (210 studies) or inca-pacitated (65 studies) research subjects. The 275 judgements related to therapeutic research in 108 cases, and non-therapeutic research in 167 cases. In the latter studies, 156 cases involved obser vational research and eleven (non-therapeutic) intervention research reviewed by the ccmo (see below).
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Research with minor research subjects
Of the 210 studies with minor research subjects, 46 pertained to studies with a medicinal product. In two cases this was an early phase medicinal product study (phase i). In nine cases this was a phase ii study, and in nineteen cases a phase iii study. Seven files related to research with an accredited medicinal product (phase iv). The submitting party filled out ‘other’ under category for the other studies with medicinal products.The eleven non-therapeutic intervention studies in minor research subjects were assessed by the ccmo. The committee approved five studies. The topics were, in order, the reliability of a test to determine a lack of growth hormone, the effect of mechanical ventilation on airway problems and cognition, the effect of a standardised running test on the salivary cortisol response, the pharmacokinetics of oseltamivir (Tamiflu) in infants with influenza, and a study into the effects of alcohol in adolescents.Six studies were rejected by the ccmo. In five cases, the risks and/or burden were more than minimal (in combination with other factors). In four of these studies, the committee was also of the opinion there were methodological short-comings and limited scientific relevance of the research question. In one of these studies, the group-specific nature was not convincingly demonstrated. This was also the case for the sixth rejected study, in which the ccmo additionally felt the risks for the minor research subject were too great. The applicants of two of these rejected studies filed an objection in 2010. The objections procedures had not yet been completed by the end of the reporting year.
In 2010, the ccmo received eight new research files on research with gametes and (supernumerary) embryos. Three files related to supernumerary embryos. The topics were, in order, the fate of aneuploid blastomeres, the effect of culture environment and growth factors on early differen-tiation of supernumerary embryos and the cause of repeated miscarriage. The last study uses super-numerary embryos and uterine lining tissue from women with and without repeated miscarriages. The ccmo approved these three studies.Five files related to research with gametes (and embryos for in vitro fertilisation, ivf). The first study is a cohort study examining the presence and precise location of the human papilloma virus (hpv) in semen. A second study with gametes aims to test a new method for ovum injections within the context of an ivf treatment. The third file is a comparison between two commonly used culture media for culturing egg cells and embryos for ivf treatments. The goal is to determine which medium results in the highest percentage of live births. The ccmo approved all of these studies after a few adjustments.The fourth and fifth files were two versions of a study into the safety and efficacy of freezing egg cells of women at risk of ovarian failure. The first version was rejected because the ccmo, due to a lack of data on animal and human (pre-)clinical research, was unable to determine whether a step towards a cohort study among children born from vitrified egg cells was justified. The second version of this study was also rejected. The reason was that the proposal, in the opinion of the committee, did not meet the quality requirements for a scientific research protocol and could not lead to valid, generalisable insights.
New developments
In June 2010, an addendum was published to the Position on vitrification of human egg cells and embryos (2008) by the professional organisations of gynaecologists and clinical embryologists
(nvog/klem). The former State Secretary for Health, Welfare and Sport (vws) had requested this from the professional organisations after a storm of media and political attention in the summer of 2009, when the amc announced plans to freeze egg cells for non-medical reasons and use them for ivf treatments. In the addendum, the professional organisations state that there are no good arguments for rejecting the collection, vitrification and storage of egg cells for use during an ivf treatment in advance, even if there is no strict medical necessity. However, the pro-fessional group does view vitrification of egg cells and their use as experimental; the intervention may only be offered within the context of scien-tific research focused on obtaining additional data on the safety and efficacy for (above all) the child. In September, the research group from the amc published the first results of freezing human egg cells as part of an experimental ivf treatment, during which two completed pregnancies resulted in two healthy children.
Twelve years after the first human embryonic stem cells were isolated and cultured, the first clinical study with human subjects was launched in the usa. In the summer of 2010, the us regulator, the fda, gave permission for this study into the safety and tolerability of stem cell administration to humans with recent spinal cord injury. The study started in October with a single patient. Nine more patients may be included in the future. It will be some time before it becomes clear whether the experimental intervention is safe and has the desired effect.In late August 2010, the US government banned government funding of research with human embryonic stem cells. The ban was put in place while awaiting the ruling in a court case filed by an American research centre that is supported by Christian groups. They were of the opinion that the government should not support research in which human embryos are lost. In September,
Gametes, embryos and the foetus
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Research with medicinal products on minors by committee
amC
erasmus mC
Cmo
umCg
umCu
azm
lumC
vumc
bebo
CCmo
Catharina zh
vCmo
nKI
medisch Spectrum twente
metC Zuidwest Holland
mettoP
mettigg
Isala Klinieken
Wageningen universiteit
Steg
atrium mC & maasland zh
St elisabeth zh
tWoR
metC noord-Holland
RtPo
IRb amsterdam
St Slotervaart zh
IRb nijmegen
máxima mC
3
7
4
3
5
0
1
6
0
7
0
0
0
2
4
0
0
3
0
0
0
0
0
0
0
1
0
0
0
22
30
18
17
31
12
13
21
0
16
1
0
0
4
5
2
4
4
1
0
1
1
1
3
2
1
0
0
0
180
159
153
149
144
140
140
129
68
47
42
41
31
33
28
22
23
25
22
5
19
18
16
15
19
3
14
7
10
tota
l 201
0
tota
l min
ors
of
whi
ch r
esea
rch
wit
h m
edic
inal
pro
duct
s
phase 1
phase II
phase III
phase Iv
other
na
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Vaccines
In 2010, the ccmo assessed nine research files for vaccine studies. Additionally, the ccmo also reviewed three files for research looking into a cellular vaccine. The discussion of these studies follows below (see Cell therapy).Of the nine research files assessed by the ccmo, one was initially rejected. This was an additional study in an ongoing vaccine study into the prevention of pneumococcal infections in elderly people. The committee felt the primary endpoint was incorrect and found the study underpowered. The applicant subsequently submitted a revised research proposal as a new file, with a modified primary endpoint and a statistical paragraph. This study was approved by the ccmo. The other eight research files were approved by the ccmo. One approval was a ruling on a objection filed regarding a study rejected in 2009 into the vaccination schedule in the National Vaccination Programme (rvp). After modifications to the research protocol and limitation of the study to a single research question, the ccmo was able to approve the study. Another approved study was the study into the optimum vaccine and vaccination schedule for protection against pneumococcal infections in children who had undergone stem cell transplantation. In a third study, it was examined whether adding an adju-vant to a new vaccine against Alzheimer's disease had added value. The ccmo also approved a study in which the immunogenicity and safety of intradermal vaccination using a jet injector with a reduced dose of inactivated polio vaccine was examined. The goal was finding an antigen-sparing, reliable and easy vaccination method that can contribute to the global eradication of polio. The fifth vaccine study approved by the ccmo aimed to study the mechanism of action of a vaccine designed to help people stop smoking. A sixth study looked at a pertussis vaccine to be given at birth. This research file was withdrawn
Centrally reviewed research
The ccmo’s reviewing mandate is limited to a number of specific fields of research:– non-therapeutic intervention research with
minors and incapacitated subjects;– research into vaccines (since 1 November
2009, this only applies to vaccines without marketing authorisation);
– research in the field of cell therapy;– research in the field of gene therapy;– research with antisense oligonucleotides;– research in the field of rna interference;– research in the field of xenotransplantation
with live animal components;– research with substances covered by the
Opium Act (such as heroin addiction);– research with gametes for which obtaining
these cells research subjects are subjected to interventions within the context of research (for example obtaining sperm surgically);
– research with gametes for which embryos are created within the context of an ivf treatment (Embryos Act);
– research with embryos left over after an ivf treatment (supernumerary embryos) (Embryos Act).
Review by the ccmo of non-therapeutic inter-vention research with minor and incapacitated subjects was discussed previously, as most other research with this group of research subjects is assessed by accredited mrecs (page 22). The central review of research with gametes, supernumerary embryos and the foetus has also been covered previously (page 22).
This part of the report takes a closer look at the other areas of research mentioned. This type of research is difficult to classify by type of research subject. The criterion applied is that, given the social, ethical and legal aspects associated with the research, central review is desirable. In 2010, this involved a total of 27 decisions:
the ban was temporarily lifted; the judges wanted more time to examine the government's appeal.In November 2010, the results of research into a method to produce blood based on human skin cells without the need for stem cells were published. Using this new method, connective tissue cells are transformed into blood cells by exposing them to a mixture of chemicals.
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during assessment due to other priorities of the sponsor, related to budgetary limitations.Three reviewed studies involved research into the application of so-called tumour vaccines in patients with certain types of cancer. One of these studies examined the safety and efficacy of a new vaccine for melanoma patients. Another study was research into the added value of vaccination in addition to hormone therapy in patients with breast cancer. The third study with tumour vaccines related to the potential added value of a human papilloma virus vaccine (hpv vaccine) combined with chemotherapy in women with cervical cancer. This study explores the best moment for vaccination.
In addition to the nine research files assigned for legal reasons, the ccmo also reviewed two studies with a malaria infection model that could be used to determine the effectiveness of malaria vaccines. The assessment was conducted by the ccmo for pragmatic reasons; there was a strong relationship with previous studies by the same research group that had been reviewed by the ccmo. The mrec cmo Arnhem-Nijmegen region had previously transferred a study from this line of research to the ccmo. Both studies were approved.
Since 1 November 2009, the ccmo only reviews vaccine research involving vaccines without marketing authorisation or non-therapeutic research with minor or incapacitated subjects. In 2010, five studies with accredited vaccines were reviewed by an accredited mrec.
Cell therapy
In 2010, the ccmo completed review of twelve new cell therapy studies. Three were rejected. The first rejected study was a study into an experimental knee implant, consisting of a degradable carrier combined with autologous bone marrow and cartilage cells as a possible new
treatment for cartilage injury. The ccmo felt the scientific underpinnings and pre-clinical research findings were insufficient. Additionally, the ccmo was of the opinion that the study focused too strongly on the potential effectiveness of the experimental implant while there were still too few results available from preliminary studies.The second rejected study was research in which patients suffering from multiple myeloma receive an allogenic stem cell transplant from which the donor t cells have been removed after disease progression or relapse. The idea behind removing the donor t cells from the transplant is to reduce the risk of a graft-versus-host reaction. Subsequently, the patients in the study were given donor lymphocytes in order to induce a graft-versus-myeloma effect. In the interim, patients would be randomised to receive one of two different maintenance therapies. The ccmo was of the opinion that a new intervention should be compared with current standard treatment, which also included abstaining from treatment targeting the myeloma as an option. Additionally, the study did not examine the effect of the new intervention on the patient’s quality of life. The heavy burden of the study on these patients with a limited life expectancy, who in part would not benefit from partici pation in the study, was not acceptable in the ccmo’s opinion.The third rejected study was research into the use of an allogenic stem cell transplant from which ∂ß-t-cells and cd19-positive b-cells have been removed. This new form of stem cell transplant was to be tested in patients suffering from acute myeloid leukaemia (aml) and myelodysplastic syndrome (mds) with a relatively high mortality risk as a result of stem cell transplantation. After stem cell transplantation, the researchers wanted to treat patients with medication that modulates
and suppresses the immune system. The study was rejected because the number of research variables within a single study was too great. Due to the introduction of a modified method for stem cell transplant and immuno-modulating medication, the ccmo was of the opinion this study could not, in the form proposed, yield generalisable results. Of the nine approved studies, five related to research into new treatment methods for patients suffering from various forms of cancer. In three studies, vaccination using autologous dendritic cells was used. In the first study, two different maturation processes for dendritic cells loaded with tumour antigens were examined in melanoma patients. The second study was a controlled, randomised study into the effect of the cytostatic agent cisplatin on vaccination with autologous dendritic cells loaded with tumour antigens, again in melanoma patients. The third study is a phase i/ii study in which research subjects with Lynch syndrome (a hereditary form of colon cancer) or carriers of the gene for the disease were vaccinated with autologous dendritic cells loaded with tumour-specific peptides. The fourth approved oncological cell therapy study was a study into the efficacy and safety of administration of donor lymphocytes, in which the alloreactive t cells are removed from the donor material. This study was performed in patients with haematological malignancies who had undergone allogenic stem cell transplantation. It is a new proposal of a study reviewed in 2009 and withdrawn at the time. The final approved oncological cell therapy study is a phase I study into the safety and feasibility of allogenic trans-plantation with natural killer (nk) cells. These nk cells are cultured in the laboratory and subsequently administered to older aml
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with Opium Act substances in addicts that was submitted to an accredited mrec for review. Because the scope of the provision in the bcb proved unclear, this research file was referred back to the mrec to which it was originally submitted. The ccmo will consult with the ministry in order to clarify this provision in the bcb. In 2010, the ccmo did not receive any new research proposals in the field of rna inter ference and xenotransplantation for review.
of autologous stem cells obtained from fat tissue is compared with the current practice of jawbone build-up.
Gene therapy
In 2010, the ccmo assessed one gene therapy study. This study was approved. It is a study into the administration of an experimental tumour vaccine to patients with advanced non-small cell lung cancer. The tumour vaccine is composed of four allogenic, genetically modified tumour cell lines. These cell lines produce a molecule that may increase recognition of the vaccine by the patient’s immune system. The goal of the study is to examine whether the vaccination can lead to an immune reaction against the patient’s tumour cells, thereby increasing survival.
Antisense
In 2010, the ccmo received five new clinical studies with antisense oligonucleotides for review. One study with an antisense oligonucleotide that is being developed for the treatment of hepatitis C was approved. In three studies, the focus lies on research into a possible new treatment for Duchenne muscular dystrophy. Two studies were approved (see also page 28–29 Case study). The third study was submitted in late November 2010. The review of this study had not yet been completed at the end of the reporting year. Finally, the ccmo received one study into the safety and efficacy of an antisense oligonucleotide being developed for the treatment of hypercholesterol-emia in late December 2010. The review of this study is expected to be completed in early 2011.
Other
According to the Central Review of Medical Research Involving Human Subjects Decree (bcb), the ccmo must also review research involving substances classified under the Opium Act and provided within the context of treating an addiction. The ccmo reviewed one study
patients who are in complete remission following standard chemotherapy, and who do not qualify for stem cell transplant due to their age.
Two approved cell therapy studies involve patients with heart diseases. The first study was research into administration of autologous bone marrow cells into the heart in patients with remaining or new refractory angina pectoris. This is a study into the repeated administration of autologous bone marrow cells in patients in whom a positive effect was noted in a previous cell therapy study. The second study is a randomised, double-blind, placebo-controlled study in which patients with terminal heart failure are given autologous bone marrow stem cell into the heart. After questions about the burden on the placebo group, the ccmo agreed with the applicants that the previously noted positive results from phase I research had to be examined in a controlled study.
The ccmo reviewed two cell therapy studies with patients suffering from Crohn’s disease. The first study is a phase I study: a dose-escalation study in which patients with refractory Crohn’s disease are administered allogenic mesenchymal stem cells in the fistulas. Additionally, a follow-up study was reviewed that continued along the path of a previous study approved by the ccmo. The goal of this follow-up study was to collect long-term data for autologous fat stem cells for the treatment of perianal fistulas in patients with Crohn’s disease. The study was withdrawn by the applicants during review, because the original study was terminated prematurely. The reason for this was that withholding anti-tnf treatment from these patients proved unfeasible.
The ccmo also approved an open-label, randomised phase I study in which research subjects will undergo upper jaw/sinus floor bone build-up for the purpose of placing a tooth implant. In this study a bone substitute consisting
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on 4 april 2001, the eu Directive on good Clinical Practice (2001/20/eg) was published. this
directive regulates the assessment of research with medicinal products within the eu. two years later
(on 1 march 2006), the directive came into effect in the netherlands. Since the introduction of the
eu directive, a medicinal products study must be reviewed by two bodies in each member state:
by an mReC and by the competent authority (Ca). this method is referred to as dual assessment.
the goal of the eu directive is to harmonise the review of studies with medicinal products within
the eu, particularly for the pharmaceutical industry.
the way in which this dual review is interpreted differs between member states. an integrated
approach was chosen in the netherlands. In our country, the full research file is reviewed by one
accredited mReC; the competent authority only carries out a marginal review. most member states
do not have a review system with accredited mReCs and a single regulator overseeing the quality
of these committees, as is the case in the netherlands. these member states therefore chose a
different approach when the eu directive was introduced: the mReC only performs an ethical review
of part of the research file, and the national marketing authority (acting as the competent authority)
reviews another part of the research file, namely the product information for the medicinal product
to be studied.
no systematic research has been conducted into the quality of assessments by mReCs and competent
authorities within the eu. this is remarkable, as there is a great deal of discussion about far-reaching
harmonisation of various assessment regimes, while a discussion on the quality of reviews of the study
content within the eu is still lacking. this was the reason the CCmo decided to examine in detail
the assessments conducted within the eu of an international study in boys suffering from Duchenne
muscular dystrophy for this annual report.
the goal of the Duchenne study is to determine the efficacy, safety and tolerability of two different
dosing regimens (continuous or intermittent) of an experimental medicinal product (antisense oligo-
ribonucleotide). It is hoped that uptake of this substance by muscle cells will lead to the production
of a protein involved in muscle function.
the boys taking part in the study were divided into two groups: one group received the investigated
medicinal product, the other a fake (placebo). the boys are subjected to a number of exertion and
muscle strength tests as part of the study. two muscle biopsies and 26 blood samples are also taken
for study purposes. In some member states, body composition and bone density is also determined
three times using x-ray radiation (DeXa scan). the total study duration is a minimum of 24 weeks.
the research file was submitted in six member states (belgium, France, germany, the netherlands,
Spain and united Kingdom). In the netherlands, the research content was assessed by the CCmo,
who acted as the ruling medical research ethics committee for this study. the CCmo asked
questions pertaining to the relevance of the placebo group and the burden of taking the muscle
biopsy versus two key goals of the research. the researchers wanted to demonstrate both the
efficacy of the experimental substance and the protein production in muscle tissue in two dosing
regimens.
Case study
Assessment of a Duchenne study in the EU
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In order to answer the question of efficacy (among other things based on a walking test), double-
blind, placebo-controlled research is desirable, but muscle biopsies are not needed. In order to
determine whether protein production in muscle tissue is comparable for the two dosing regimes,
muscle biopsies are required, but a placebo group is not. Combining these two goals in a single study
could place an unnecessary burden on the boys. Due to the risks of renal and liver function disorders
following administration of the experimental medicinal product, the CCmo also wanted intensive
monitoring of the boys’ health status for the duration of the study. the CCmo also had questions
about the manufacturing process and purity of the experimental medicinal product the boys were
given. after the sponsor responded to these questions to CCmo’s satisfaction, the research file was
approved.
an analysis of the assessment of the same study in other eu member states showed that none of
the foreign mReCs had asked these questions. the questions from these mReCs were largely limited
to comments on the research subject information sheets and the (further) use of data and blood
and tissue samples. Commentary on the study design and the burden of taking the muscle biopsy
represented on the boys was absent. the foreign competent authorities did not ask any questions
on these topics either. two of the five foreign competent authorities did not even formulate a single
question before providing a declaration of no objection. the other three competent authorities had
questions similar to the CCmo regarding the manufacturing process and the relatively low degree
of purity of the experimental medicinal product.
In summary, there appears to be a significant difference in the depth of assessment between the
various eu member states. this raises a number of questions, such as what should be considered
an adequate level of assessment, and whether harmonisation within the eu could have any negative
effects on the quality of assessment, and consequently on the protection enjoyed by research
subjects.
the question is whether the result described above is due to chance, or because other member
states expressly decided for a less thorough substantive assessment of the full research file and
hardly had any questions relating to the risks to and burdens for the research subjects. only a
systematic analysis of the assessment of multiple international research files can lead to an answer
to this question. the CCmo is an advocate of such an analysis, as it is of the opinion that assessment
of the research content must play a key role in the call for greater harmonisation within the eu.
* More information about this study is available in the public CCMO register under file number
ToetsingOnline NL32173.000.10. The register may be found at http://www.ccmo.nl, under 'Registration',
then 'Go to registration'.
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after the decision of the ruling mrec has been registered, but six months later.
In late 2011, the ccmo will evaluate the publication of key data on clinical research. This may be followed in future by an expansion to include publication of the approved information sheets for research subjects. Society in general and patients considering to apply for participation in a clinical study in particular can then access the research subject information via the public ccmo register. It contains an explanation of what partici-pation in a specific clinical study means in easy to understand language. The publication of research subject information also enables comparative research on its readability to be conducted. Including research subject information in the public ccmo register requires an expansion of ToetsingOnline and is in line with the ccmo’s goal to fully digitise the submission of research files.
In late 2010, data for over 6,300 studies could be consulted in the ccmo register. The figure to the side shows that the degree of disclosure increased significantly following the policy change in 2010. Compared to 2009, the greatest increase is visible in the pharmaceutical industry: from 48% in 2009 to 89% in 2010. This means it almost doubled. The greatest readiness to publish key data was noted in studies sponsored by hospitals and umcs; they were already almost at 100% in 2010.
Of all studies reviewed in 2010, abr key data were included in the ccmo register in an average of 96% of cases. The key data were not included in the public ccmo register for 4 percent of studies that received a judgement in 2010. These were studies submitted prior to 1 November 2009: the date on which the policy change came into force. It is expected that the ccmo will be able to report that in 2011, abr key data for (practically) all studies will be available in the public register.
research. The ccmo has been striving for greater transparency in medical research for years. To this end, it annually reports on the willingness of sponsors to publicise key data prior to the start of the clinical study.
In the 2009 annual report, the ccmo wrote that it decided to change its policies regarding publi-cation of key data in the public ccmo register. This decision was made following extensive consultation with umcs, hospitals, the Dutch umbrella organisation for the pharmaceutical industry, Nefarma, and is in line with the state-ment of the international pharmaceutical industry umbrella organisations published in late 2009. The change means that from November 2009, key data from the national application (abr) form for new studies are published automatically as soon as the review has been completed and regis-tered in the ToetsingOnline portal. The sponsor can send a written request to the ccmo not to publish the data for a specific study in the ccmo register. Such a request must be well motivated. The ccmo will then weight the (commercial) interests of the sponsor against those of society. In 2010, the ccmo did not receive any motivated requests from sponsors to keep key data of a specific clinical study confidential.
In connection with the new policy, the ccmo held talks with a number of Contract Research Organisations (cros) in early 2010, who were of the opinion that the change in policy would harm their competitive position relative to foreign actors. This position was not shared by all cros active in the Netherlands. The ccmo appreciated some of the concerns voiced by the visiting cros. These companies often work for foreign clients, and it takes some time to explain the Dutch policy changes. The ccmo therefore decided to adjust its policy in 2010: publication of data from the abr form for phase I studies with healthy volunteers does not occur immediately
Transparency in research
Society is demanding greater insight into research carried out on human subjects. This is a global trend with multiple causes. Patients are increas-ingly interested in research conducted on ‘their’ disease. Sometimes they are specifically looking to take part in clinical studies.Another reason for the call for greater transpar-ency is the fact that important data from clinical studies sometimes are not made public. This has had grave consequences in a number of cases. A well-known example is the English phase i study tgn1412 which almost cost six h ealthy volunteers their lives in March 2006. Research into the chain of events showed that a substance with a similar mechanism of action had previously been tested in humans and had led to serious adverse reactions, resulting in the premature termination of that study. However, those data were not known to the sponsor of the tgn1412 study or the independent reviewers. Had the results of the previously conducted study been widely publicised, the dramatic outcome of the tgn1412 study would probably have been prevented. These and other incidents could easily lead to crumbling support for clinical research in society.For the industry, greater transparency regarding research with human subjects is also beneficial for the following reason. If clinical studies conducted by the own company or competitors show that a certain substance does not have the desired effect, further investments in that type of medicinal product may no longer be worthwhile. Manpower and facilities can then be employed to study substances that are more promising. This could allow lines of research to be terminated at an earlier stage, preventing exposure of research subjects to unnecessary risks and burdens.
Editors of medical journals also demand full disclosure from researchers with regard to planned research. They assume that this can prevent medical fraud and avoid comparable
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89%
48%
36%
35%
27%
Consent for public disclosure
pharmaceutical industry
biotechnological industry
other industry
university medical centres
other hospitals
other
total
2010
2009
2008
2007
2006
86%
69%
61%
64%
59%
89%
48%
46%
42%
36%
98%
86%
86%
83%
79%
99%
91%
83%
83%
86%
97%
82%
74%
71%
69%
96%
78%
73%
70%
66%
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218 177 81%
195 162 83%
169 118 70%
160 125 78%
156 146 94%
154 129 84%
139 112 81%
149 129 87%
62 16 26%
54 45 83%
37 22 59%
29 25 86%
36 28 78%
23 22 96%
27 22 81%
29 13 45%
28 28 100%
23 16 70%
26 21 81%
42 20 48%
28 23 82%
21 19 90%
19 17 89%
16 15 94%
11 9 82%
26 12 46%
12 6 50%
13 6 46%
10 8 80%
180 172 96%
159 152 96%
153 146 95%
149 143 96%
144 139 97%
140 137 98%
140 138 99%
129 126 98%
68 66 97%
47 45 96%
42 37 88%
41 38 93%
31 30 97%
33 31 94%
28 27 96%
22 22 100%
23 23 100%
25 25 100%
22 21 95%
5 3 60%
19 18 95%
18 18 100%
16 16 100%
15 14 93%
19 19 100%
3 2 67%
14 14 100%
7 6 86%
10 9 90%
academic mReCs
other institutional mReCs
non-institutional mReCs
academisch medisch Centrum
erasmus medisch Centrum
Commissie mensgebonden onderzoek regio arnhem-nijmegen (Cmo)
universitair medisch Centrum groningen
universitair medisch Centrum utrecht
academisch Ziekenhuis maastricht
leids universitair medisch Centrum
vrije universiteit medisch Centrum
Stichting beoordeling ethiek bio-medisch onderzoek (bebo)
Centrale Commissie mensgebonden onderzoek (CCmo)
Catharina Ziekenhuis
verenigde Commissies mensgebonden onderzoek (vCmo)
nederlands Kanker Instituut
medisch Spectrum twente
metC Zuidwest Holland
medisch-ethische toetsing onderzoek Patiënten en Proefpersonen (metoPP)
medisch ethische toetsingscommissie Instellingen geestelijke gezondheidszorg (metigg)
Isala Klinieken
Wageningen universiteit
Stichting therapeutische evaluatie geneesmiddelen (Steg)
atrium medisch centrum & maaslandziekenhuis
Sint elisabeth Ziekenhuis
toetsingscommissie Wetenschappelijk onderzoek Rotterdam eo (tWoR)
metC noord-Holland
Regionale toetsingscie Patiëntgebonden onderzoek
Independent Review board amsterdam
Stichting Slotervaartziekenhuis, jan van breemen Instituut en bovenIj Ziekenhuis
Independent Review board nijmegen
máxima medisch Centrum
name institute/committee
tota
l num
ber
of
deci
sio
ns
of
whi
ch a
re p
ublic
% c
ons
ent
for
publ
ic d
iscl
osu
re
tota
l num
ber
of
deci
sio
ns
of
whi
ch a
re p
ublic
% c
ons
ent
for
publ
ic d
iscl
osu
re
type
co
mm
itte
e
2009 2010
Consent for publication by committee
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Government Information (Public Access) Act (Wob) requests
In 2009, the ccmo received one request for information based on the Government Information (Public Access) Act (Wob). This was a request on behalf of the steg/mrec for publi-cation of the ccmo documents that led to the withdrawal of accreditation. The ccmo held the position that the documents requested were drafted for the purpose of internal review. The positions of ccmo members and employees outlined therein can be considered personal policy beliefs. In order to protect the free, open and unfettered communication essential to the decision-making process within the ccmo, the ccmo decided not to publish the internal documents in full. However, in order to ensure a good and democratic operational process, the ccmo did decide to provide the requested information in such a manner that it could not be traced back to individuals and in a (partially) objective form.
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Prof dr eduard Klasen, PhD member of the board of directors and Dean of the leiden university medical Centre (lumC)
‘ not every mReC has all the necessary expertise’
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Interview
‘ It is the interpretation of regulations that is par ticularly important’Prof dr Eduard Klasen is member of the board of chairs and Dean of the University Medical Centre of Leiden (LUMC). Together with the Erasmus Medical Centre the LUMC installed a cooperative Data Safety Monitoring Board (DSMB) in December 2010. The LUMC also has a GRP committee. ‘Quality assurance is primarily a task for the organisation itself.’
The focus of ccmo’s oversight is on the content, according to Klasen. ‘Of course you have you comply with regulations, but the ccmo’s opinion on the content is more interesting as you can use it as a tool for improving your work. In the process of carrying out a research you are sometimes met with complex situations, such as in the case of cell therapy. In this case it is the interpretation of the regulations that is particularly important. Frequent contact is necessary. I believe the ccmo is satisfied with this’, he says. ‘But it’s not only on a friendly basis. Now and again heated discussions are the order of the day. And that is a good thing, because it is the ccmo’s task to remain focussed and to oversee.’
The ongoing developments in the field of medical science means ever more specific knowledge is required within the accredited mrecs, states Klasen. In the past few years the reviewing commit-tees have been filling these gaps. ‘Not every accredited mrec has all the necessary expertise’, he says. ‘It is conceivable that new knowledge is anchored at the ccmo to start with, so that accredited mrecs can make use of this knowledge and direct their questions to the ccmo. In this way the ccmo could act as a kind of market leader. Perhaps this is an effective system. In this way you can incorporate an ever more level of quality. The ccmo is the perfect vehicle for this.’
In June 2010 the Dutch Federation of University Medical Centres (Nederlandse Federatie van Universitair Medische Centra) published the report ‘Quality Assurance of Research on Human Subjects’ (Kwaliteitsborging van mensgebonden onderzoek). It contains measurements for tightening and monitoring the quality of research. One of these measurements is operating with the use of a Data Safety Monitoring Board (dsmb). In the middle of December the lumc and the Erasmus mc installed a coopera-tive version of the dsmb. ‘If we come up against challenging issues during the course of the study we ask the Rotterdam members of the dsmb to have a look at these independently. Vice versa, the Erasmus mc can hire members of the Leiden mc to do the
same’, says Klasen. ‘The advantage of this is that the ccmo can concentrate on the monitoring of the accredited mrecs. With the monitoring task in mind that seems to me to be a fine idea. Saying that, quality assurance with regard to the execution of research on human subjects remains primarily a task for the organisation itself.’
One year ago the lumc set up the so-called grp committee. One of its tasks is to carry out audits at the departments to determine whether research involving human subjects is being carried out according to the principles of good research practice. ‘That is in harmony with the work of the mrec’, says Klasen. ‘Audits are quite challenging for researchers in the beginning, but once they get used to them, they don’t mind them. After all, they do help you to do a better job.’ According to him, an audit system is a way for the ccmo to oversee the quality of the accredited mrecs. ‘The ccmo could make an agreement with the field regarding the execution of audits. In doing so you could perhaps meet the wish of the mrec to not only be audited when there are signs that something is wrong. For example, you could introduce a lighter auditing system whereby everyone gets a turn’, he says. ‘But visitations are labour intensive. The ccmo could also ask the accredited mrecs to report on how they assure quality of their own activities.’
With regards to overseeing research involving human subjects, sometimes you find yourself wrestling with the question where the ccmo begins and the Health Care Inspectorate (igz) ends, according to Klasen. ‘It is important that they continue to converse with one another. The ccmo was closely involved in the research into the propatria study and cooperated in this with the igz. This must have been one hell of a job, as you cannot skim the surface of such a complicated problem with so many consequences. The ccmo takes this task very seriously’, he believes. ‘While you may be able to discuss the outcome of the study, you cannot discuss the efforts of the ccmo.’
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Patients taking part in medical research often do this based on altruistic considerations. they
contribute to greater knowledge about their disease and, ultimately, to improving health care.
to put it briefly, medical research is focused on ultimately demonstrating that a new medicinal
product or experimental treatment is both effective and safe. at the time of the study, there is
still uncertainty. this means that a patient taking part in scientific research may be exposed to
(unknown) risks and (usually) cannot count on their participation yielding personal health gains.
of course, the intention is for a successful course for all studies, but this can never be guaranteed
fully. It may be that the patient is harmed by participation in the study. the legislator has there-
fore required mandatory injury insurance* be taken out for medical research. the idea is that
if a patient is harmed as a result of the study, the insurance company will compensate the injury.
Compensation does not occur in all cases of injury. For example, no compensation is given if
the injury would also have occurred had the study not taken place. additionally, injuries that the
patient was informed of at the start of the study are generally not covered, unless they are more
serious than predicted. this provision stimulates (pharmaceutical) companies and researchers
to write research subject information sheets with long passages on all possible adverse reactions.
this does not contribute to the readability and decreases the odds of compensation in the event
of injuries. additionally, the maximum sum paid out is determined by law and depends on the
damages suffered. For example, a maximum of 60,000 euro per year is paid out if the patient’s
capacity to generate income is harmed by the injuries. the maximum sum the patient receives
for medical aid and facilities is 50,000 euro.
the law has determined that the study sponsor (the party organising the research) must provide
for injury insurance cover. He does not have to purchase insurance himself, but must submit
documents demonstrating that injury insurance is available to all patients in the study. the ruling
mReC checks these documents during the review of the research file. If no proper injury insurance
has been obtained, the mReC cannot approve the research file.
on paper, this regulation appears clear-cut. In commercially funded research, the organisation
and review of injury insurance is generally swift. the sponsor in these cases is a (pharmaceutical)
company that takes out a single insurance policy for patients to be included in the study at all
participating hospitals.
Problems arise primarily in non-commercial studies conducted in several Dutch hospitals
(investigator initiated multi-centre research). the board of directors at the principal investigator’s
institution takes on the role of sponsor. usually, this board of directors purchases injury
insurance for the patients to be included within their own hospital. other participating hospitals
must purchase injury insurance for participating patients themselves and submit the relevant
documents. the sponsor subsequently submits these documents to the ruling mReC, which checks
the information. the sponsor does not need to wait until all data from all hospitals has been
received. If desired, the documents may be submitted per individual hospital, and subsequently
reviewed by the mReC. once suitable injury insurance has been taken out for a participating
hospital, the ruling mReC may approve the hospital for participation. this complex state of
affairs leads to a great deal of correspondence between all parties involved, high administrative
burdens and a delay in the research. this delay can sometimes be more than a year (see page
66–67 the CCmo as regulator).
Injury insurance or compensation fund for Dutch research subjects?
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the current regulation can also lead to errors, as demonstrated by the PRoPatRIa study.
In this study, in which a large number of Dutch hospitals participated, the board of directors
for the umC utrecht acted as the sponsor. However, one of the participating hospitals failed
to obtain injury insurance. unfortunately, a patient died at that hospital during the study.
In the joint report from the three authorities (CCmo, IgZ and vWa) written in response
to the PRoPatRIa study, they recommended that the ministry of vWS draft a bill for central
regulation of compensation of injury to patients (report ‘Onderzoek naar de PROPATRIA-studie’
(Investigating the PRoPatRIa study), December 2009, page 14).
unfortunately, problems associated with the injury insurance scheme are not limited to a single
incident. Previously, execution of the regulation also had been found to lead to errors (see CCmo
annual report 2004, page 57; CCmo annual report 2005, page 18). the conclusion is therefore
that despite the best efforts of sponsors, institutions, accredited mReCs and the CCmo, imple-
mentation of the regulation for injury insurance remains susceptible to error, particularly where
non-commercial multicentre research is concerned. For the CCmo, this was one of the reasons
to look for possible alternatives.
there are various examples of national regulations for patient compensation abroad. two examples:
the uSa has the National Childhood Vaccine Injury Act, a fund created to compensate individuals
for injury caused by vaccination. the fund is ‘fed’ by a small surcharge on the price of vaccines.
the second example is Denmark: the Act on the Right to Complain and Receive Compensation
within the Health Service. this act provides for a compensation fund and a government-appointed
committee to rule on claims. the phenomenon of a government appointed compensation fund
also exists in the netherlands, albeit in a field other than health care, the Criminal Injuries
Compensation Fund.
the possibilities and legal and practical implications of a compensation fund managed by the
government for research subjects should be examined. at first glance, the advantages of such a
fund are significant. It could lead to a simple regulation, under which all Dutch research subjects
in all participating centres can count on being ensured of compensation in the event of damage
due to participation in medical research. a relatively simple regulation would also significantly
reduce the administrative burden for sponsors and accredited mReCs as well as provide good
insight into and an overview of submitted and granted claims. Such a regulation would also allow
shorter and more readable research subject information based on which the patient can decide
whether or not to take part in medical research.
* This insurance is also known as study subject insurance.
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Independent Governmental Bodies Framework Act
In 2009, a proposed amendment was submitted to Parliament, aiming to bring a number of the Independent Governmental Bodies (zbos) appointed by the ministry of vws under the purview of the Independent Governmental Bodies Framework Act. The latter came into force on 1 February 2007 and aims to increase the recognisability of public administration by creating a framework for regulations surrounding zbos.
Because zbos are not hierarchically subordinate to a minister, a key part of the Framework Act is creating adequate oversight and steering instruments for safeguarding democratic control of zbo performance. One of the provisions in the Act provides for veto power for a minister regarding zbo decisions. However, the minister of vws felt that intervention at this level was not desirable for a number of these public bodies. With regard to the ccmo, the minister indicated there are already sufficient avenues for inter-vention. For example, a permanent observer from the ministry is present during committee meetings, and the minister can exercise control via an order in council (AMvB). The minister further felt it was not desirable to allow political consideration to lead to intervention when reviewing individual research files, which must occur based on scientific arguments. Therefore, the bill includes an exception based on which the minister of vws cannot veto rulings by the ccmo regarding individual research files.
In late 2010, the debate surrounding other zbos of the ministry of vws was not yet complete, so that the proposed amendment will be put on the agenda for further discussion in 2011.
Changes to the Embryos Act
In the summer of 2009, the then State Secretary of vws send a letter to Parliament outlining, among other things, a number of planned changes to the Embryos Act. One of the changes involved greater freedom for performing medical research on the foetus in utero. Based on article 20 of the Embryos Act, scientific research with the foetus is currently only allowed if it benefits the foetus in question directly. Non-therapeutic research, even if it involves risk-free imaging such as echography, is currently not possible as it does not benefit the foetus itself. The proposed changes to the law would create room for risk-free medical research with foetuses.It was expected that the bill containing this and three other amendments could pass through Parliament in early 2010. However, in the spring of 2010, after the fall of the government, the bill was declared to be controversial. The bill is now expected to be sent to Parliament in early 2011.
State of affairs regarding changes to the Medical Research Involving Human Subjects Act (WMO)
In 2008, a bill was submitted proposing changes to the Medical Research Involving Human Subjects Act (wmo). This was a result of the evaluation of the Act in 2004, and a single critical note by the Council of State relating to the mode of implementation of European legislation. In its 2009 annual report, the ccmo already included a brief description of the key proposed changes. The proposal was discussed in the House of Representatives a few times in 2009. The discus-sion was suspended until the joint report of the Health Care Inspectorate (igz), the Food and Consumer Safety Authority (vwa) and the ccmo on the propatria study was published. This occurred in late 2009. With the fall of the government in early 2010, the proposal was deemed controversial and further discussion was suspended. The proposal was not put on the agenda of the House of Representatives again in 2010.
Part 2. Legislation and regulations
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Human Tissue Bill
During the drafting of the Medical Research Involving Human Subjects Act (wmo), a separate regulation for (research involving) body tissue was announced, the Human Tissue Bill (wzl). However, such a bill has yet to be submitted to Parliament. The lack of a solid regulation has had consequences for the review of research that is part of the Parelsnoer Initiatief. This is a joint project by the eight university medical centres, in which clinical data and biological materials are collected for joint scientific research. The collection of body tissues can, in the opinion of the ccmo, fall under the purview of the wmo in certain situations, but the current stipulations of this Act cannot be used to approve this collection without a detailed research proposal. The idea behind the Parelsnoer Initiatief, however, is the reverse: first collect body tissues, then detail research proposals.
In early 2010, upon request of the ministry of vws, consultation took place between the Netherlands Association of mrecs (nvmrec), the Federation of Medical Scientific Organisations (Federa/fmwv) and the ccmo. The goal of the meeting was to find a temporary solution until a regulation regarding control over body tissues, such as the planned Human Tissue Bill, is in place. The discussion did not result in a broadly supported interim solution. This means that either the wmo needs to be adjusted or the introduction of the Human Tissue Bill must be awaited before there is a clear legal basis for the collection and storage of body materials for future research, for which the research question is as yet undefined.
VWS regulation on cell transplantation
Based on article 2 of the Special Medical Procedures Act (wbmv), the minister of vws may decide to ban certain procedures or to attach certain conditions to them. This took place in 2007 in the Designation of Special Medical Procedures Decree for transplantation of haematopoietic stem cells. Upon further elaboration – in the Planning Regulation on Stem Cell Transplantation – stem cell research was only permitted in the eight academic medical centres and the Netherlands Cancer Institute. This made research into stem cell therapy in other Dutch centres impossible. On 15 October 2010, a replacement for the planning regulation was published: the new Cell Transplantation Regulation. The original plan of the ministry of vws was to bring this new regulation into effect on 1 January 2011. However, because the new regulation would unintentionally limit the provi-sion of certain registered cell therapy products, on 13 December 2010 the validity date for the new regulation was postponed until 1 July 2011, allowing the ministry the time to adjust the regulation.
According to the new vws regulation, in addition to stem cell therapy, cell therapy also requires a license. For cell therapy studies, this means that in addition to approval of the research file by the ccmo and the institution where the study is to be performed, a license from the ministry of vws is required. A permanent license has been given to the academic medical centres and the Netherlands Cancer Institute. Other institutions may qualify for a temporary license for the duration of the study, providing the research file has been approved by the ccmo.
The ccmo has argued for simplification of the vws regulation, so that medical research in the field of (stem) cell therapy is exempt from licensing requirements. After all, the ccmo
already determines whether the study can be performed with the necessary care by the institution in question when reviewing all research files (including those for cell therapy research). The ccmo feels an additional safety valve – vws licensing – for the performance of (stem) cell therapy studies is an unnecessary additional administrative burden for Dutch researchers, institutions and companies, without there being any significant added value for the protection of study subjects.
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Evaluation of CCMO directive Assessment of Clinical Trial Agreement
In early 2010, the ccmo began evaluating the performance of its directive on the Assessment of Clinical Trial Agreement, published in 2009. The problems that were experienced during its implementation in assessing practice were inter-nally investigated, based on which potentially useful improvements were proposed. Additionally, extensive written consultation was performed, resulting in various responses from review committees, researchers as well as the industry. The positive experiences of the ccmo itself were confirmed by the responses.
The directive indicates that the Clinical Trial Agreement between sponsor and investigator must be included in the review of the research file by accredited mrecs. The directive aims to safeguard the importance of disclosing research results and to prevent premature termination of research for non-scientific reasons. After all, this may lead to included research subjects being subjected to clinical research in vain.
Due to a number of urgent projects that had to be handled with priority, the ccmo was only able to adopt the results of this evaluation, the proposals for modification and the clarification of the directive in late 2010. The results and a modified version of the directive are expected to be presented in the second quarter of 2011.
Furthermore, the ccmo deems it necessary to further clarify the requirement that a (candidate) research subject member may not act as a repre-sentative of a patient (interest) group. Per case, the specific nature and content of the function and activities the candidate member performs within the patient (interest) group will be examined.The final change discussed was the addition of expertise requirements for the member method-ologist. The training requirement has been expanded to include a complete masters degree accredited as an epidemiology degree (msc level) by the Epidemiology Association (Vereniging voor Epidemiologie). In early 2011, the accredited mrecs will be informed of the changes, and the modified guideline will come into effect later that year.
Modification of directive for Expertise Requirements for (WMO) members of MRECs
In 2010, the ccmo discussed the modification of the directive for Expertise requirements for (wmo) members of mrecs of February 2007 on four points. The first modification was the general independence requirement of mrec members. Based on new insights, the ccmo no longer feels it is acceptable for employees of an mrec secretariat to also hold a seat as a (deputy) member in the committee they already work for. Given the frequent and substantive contacts an mrec secretariat maintains with applicants of medical research, their independent position as (deputy) members may be endangered. Additionally, the fact that a (deputy) member is also dependent on the committee he/she sits on as part of the secretarial staff also plays a role. The ccmo decided to adjust the directive on this point. An ample transitional period will be observed for active members currently working within the same mrec secretariat.A second discussed change flows from the increased complexity of medical research. As a result, suitable demands must be placed on mrec member expertise in order to safeguard solid and critical assessment of research files. The decision was made to modify the requirement for demon-strable knowledge of health ethics (ethicist) or demonstrable research experience (doctor, methodologist, hospital pharmacist and clinical pharmacologist). Currently, the required demon-strable knowledge or research experience is considered sufficient based on either a dissertation (without publications) or scientific publications (without a dissertation). However, the ccmo believes that in 2011, knowledge and experience should be demonstrated by both a dissertation and relevant scientific publications. This modifi-cation therefore represents a more stringent knowledge and experience requirement. The modification will apply to new members, with the exception of the legal expert and research subject member.
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michiel Denkers Head of the oversight group of Financial businesses at the Financial markets authority (aFm)
‘ Problems are often sector wide issues’
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Interview
The Netherlands has more than 12,000 financial businesses. Around fifty of these are large banks and insurance companies. The others are smaller, for example financial advisors and brokers. ‘In the past each team monitored a small number of institutions’, says Denkers. ‘Looking at it in black and white, the monitoring philosophy was: we go in with the Legal documentation in one hand and the checklist in the other, pulling open drawers and asking questions to find out how matters stand.’
Gradually the realisation grew that problems were primarily not found in just one institution, but are rather market or sector wide issues, says Denkers. And that a versatile organisation is needed to establish efforts to counteract this. ‘Inspired by the work of Malcom K. Sparrow, of the Harvard Kennedy School, the working methods have been changed. The afm is the monitory body and wants to ensure markets are honest and clients are treated in a correct manner. However, if you want to monitor effectively, you have to first find out what the most important issues are. And to do this you need to have a good radar. At the moment the afm annually receives 10,000 signals and complaints by consumers and financial institutions on the conduct of other parties. These allow us to signal trends. Twice a year we organise a priority session on the basis of risk research in which we select the most important issues from a long list. Additionally we estimate our chances of solving these issues.’
‘Influencing conduct is our core business’, argues Denkers. ‘A strictly legal mission statement, whereby you monitor whether regulations are being complied at all times, does not work by definition. You cannot have a policeman at all traffic lights at all times. Most important you must focus oversight on the most hazardous conduct.’‘Furthermore the financial market develops very quickly. Just as in the medical research world there is a high level of complexity and dynamics. That means that you are often lagging behind.
Rule-based oversight is not enough in this case. It is for this reason that the legislation for financial oversight is more principle-based and has more open norms. For example, the legislation states that financial advisors must advise accordingly. It cannot be the case that someone who loses sleep over the stock market crash be advised to take on an investment mortgage.’The afm still works in teams, but the working method has been completely overhauled. ‘An average 30 percent of their time they spend monitoring individual institutes. However, the majority of their time is spent on collectively influencing and the teams now operate on a project and problem-solving basis’, says Denkers. ‘For example, the afm wants to see an improvement in the quality of mortgage advice. However, this type of work has many aspects and dimensions. And this needs a large array of monitory activities.’And so the afm argued for stricter norms for credit loans at the Ministry of Finance, but it also publishes guides for mortgage advice. ‘Furthermore we urged software suppliers to include a module in their software packages that compels advisors to ask for the correct information’, says Denkers. ‘Though as software suppliers don’t fall under our monitory jurisdiction we have to convince them that it is in their best interests to supply such soft-ware. This we could do by having the Consumer body promoting them, which in turn will make the customers wonder why there are differences in turn leading to public pressure. These are all different ways in which we can exert influence.’
Enforcement also remains an important instrument, though it is but one of the many’, emphasises Denkers. ‘We take action against parties who cause damage. And this is necessary. Repressive enforcement is our license to operate. Fining is also necessary to pick out the rotten apples of the bunch. This you cannot achieve with a soft approach. Above all, it cannot be the case that parties that do well have unfair competition from institutes that make a mess of things. These parties cannot get away with this.’
‘A strictly legalistic approach does not work by definition’Michiel Denkers is head of the Monitory Groups of Financial Businesses (Toezichtgroepen Financiële Ondernemingen) at the Financial Markets Authority (AFM). For some years now monitory bodies operate according to a new monitory philosophy. ‘The key is focussing monitoring activities on the most hazardous conduct.’
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Training of committee members and secretarial staff of the accredited MRECs.
In its vision paper ‘Toetsing en toezicht in de toekomst’ (assessment and oversight in the Future)
from 2009, the CCmo wrote the following: ‘the CCmo sees training of mReC members and
employees as one of the spearheads for improving the quality of substantive assessment and
improved service provision.’ (page 27). Currently, the training opportunities for mReC members
are still unfortunately limited. the so-called nomet course developed by maastricht university
in 2003 in consultation with the field and with a subsidy from the ministry of Health Welfare and
Sport (see CCmo annual report 2003, pages 24-25) sadly no longer exists. Specific training options
for employees of mReC secretariats are actually almost entirely absent. this is a great miss, as
these secretariats represent the beating heart of the review committees. the secretary in 2011
must be familiar with a broad array of legislation and regulations and the performance of medical
research involving human subjects. However, this knowledge is not easy to obtain for individual
secretaries.
there are also calls from the field for more training of mReCs. Well-trained mReC members
are better equipped to deal with comments from researchers regarding the work of the review
committee (CCmo annual report 2009, page 17). For the CCmo, this was reason to call for
expansion of it secretariat to include a training coordinator in its vision paper. In the CCmo’s
opinion, oversight and training should go hand in hand. If a lack of knowledge regarding a
certain aspect of review is identified within the mReC or the secretariat during an supervisory
intervention, targeted training can be used to fill this knowledge gap. During oversight it
can subsequently be determined whether the newly obtained knowledge is used in practice.
unfortunately, the CCmo’s request for expansion for training purposes has not (yet) been
approved. In its letter of 2 july 2010 to Parliament, former minister Klink wrote he felt it was
still too early to place this task in the hands of the CCmo.
the end result is that the CCmo currently lacks the means to create and offer an mReC training
programme to the field. However, the CCmo will contribute to broad-based training organised
for mReCs by institutions wherever it can. For example, the CCmo contributed significantly to
the mReC course organised by the vu university medical Centre in november 2010. the CCmo
provided a number of lecturers and ran a workshop in which committee members role played
a committee meeting based on a specific case. two cases were selected for this purpose: the
tgn1412 study performed in london in 2006, and the Dutch PRoPatRIa study. Course partici-
pants were given the assignment to study one of these research files in advance and draft a written
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recommendation which was subsequently discussed. During the workshop, course participants
made a risk analysis based on the methodology developed by the CCmo. a specific afternoon
programme was developed for secretarial staff, focusing on the activities of an mReC secretariat.
all course participants were sent an entrance exam created by the CCmo in advance. the goal
was to determine the level of knowledge beforehand. the response to the request to complete
the exam was high: more than 90 percent of course participants submitted their questions
before the start of the course. this allowed trainers to address specific knowledge gaps.
For example, it was found that 62 percent of mReC members and 78 percent of secretarial staff
were of the opinion that the recommendation of the Data Safety monitoring board (DSmb)
always had to be sent to the ruling mReC. During the presentation on the role of the DSmb,
it was therefore explicitly explained that the DSmb recommendation is intended for the study
sponsor. only if the sponsor decides to deviate from the DSmb recommendation will he
forward this to the ruling mReC. Furthermore, it was noteworthy that 49 percent of mReC
course participants thought that research subject information sheets had to be assessed
independently in each centre in multcentre research. this is not the case. Regardless of the
number of participating centres, only one accredited mReC reviews the research file, including
the research subject information. Reassessment of the research subject information sheets
and informed consent forms in all participating centres is one reason for the slow issue of
local feasibility statements (luv) by boards of directors at participating centres. the above-
mentioned findings, by the way, were exceptions. the majority of mReC members and
secretarial staff scored well on most questions on the entrance exam. Some even answered
more than 90 percent of questions correctly.
based on experiences and participant feedback, the CCmo will optimise the entrance exam.
Furthermore, if the necessary means are present, the CCmo wishes to use this exam as the
foundation for creating an e-learning module. Researchers, mReC members and secretarial staff
can then test their active knowledge of research involving human subjects at any time via the
CCmo website.
* See Kenter MJH and Cohen AC, Establishing risk of human experimentation with drugs: lessons from
TGN1412. [cursief]The Lancet 2006, 268: 1387-8.
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Part 3. Review system
Ethics committees on 31st December 2010
academic mReCs
other institutional mReCs
non-institutional mReCs (incl CCmo)
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committees are spread out evenly across the country.
Judgements per committee
The number of judgements issued by the various review committees in 2010 is displayed in the table on page 50. The committees are ranked by the number of judgements they issued, on average, over the past two calendar years. The overview shows that this list does not fluctuate signifi-cantly. The mrec of the Academic Medical Centre in Amsterdam remains the undisputed leader, with an average of 180 reviews per year over 2009 – 2010. The eight academic mrecs firmly hold the first eight positions. Seven of them reviewed fewer research files during the reporting year than in 2009. A notable climber is the vcmo (Nieuwegein). In 2009, this mrec reviewed 29 new research files; in 2010 the total came to 41 files. It is also noteworthy that the metigg, despite temporary suspension of its activities, did not show a significant drop in reviews for the reporting year. The ccmo completed reviews of 47 research files during the reporting year. After two busy years, it has returned to the level of 2007.
Judgements per type of committee
There are three main types of committees within the group of accredited mrecs: the committees of the eight umcs, those of the fourteen other institutions and hospitals, and six mrecs not affiliated with an institution (the so-called non-institutional mrecs).The accredited mrecs of the umcs review the most research files. In 2010, they were jointly responsible for reviewing 70 percent of all research in our country (see page 53). This is the same as in 2009. The number of research files reviewed by the other institutional mrecs increased slightly compared to the previous year (from 16 to 20%). The percentage of research files reviewed by non-institutional mrecs
review tasks, the ccmo has a number of other legal mandates. One is the accreditation of mrecs and oversight of their activities. An overview of all ccmo tasks is available on page 65.
Number of review committees
There were a total of 27 accredited mrecs in our country at the end of the reporting year. This is one less than at the start of 2010. Accreditation of the steg/mrec was withdrawn in the past year. The ccmo made this decision after an in-depth supervisory intervention demonstrated that this mrec did not meet the requirements outlined by law (see page 10 –11).
The ten-protocol requirement has applied since 1 January 2008, which is based on the average number of new protocols to be assessed over a period of two calendar years. mrecs who review less than ten protocols per year lose their accred-itation. As can be seen in the table (see page 65), all committees met this requirement. One committee, the irb in Amsterdam, announced it would suspend its activities. It decided not to accept any new research files in 2010. Active files will be completed by this committee, after which it will be disbanded at the end of 2011.The overview also shows that one mrec, irb Nijmegen, entered the danger zone. In the past year, it completed reviews of seven new research files. Because it reviewed thirteen files in 2009, it only just meets the ten-protocol requirement. In the coming year, it will have to review at least twelve research files in order to maintain accreditation. Another committee that only just meets the ten-protocol requirement is the mrec of the Maxima Medisch Centrum in Veldhoven.
In 2010, no new applications for accreditation of mrecs were submitted. The map displayed here shows all committees accredited to review research covered by the wmo, including the ccmo. The figure shows that accredited review
Review committees
Before research involving human subjects can commence in our country, the research file must be approved by an independent committee of experts. This is defined in the Medical Research Involving Human Subjects Act (wmo). The principle is that decentralised accredited review committees spread throughout the country take on this assessment task. When drafting the wmo, the legislator expressly chose not to have central government perform the reviews. The goal was to prevent the central government from unduly influencing medical ethical review of scientific research and thereby creating a form of state ethics.
In this third part of the annual report, the most relevant events of 2010 are outlined for all review committees, the accredited mrecs and the ccmo. A separate sub-chapter is dedicated to the ccmo (see page 65).
Two types of committees
The decentralised review in our country is handled by accredited medical research ethics committees ( mrecs). They review the vast majority of research. In general, this covers all research involving legally competent adults. It also covers therapeutic research with minors and incapacitated adults, as well as non-therapeutic observational research in these same vulnerable groups. The legislator has chosen to bundle expertise in a single committee only for specific types of research. This pertains to the review of research with specific ethical, legal or social aspects. For example, research in the field of gene therapy or xenotransplantation. Or research involving minors who will not benefit personally from participation, so-called non-therapeutic intervention research. The legislator has appointed the Central Committee on Research Involving Human Subjects (ccmo) for the review of these forms of research. The ccmo reviews a few dozen research files each year. In addition to its
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This is going to change, however. In late 2010, the ccmo decided to make the use of ToetsingOnline, including recording the review process in this portal, mandatory for all accredited mrecs (see page 64). Once this requirement is introduced, all applicants can follow the review of their research file and the associated timeframe via ToetsingOnline. ToetsingOnline helps accredited mrecs and applicants monitor the review term. Should terms threaten to be exceeded – either by the applicant or the review committee – the system automatically sends a reminder to all involved parties. This form of monitoring provides both the review committees and the applicants with a better and more clear overview of the time involved in the review process. An additional advantage is that clear insight for the applicant into the applicable terms and/or suspension of terms may prevent a potential application of the Penalty Act. This benefits all parties.
Other events in 2010…
A relatively large number of government bodies are involved in the review of gene therapy research in the Netherlands. In order to simplify application procedures for these institutions, the central Gene Therapy Desk was opened in late 2004. Applicants can submit research files here. The ministries of vws and vrom opened this desk at the rivm. In the reporting years 2007, 2008 and 2009, the ccmo reported on an eval uation, commissioned by the ministry of vrom, of this desk. In its annual reports, the ccmo reported that the final report had not yet been sent to Parliament. This was also the case in 2010.In 2010, the ministries of vrom and vws worked on a new evaluation of the desk. The research report described a number of improvement measures aimed at streamlining the Gene Therapy Desk, but no short-term options were identified for simpler and shorter procedures. Additionally, two options were put forward for
In none of the cases did the mrec in question make use of the possibility to object the rejection. In 2009, a single objection was filed in response to a negative judgement regarding a proposed member. Over the past years, there has been a clear downward trend in the number of formal objections against rejections of candidate mrec members. However, there has been a rise in the number of members requesting membership as other member of an mrec after rejection. After approval by the ccmo, they can gain experience reviewing research files as other members.
Terms
Review committees must adhere to terms when reviewing research files. For ‘regular’ wmo research, the term is set to a maximum of 112 days. If the review committee has asked the applicant questions, the clock is stopped. The review time starts running again once the requested information has been provided by the applicant. The total duration of a review may therefore last longer than 112 days. Other, shorter terms apply to research with medicinal products. The review of research with medicinal products must be completed by the review committee (the accred-ited mrec or the ccmo) within a maximum of sixty days. There are a number of exceptions, but these only apply to certain forms of medicinal product research that are furthermore only reviewed by the ccmo. Only one clock stop is permitted during the review by the committee.
The marginal review of research with medicinal products by the competent authority (ccmo or the minister of vws) must be completed within a maximum of fourteen days. There is no facility for a clock stop during the review by the compe-tent authority.
The ccmo currently has no insight into the review terms for the accredited mrecs. It currently only maintains records of its own terms (see page 65).
dropped from 10 percent in 2009 to about 7 percent in 2010. This drop was probably caused in part by the withdrawal of accreditation of the non-institutional steg/mrec.The ccmo is distinct from the accredited mrecs in that the research files it reviews are assigned to it by law, whereas the accredited mrecs are – up to a point – in competition with one another. The ccmo received about 3 percent of the total of 1,702 reviewed research files for assessment in 2010.
MREC members
In 2010, the ccmo received 107 requests from mrecs for approval of new committee members. This represents a significant increase compared to 2009, when the ccmo only received 78 requests for approval. In 100 cases (93%), the ccmo ruled positively on the expertise and suitability of the nominated members. This positive ruling was issued based on a ccmo mandate in thirty cases, outside the plenary meeting. It involves the assessment of nominated committee members belonging to the so-called other (not legally required) disciplines and members already deemed experts wishing to take up membership in the same discipline in another accredited mrec. Regarding the latter category, their expertise is assessed during a meeting if expertise require-ments have changed in the interim. The seventy other positive rulings were issued during the plenary meeting by the ccmo.The ccmo did not give its approval in seven cases. The rejections were for two doctors, three methodologists and two hospital pharmacists. Both doctors were considered insufficiently expert due to a lack of working experience and insufficient demonstrable experience with scien-tific research, respectively. All three methologists lacked both working and research experience. Both hospital pharmacists were assessed nega-tively due to a lack of demonstrable experience with medical research.
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creating a single integrated reviewing body. However, to make this possible existing Dutch legislation and regulations would need to be modified. The report, commissioned by both ministries, is not positive about this option due to the costs involved. By contrast, and in line with the industry (see ccmo annual report 2006, page 66) the ccmo remains an advocate of modifying legislation and regulations, so that clinical gene therapy studies in future only require one substantive review by a single government body. For researchers and companies alike, this would represent a significant simplification of procedures and a smaller administrative burden. Additionally, the changes proposed by the ccmo clearly answer the question of which government body holds final responsibility for the substantive assessment of clinical gene therapy studies.
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academisch medisch Centrum
erasmus medisch Centrum
Commissie mensgebonden onderzoek regio arnhem-nijmegen (Cmo)
universitair medisch Centrum groningen
universitair medisch Centrum utrecht
academisch Ziekenhuis maastricht
leids universitair medisch Centrum
vrije universiteit medisch Centrum
Stichting beoordeling ethiek bio-medisch onderzoek (bebo)
Centrale Commissie mensgebonden onderzoek (CCmo)
Catharina Ziekenhuis
verenigde Commissies mensgebonden onderzoek (vCmo)
nederlands Kanker Instituut
medisch Spectrum twente
metC Zuidwest Holland
medisch-ethische toetsing onderzoek Patiënten en Proefpersonen (metoPP)
medisch ethische toetsingscommissie Instellingen geestelijke gezondheidszorg (metigg)
Isala Klinieken
Wageningen universiteit
Stichting therapeutische evaluatie geneesmiddelen (Steg)
atrium medisch centrum & maaslandziekenhuis
Sint elisabeth Ziekenhuis
toetsingscommissie Wetenschappelijk onderzoek Rotterdam eo (tWoR)
metC noord-Holland
Regionale toetsingscie Patiëntgebonden onderzoek
Independent Review board amsterdam
Stichting Slotervaartziekenhuis, jan van breemen Instituut en bovenIj Ziekenhuis
Independent Review board nijmegen
máxima medisch Centrum
199
177
161
155
150
147
140
139
65
51
40
35
34
28
28
26
26
24
24
24
24
20
18
16
15
15
13
10
10
Number of decisions per committee* * *
name institute/committee 2008 2009 2010
average
’09 – ’10
type
co
mm
itte
e
218
195
169
160
156
154
139
149
62
54
37
29
36
23
27
29
28
23
26
42
28
21
19
16
11
26
12
13
10
180
159
153
149
144
140
140
129
68
47
42
41
31
33
28
22
23
25
22
5
19
18
16
15
19
3
14
7
10
205
158
157
160
178
138
144
146
65
66
30
30
26
17
39
33
35
28
21
46
24
21
17
28
9
33
10
15
11
209
180
179
113
159
163
139
125
80
45
51
32
19
11
30
35
30
27
23
26
19
10
14
13
12
31
12
12
12
229
180
159
161
181
138
123
120
63
23
47
33
25
11
22
22
35
21
14
51
17
16
11
23
13
30
10
17
13
20072006
academic mReCs
other institutional mReCs
non-institutional mReCs
* the numbers for 2010 may change for some mReCs as a result of forwarded decisions
** the committees are listed according to the average number of decisions that they issued over the last two years
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1913
1898
1841
1851
1702
academic mReCs
other institutional mReCs
non-institutional mReCs
CCmo
total
2010
2009
2008
2007
2006
1340
1286
1267
1291
1194
319
302
315
307
333
200
244
214
230
128
54
66
45
23
47
Decisions by type of ethics committee
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The ccmo places great value on a transparent review system. Society, research subjects and patients, as well as researchers and companies must have a clear understanding of the review of research files by accredited mrecs and the ccmo. The ccmo oversees the accredited mrecs and publishes the composition of all committees on its website. In 2009, the ccmo went a step further for its own members. Since the end of that year, the ccmo has placed the (additional) positions of all its members and deputies on the website. These additional positions were updated at the end of 2010 and again published on the ccmo website. The goal is to continue this policy and in future also publish the (additional) positions of all roughly 600 members and deputies for all accredited mrecs on the ccmo website. However, in order to achieve this, the so-called committee files must first be standardised and digitised. The first steps in this direction have now been taken.
In 2009, the ccmo announced it would place the annual reports of the accredited mrecs on its website. In these reports, mrecs provide an over-view of research files they have reviewed. In late 2010, annual reports for all accredited mrecs were actually published on the ccmo website.
The ccmo is also working on an update of the regulations and complaints procedure of the accredited mrecs. These documents will be placed on the ccmo website in early 2011, so that all researchers and companies will know what to do if they wish to file a complaint with an accredited mrec.
Thanks to the ToetsingOnline portal, applicants can follow the review of their research file via internet if the ruling mrec records the process online (see also page 64). Page 30–31 contains more information regarding transparency in clinical research and the public ccmo register.
Transparency of the review system
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academic mReCs
other institutional mReCs
non-institutional mReCs
CCmo
total 1702 decisions
of which
non-medicinal product
medicinal product
non-medicinal product
medicinal product
non-medicinal product
medicinal product
non-medicinal product
medicinal product
total 533 decisions for research with medicinal products
total 1169 decisions for research with non-medicinal products
Decisions by type ethics committee 2010
333(20%)
47 (3%)
1194(70%)
128(7%)
62%
38%
26%
74%
33%
67%
38%62%
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Number of studies with medicinal products by ethics committee
amC
erasmus mC
Cmo
umCg
umCu
azm
lumC
vumc
bebo
CCmo
Catharina zh
vCmo
nKI
medisch Spectrum twente
metC Zuidwest Holland
metoPP
metigg
Isala Klinieken
Wageningen universiteit
Steg
atrium mC & maasland zh
Sint elisabeth Ziekenhuis
tWoR
metC noord-Holland
RtPo
IRb amsterdam
St Slotervaart zh
IRb nijmegen
máxima mC
55
52
44
29
29
22
45
40
62
29
23
16
14
6
14
4
2
8
0
5
8
0
8
4
6
2
0
5
2
125
107
109
120
115
118
95
89
6
18
19
25
17
27
14
18
21
17
22
0
11
18
8
11
13
1
14
2
8
180
159
153
149
144
140
140
129
68
47
42
41
31
33
28
22
23
25
22
5
19
18
16
15
19
3
14
7
10
tota
l 201
0
non-
med
icin
al p
rodu
ct
med
icin
al p
rodu
ct
phase 1
phase II
phase III
phase Iv
other
na
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261
290
265
287
227
37
37
30
31
39
351
381
345
367
303
53
54
50
49
37
Multicentre research with a medicinal product
sponsor = industry
total medicinal products
sponsor = other
sponsor = academic hospital
2010
2009
2008
2007
2006
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110
107
104
86
89
368
324
342
328
336
64
58
61
75
58
261
290
265
287
227
multicentre research with a non-medicinal product
sponsor = industry
total non-medicinal products
sponsor = other
sponsor = academic hospital
2010
2009
2008
2007
2006
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Prof dr gerrit van der Wal, PhD Inspector general of the Health Care Inspectorate
‘ We would like to see more management by main themes, indicators and risks’
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Interview
There are almost one million people employed in the health care system in the Netherlands. The igz has the duty of monitoring the whole sector: from hospitals to nursing homes, doctors’ practices to psychiatric health institutes, pharmacies, medical technology and the pharmaceutical industry. Van der Wal: ‘The basic philosophy is risk based management, but that is easier said than done.’
In the Netherlands around 1800 studies with human subjects are reviewed by the accredited mrecs and the ccmo annually, of which around 600 are studies with medicinal products. ‘At the front end you have the risk review by an accredited mrec or the ccmo. Then you have registration at the Dutch Medicine Evaluation Board (meb) or the European Medicines Agency (ema) in the case of research with medicinal products. They can request us to gain insight into a study. But that is at the end of the study’, explains Van der Wal. ‘The monitoring period in between, the execution phase, is unsatisfactory. And that is precisely the part of the study that the igz monitors.’The inspectorate wishes to cooperate with the ccmo and the meb to determine how oversight during this intermediate period can be improved. The igz also wishes to see a transition from a paper-based method to actual practical methods. ‘The ccmo and the meb have a lot of documents to read, but we would rather see them on the work floor’, suggests Van der Wal. ‘But it takes a lot of effort to determine what to be on the lookout for. Perhaps by concentrating on a few aspects, such as for example at how many locations a trial is being carried out, how many participants are involved and whether or not it is a phase I study, you can determine where the risks are highest. And to do so, the oversight by the ccmo and the igz must go hand in hand. If you do not cooperate in this, you will never achieve an effective risk selection.’
‘In the next two years we would like to work on making the igz and the ccmo go from one plus one into three’, says Van der Wal.
‘To achieve this we are planning on setting up a project group which will focus on risk prioritising, so that we can select the most important trials at the right moment in order to prevent situations occurring with a great risk and a high level of distribution.’ It was recently agreed that the igz can make use of information from the trial database of the ccmo. ‘If we both look at the studies with our expertise the igz can better determine where she can best make use of her limited capacity. On that point we gladly take advice from the ccmo’, remarks Van der Wal. ‘We would also like to focus on the quality of the Contract Research Organisations (cros). It can be much more effective to not analyse individuals trials, though to focus on the quality of the operational organisation.’
Of the 400 full time equivalent (fte) present at the igz, there are only two to three for monitoring medical research involving human subjects. ‘That is very little. Maybe we can up the capacity, but it won’t be by very much. The risks in the entire pharmaceutical chain would also have to be considered in order to determine how many people are needed to monitor it. And the oversight methods have to be sharper, whereby we would have to manage more on the main themes, indicators and risks’, says Van der Wal. ‘The trick is to find effective measurement methods. At the moment it takes a week to go through a clinical study. This takes place in an extremely thorough and proper manner. And this is the reason that we would like to go through it on a more systematic level whereby we look at the greatest risks and the most important indicators. You go through a few parts of the study in depth, but you particularly check if the system in place is in order. In the coming years we will investigate if this can also be done in the case of clinical trials. The idea is that systematic monitoring is more efficient and can have a better learning effect. But you will always have to combine this with in depth checks. That is essential. The core issue is that you find the key to monitoring in the most effective manner possible. And that is a challenge.’
The Health Care Inspectorate (IGZ) monitors quality and safety of the health care system, including that of medical scientific research involving human subjects. And that is not an easy job. Prof. Dr. Gerrit van der Wal, Inspector General of the IGZ, argues for more intensive cooperation between the CCMO and IGZ. ‘If oversight is to be effective, then you have to come to some kind of joint priority list.’
‘Oversight by the CCMO and the IGZ must go hand in hand’
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Chair meeting
twice a year, the chairs of accredited mReCs and the CCmo meet during the chair meeting.
the goal of the meeting is improving the protection of research subjects and discussing develop-
ments in the review of medical research. Starting in 2010, the topics for discussion are chosen
in consultation with a programme committee, whose membership is composed of the chair of
the CCmo, a number of mReC chairs and the chair of the nvmReC. In 2010, the consultations
took place on 28 april and 17 november. During the meetings, eighteen and twenty committees
respectively, including the CCmo, were represented by their (vice) chair.
one of the agenda points was the Data Safety monitoring board (DSmb). It was discussed that
appointing a DSmb is the responsibility of the study sponsor (the party organising the research).
If a DSmb has been appointed, the DSmb charter should be included in the research file
submitted to the accredited mReC for review. the DSmb reports to the study sponsor, and
does not communicate directly with the ruling mReC. the recommendations of the DSmb are
only forwarded to the ruling mReC if the sponsor wishes to deviate from the DSmb recommen-
dations. In an accompanying letter, the sponsor justifies why he wishes to deviate from the
recommendations. the ruling mReC assesses whether this position is justified.
During the chair meeting in spring, overviews were presented of the number of serious adverse
events (Saes) and suspected unexpected serious adverse reactions (SuSaRs) reported to the
accredited mReCs digitally via toetsingonline. the overviews showed that the number of
reports varied greatly between various mReCs. the chairs were asked to draw the researchers’
attention to the new CCmo policy.
another topic under discussion was the voluntary Harmonisation Procedure (vHP) for review
by the competent authorities of eu member states of international research with medicinal
products. this voluntary procedure was established by the competent authorities in order to
expedite the review process for international studies. the procedure and the CCmo’s partici-
pation as from 2010 were explained. the CCmo intends in this way to gain experience with
the procedure (see also page 66).
additionally, the Wmo research subject insurance was discussed. bottlenecks identified were
that not all participating centres (and therefore not all research subjects) were insured, and that
insurance does not cover or limits compensation for certain types of injury. additionally, the
complex procedure can lead to errors, as was the case in the PRoPatRIa study. alternatives
were discussed, such as a compensation fund that could replace research subject insurance
(see box, page 36–37).
the recommendations of the Doek committee were also discussed based on a presentation
from leiden researcher anna Westra, mSc (doctor/philosopher). the Doek committee calls for
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changes to the medical Research Involving Human Subjects act (Wmo) regarding clinical
research with underage research subjects that cannot benefit them directly. Westra also called
for changes to the law, but chose a different approach. In early 2011, her thesis presenting her
research will be published, including a proposal for changes to the Wmo.
new forms of oversight by the CCmo and the activities mReCs undertake to improve the
quality of medical ethics review were also discussed. an explanation was given on the withdrawal
of accreditation of the Steg/ mReC (see box page 10–11). Key learning points from this case are
the importance of acknowledging the limits of the committee’s own expertise and of a proper
substantive review of both product information and the applicant’s written response to the
committee’s questions.
attention was furthermore given to the review of research contracts, the formation of mReC
secretariats and the funding of mReCs. a departing mReC chair looked back on his experiences.
among other things, he called for more training of clinical researchers, with a coordinating role
for the CCmo, and training for mReC members. Finally, the CCmo chair reported on his intro-
ductory meetings with all accredited mReCs.
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Secretary working group
the secretary working group, founded in 2004, consists of acting secretaries for the accredited
mReCs and the CCmo. the objectives of the secretary working group is to find generic
solutions to practical bottlenecks at the secretariats, to exchange experiences and expertise and
to further harmonise and professionalise the secretariats of accredited mReCs and the CCmo.
the working group met three times in 2010. During these meetings, attention was given to
defining and increasing the level of service of the secretariats to committee members as well as
researchers and sponsors of clinical research. Defining service levels should ultimately lead to
a best practice for secretariats.
over the past years, various actions have been taken to improve service, including the devel-
opment of various templates, models and standards. these include a standardised format for
the research file, the research protocol template, a model for the local feasibility declaration
(luv) and models for research subject information sheets and consent forms. In 2010, models
for judgements of further judgements were added. the use of these models will make it easier
for both researchers and institution managers to understand what the mReC’s judgement is,
how Wmo research subject insurance is organised, which (versions of the) documents from
the research file were reviewed, and which conditions and responsibilities are associated with
the judgement.
Within the context of improved service provision, further expansion, improvement and use
of the toetsingonline web portal was discussed. In 2010, the ‘toegang voor derden’ (third party
access) module in toetsingonline was introduced. this enables not only the applicant, but all
researchers (if accredited by the applicant) to follow the review process via toetsingonline
(see: Digitisation page 64).
the findings from supervisory interventions by the CCmo in two accredited mReCs were also
discussed in the secretary working group. the goal was to learn from them in order to improve
the workings of their own mReC. For one mReC, the supervisory intervention was discussed
from the viewpoint of this committee’s secretary. He concluded that although the oversight process
entailed a great deal of work for the mReC, it made an important contribution to improving
quality and professionalism of the secretariat (see also the interview with the chair of this mReC
on page 9). additionally, thoughts were exchanged on the new CCmo method ‘monitoring
review quality’.
the secretary working group paid extensive attention to the issues surrounding the review of
multicentre research in the reporting year. two areas were highlighted: research subject infor-
mation and research subject insurance. the idea was proposed to, following the Danish model,
create a compensation fund for research subjects to replace the error-prone Dutch regulation
for research subject insurance. Such a fund would minimise the risk of errors and decrease
the administrative burden for institutions and accredited mReCs. a proposal for extensive
standardisation of the research subject information sheets was also discussed. Initial results
of a feasibility study examining a new It tool were presented. this tool can help researchers
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draft a structured research subject information sheets and informed consent forms that meets
current legislation and regulations. other topics included training and education of secretarial
staff, assessment of product information in nutrition research and an inventory of the staff
establishment of secretariats.
During the final meeting in 2010, the results of an evaluation of the working group were
discussed. the key question was whether the working group still met the previously formulated
goals and expectations. a questionnaire was distributed prior to the meeting. the response
rate was high: Representatives from 25 of the 27 accredited mReCs’ secretariats completed the
questionnaire. the conclusion is that participants wish to continue the secretary working group.
additionally, more time will be scheduled to learn from each others’ experiences and expertise.
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Digitisation
2010 saw web portal ToetsingOnline go into its fifth year. Via the portal, applicants can complete and submit the national application (abr) form online. Most review committees and the compe-tent authority use the web portal to record the review process. Using ToetsingOnline, applicants of research files can follow the review of their file via internet. The number of ToetsingOnline users has risen from over 8,000 in 2009 to about 10,000 in 2010. The number of active users is slightly lower.
In late 2009, ToetsingOnline was expanded to include a so-called mrec upload module. This application can be used by accredited mrecs to digitally store their (further) judgement in ToetsingOnline. These rulings can subsequently be accessed by the applicant of the research file, the ruling mrec and the ccmo. In 2010, a few accredited mrecs did not yet use this new appli-cation, so that some researchers do not yet have access to the mrec judgement via ToetsingOnline. The review terms for these mrecs are not yet clearly visible to researchers and (pharmaceutical) companies. In late 2010, the ccmo decided to make full use of ToetsingOnline mandatory for all accredited mrecs so as to increase transparency regarding the review process of research files for researchers and (pharmaceutical) companies.
ToetsingOnline was expanded with the ‘Toegang voor derden’ (third party access) module in 2010. Using this application, applicants can give co-investigators participating in a (multi-centre) study read-only rights for the file in ToetsingOnline. These researchers can be given rights to report saes and susars electronically for a specific study – just like the applicant. The module makes it easier to share key safety data with all co-investigators in various participating centres in multicentre studies.
From 1 January 2010, the ccmo made electronic reporting and review of suspected unexpected serious adverse reactions (susars) and serious adverse events (saes) via ToetsingOnline manda-tory for investigator initiated research for studies with an nl number. The direct reason for this was the propatria study, in which 31 of 33 deaths were not reported to the ruling mrec in a timely manner. In practice, this new obligation means that all accredited mrecs need to use the module Adverse reaction/event in ToetsingOnline.In total, through 31 December 2010, 1,044 saes were reported electronically to accredited mrecs and the ccmo combined. The number of susars is lower, as these are unexpected reactions that only occur in research with medicinal products. At the end of the reporting year, a total of 168 susars were reported electronically to accred-ited mrecs and the ccmo combined via Toetsing-Online. The reported susars came from 43 studies, including 24 research files submitted by the pharmaceutical industry or a Contract Research Organisation (cro), and nineteen by (academic) researchers. There are significant differences between the number of reports per committee. In 2011, the ccmo and accredited mrecs will once again draw (academic) researchers’ attention to reporting saes and susars electronically. Accredited mrecs will be urged to specifically include the paragraphs in research protocols describing the reporting procedure in their review of research files.
In late 2010, the ccmo presented the first results of an it tool that researchers and (pharmaceutical) companies can use to easily draft structured research subject information (pif) for their studies. The underlying idea is that the applica-tion creates a lay-out for the information sheets and informed consent forms using a standard structure and a number of standard passages after completing a number of questions about
the study. The feasibility study will be completed in 2011. If implementation proves possible – provided the required financial means are available – application building will commence. Additionally, the ccmo will elaborate a proposal for an e-learning module. The principle behind this module is that researchers can test their active knowledge of legislation and regulations online at any time. The development of this module will make use of, among other things, the entrance exam the ccmo created for the course organised for mrec members and secretarial staff at the VU University Medical Centre.
Following the ccmo example, one mrec (in the umc Groningen) moved to publish meeting documents digitally in 2010. Some mrecs received further information and instructions regarding this form of digitisation from the ccmo upon their request. They decided to postpone moving from paper to digital distribution of documents until submission of research files via ToetsingOnline is realised. At such time, the submission of many paper copies of the voluminous research files to these mrecs will be a thing of the past.
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The Central Committee on Research Involving Human Subjects (ccmo) was established based on article 14 of the Medical Research Involving Human Subjects Act (wmo). The ccmo is an independent governmental body with an independent secretariat: ‘There is no hierarchical subordination to the minister. Members of the committee, including the chair, are appointed by Royal decree and the committee has an inde-pendent secretariat, while the minister – as the Council (Council of State, ed.) correctly notes – has no influence on the committee’s individual decisions. (source: Parliamentary Papers ii 1991/92, 22 588, A, p 7). The committee was installed by Mrs Borst, the then minister of Public Health on 6 April 1999.
Tasks and methods
The ccmo has the following statutory tasks:– Oversight of accredited mrecs. The ccmo
is mandated with accrediting and overseeing the activities of accredited medical research ethics committees (mrecs). How the ccmo performed this task over the past reporting year can be found in part 3 of this report (see Review system, page 66–67 and the box text on page 69).
– Review committee (TC). The ccmo’s reviewing mandate is limited to a number of specific fields of research as outlined in the Medical Research Involving Human Subjects Act (wmo) and the Embryos Act. More infor-mation on the subject can be found in part 1 of this report (see Centrally reviewed research, page 22–27).
– Competent Authority (ca). The ccmo has acted as the competent authority for research involving medicinal products since 1 March 2006. As ca, it only carries out a marginal review, which only pertains to the part of the review that mrecs cannot perform themselves. A brief description of the ca task is included later in this section.
– Appeals body. The ccmo is the appeals body for objections or appeals against itself (objec-tions) or a judgement issued by an accredited mrec (appeal). Since 1 March 2006, it no longer acts as an appeals body for judgements issued on or after said date by accredited mrecs regarding research with medicinal products. The applicant can raise an objection against these judgements with the ruling mrec. More information on appeals and objections against negative judgements in 2010 is available on page 16 and 22. Objections against mrec members rejected by the ccmo are listed on page 48.
– Registration of research. The ccmo maintains an overview of all research reviewed in the Netherlands since 1 December 1999. These data enable the ccmo to identify trends in the field of research with human subjects in the Netherlands. The ccmo regularly issues reports on this subject to involved parties, among other things via annual reports. Since late 2008, key data for research have been recorded in the public ccmo register; since late 2009, this is standard procedure (see page 30–31).
– Monitoring task. The ccmo reports annually on new developments in the field of research with gametes, (supernumerary) embryos and the foetus in utero. Data for 2010 is available on page 22 and 31.
– Information task. As an implementing body, the ccmo plays a pivotal role as (inter)national information point for medical research involving human subjects conducted in the Netherlands. Researchers, politicians, the press and members of the public are increasingly finding their way to the ccmo. What this means in terms of figures for 2010 is listed elsewhere in this section and under ‘ccmo presentations and publications 2010’ (page 72–73).
ccmo methods and procedures are elaborated and recorded in regulations, Standard Operating Procedures (sops) and a Secretariat Handbook. The sops and the handbook are updated periodi-cally and reviewed by the secretarial staff.
Terms for review committee and
competent authority
The ccmo must adhere to statutory terms when reviewing research. In 2010, the ccmo needed an average of 59 days, excluding any clock stops, to come to a decision in 49 primary submitted research files. However, an average term is not particularly illustrative, as longer terms apply to a great deal of the research reviewed by the ccmo. What is more telling is whether the ccmo has exceeded the statutory term applicable for a particular type of research during the review process. This was found to be the case for nine of the 49 primary reviews conducted in 2010 (18%). In most of these cases, the term was exceeded by only a few days.
In its role as competent authority, the ccmo carried out a marginal review for 527 research files. A fourteen-day term applies for the so-called ca review. The average review term in 2010 was nine days. For 491 of 527 research files, the ccmo was able to complete its review within the fourteen-day term. The term was exceeded for 36 research files. In most of these cases, the term was exceeded by only a few days.The judgement of the competent authority loses validity if the research is not initiated within one year of review. As the competent authority, the ccmo had to extend the review of a research file eight times. Additionally, the ccmo received 1,401 substantial amendments and processed them within an average term of fourteen days.
Central Committee on Research Involving Human Subjects
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The CCMO as Competent Authority (CA).
Since 1 March 2006, the ccmo has acted as the competent authority (ca) for the review of research with medicinal products, assessed on content by an accredited mrec. By law, the ca only carries out a marginal review. This review consists of consulting the adverse responses database of the European Union (eu), Eudravigilance, for relevant adverse reactions (susars) not included in the research file. The accredited mrec carrying out the substantive review of the research file may therefore not be aware of these adverse reactions. mrecs do not have access to the eu adverse reaction database, but can request information from it via the ccmo if necessary. The ccmo only consults the eu adverse reactions database for research files involving unauthorised medicinal products. Additionally, the ccmo verifies whether the applicant has made a validated application form available for the entry of basic data on medicinal product studies (Eudract) in the eu database. In 2010, the ccmo carried out marginal reviews on 527 new studies. In all cases, a declaration of no objection was issued. For none of the research files was it was necessary to inform the ruling mrec of additional data from the eu adverse reactions database. During the reporting year, the ccmo forwarded safety information from other member states (via the Clinical Trial Facilitation Group, ctfg) twice to mrecs involved in the review of studies with the corresponding investigational medicinal product. Additionally, the ccmo forwarded safety information from the Medicines Evaluation Board (meb) to the ruling mrec for two research files.
For substantial amendments, the ccmo auto-matically issues a declaration of no objection with the understanding that review is in good hands with the ruling mrec. The latter may, if desired, request advice from the ccmo if it
feels data from the eu adverse reactions database will be required to issue a judgement.
The competent authority fairly regularly receives notices from the European Eudract database. This database contains basic information on all medicinal product studies conducted in one or more member states. Eudract reports are auto-matically forwarded to the competent authorities if a clinical medicinal product study is rejected in an eu member state, the research file is with-drawn, the study is temporarily suspended or a study has been terminated prematurely. Upon receiving these reports, the ccmo informs the ruling mrec. In 2010, the ccmo informed the ruling mrec of such reports 95 times.
Voluntary Harmonisation Procedure
In 2009, the competent authorities in eu member states initiated the Voluntary Harmonisation Procedure (vhp). This voluntary procedure encompasses a coordinated pre-assessment of multinational research with medicinal products by competent authorities in different member states. The goal of the procedure is to identify any shortcomings in such research which might lead to rejection in eu member states prior to the official submission of the research file. These shortcomings are collected by one of the competent authorities and sent to the applicant.The vhp precedes the official submission of the entire research file to the ruling mrec and the competent authority. The outcome of the vhp is documented. Documentation is included in the research file submitted for review with the accredited mrec, allowing the committee to use the vhp information in its review.
The Netherlands has been taking part in the vhp since 1 January 2010. The review of research files based on the vhp has consistently taken place based on recommendations from two ccmo members. In total, the ccmo has assessed four-
teen research files according to this procedure. By the end of 2010, the review of ten of these files was completed. The review of the other files will be completed in early 2011.
In late 2010, the ccmo evaluated the vhp. In 2011, the ccmo will ask the mrecs whether individual members are interested in contributing to this voluntary procedure. Participation in the vhp may provide the mrecs with valuable insights that they can use in their formal review of the research file.
The CCMO as regulator
In its 2009 annual report, the ccmo reported on the start of supervisory interventions in two accredited mrecs. The first case concerned a report of a former member of the metigg south chamber. In response, in late 2009, the ccmo requested six reviewed research files and under-lying documentation from the metigg south chamber, including the minutes of the meeting during which these files were discussed with the metigg. All six files were examined and discussed by the ccmo during plenary meetings. The focus of the ccmo was on analysing the substantive review conducted by the metigg. The ccmo concluded that the review by the metigg south chamber displayed significant substantive and procedural shortcomings. The ccmo therefore decided to temporarily suspend this chamber. Concurrently, the ccmo requested all documentation for three research files reviewed by the metigg north chamber. The ccmo also came to the conclusion that this metigg chamber was not functioning properly and decided to suspend its activities. Consequently, the entire metigg temporarily could not accept new research files for review. The metigg received an extensive report on the ccmo’s findings. All other accredited mrecs received a summarised version, so that they could learn from the identified shortcomings.
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The ccmo asked the metigg to draft an improve-ment plan and work on necessary improvements. During the reporting year, the metigg worked hard on making the requested improvements. The internal organisation was reorganised, and the mrec combined the secretariats of the north and south chambers into a single secretariat. In mid 2010, the ccmo decided to cancel the temporary suspension, at which point the metigg could once again accept new research files. Nevertheless, the ccmo announced it would request a number of research files from the metigg for analysis later that year. It was reported that the focus would lie on whether the improvement actions had led to better substantive reviews by the metigg. In late 2010, the ccmo once again requested five research files from the metigg. These will be examined in early 2011.
The second supervisory intervention the ccmo reported on during its previous annual report was the report of a health insurance company requesting suspension of two approved studies with medicinal products being conducted in lung cancer patients in a large number of Dutch hospitals. The ccmo requested the research file and underlying documentation from the ruling mrec in the umc Groningen. Both files were examined and discussed by the ccmo during plenary meetings. The ccmo concluded that the mrec of the umc Groningen had correctly approved the studies. The ccmo noted, however, that there was room for improvement in the reporting procedure for saes and susars in the research protocol. Additionally, the ccmo came across a number of procedural imperfections in this mrec. Of note was the extremely long time needed for boards of directors of participating hospitals to issue a so-called local feasibility declaration (luv). In some cases, the issue of such a declaration took more than one year. By signing an luv, the board of directors declares
that the institution has suitable staff and facilities at its disposal to take part in a multicentre study (see page 68 other events in 2010). In late 2010, the ccmo asked the mrec of the umc Groningen for a plan for improvement. The ccmo will review the plan after receipt in 2011.
[kadertekst]In its 2009 annual report, the ccmo reported on an analysis of phase I studies that were reviewed in that year (see ccmo annual report 2009, page 18). During this analysis, one study stood out due to the method of adminis-tration of an experimental medicinal product in healthy volunteers. They received a synthetic peptide intrathecally (within the spinal canal). The study had been approved by the steg/mrec. The ccmo decided subsequently to request the full research file and underlying documents from this mrec. Upon receipt, the file was examined and discussed during plenary meetings.The approval of the study by the steg/mrec raised a great deal of questions with the ccmo. For example, examination of the Investigator's Brochure (ib) and the Investigational Medicinal Product File (impd) showed that a previous clinical study involving the medicinal product in the usa had been put on hold by the fda. The product information in the impd was inadequate. The ccmo also had a large number of questions regarding the manufacture and quality control of the medicinal product. It was discovered the product had not been developed for intrathecal administration. Furthermore, it was striking that the steg/mrec each time approved the administration of increasing doses of the substance to a subsequent group of healthy research subjects based on relatively superficial safety information.The ccmo therefore decided to immediately suspend the steg/mrec. At the same time, the ccmo requested five other reviewed research files from this mrec for further analysis. The ccmo noted major shortcomings in these
studies as well, particularly with regard to substantive assessment by the steg/mrec. The conclusion of the ccmo was that the steg/mrec had insufficient insight into the limits of its competence and inadequately performed its statutory tasks. The ccmo therefore decided to withdraw the accreditation of the steg/mrec. The ccmo has never before felt it necessary to take such a drastic measure to protect Dutch study subjects. An extensive description of this supervisory intervention may be found on page 10–11.
On 22 May 2010, the media reported on the premature termination of a clinical study among intensive care (ic) patients suffering from delirium. Researchers at the umc Utrecht came to this decision after a significantly higher number of deaths was found in the experimental group than the control group. Some of the patients in the experimental group were given the medicinal product haloperidol as well as rivastigmine. The fact the study had been approved, with high-risk patients receiving a combination of these two substances within the context of a scientific study, was reason enough for the ccmo to request the research file and underlying documents from the ruling mrec in the umc Utrecht. The research file was examined and discussed by the ccmo during plenary meetings. Based on initial findings, the ccmo decided to request five other reviewed research files from this mrec. The ccmo expects to complete analysis of the total of six examined studies by mid-2011.
Information Service
In 2010, the ccmo again received hundreds of questions by e-mail from researchers and (pharmaceutical) companies. In most cases, the ccmo was able to answer these questions within a relatively short timeframe (fourteen days). Additionally, the ccmo gave a large number of presentations to share its future vision and
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and a large number of government bodies involved in the medicinal products chain. One of the topics of discussion was a more efficient entry of data from the so-called eu Application Form in the Eudract database. The possibility for streamlining this via extensive digitisation is currently being investigated. In late 2010, the ccmo sent its position on the recommendation of the Doek committee to the minister of vws. Former State Secretary Bussemaker had asked the ccmo for this. The ccmo discussed the recommendation in early 2010. The fall of the government was reason to postpone the drafting of the written position until late 2010.
In 2010, the ccmo conducted various talks with representatives from the psychology field and the pharmaceutical industry regarding the scope of the Medical Research Involving Human Subjects Act (wmo). The topic of these discussions was whether psychological scientific research with research subjects and studies in which patients record the use of prescribed medication in a diary falls under the purview of the wmo. In 2011, the ccmo will present its vision on the scope of the wmo.
Finally, the ccmo performed a bottleneck analysis of the problems surrounding multicentre research in late 2010. This analysis reveals that three aspects play a key role in current problems: research subject insurance, the role of boards of directors of participating institutions in issuing local feasibility declarations (luv) and research subject information sheet and informed consent form. In early 2011, the ccmo will discuss these issues with the stakeholders and draft proposals to streamline multicentre research.
answer questions about it. During these presen-tations, it became apparent that researchers and the industry felt the slowness of hospital boards of directors to issue local feasibility declarations (luv) for multi-centre research was a major bottleneck. This feedback was reason for the ccmo to draft a bottleneck analysis of multicentre research in late 2010 (see below).
Other events in 2010
On 2 July 2010, minister Klink presented a position on the ccmo reports ‘Toetsing en toezicht in de toekomst’ (Assessment and Oversight in the Future) and the second self assessment, ‘Voorwaarts… Tweede rapportage taakvervulling ccmo periode 2004 – 2008’ (Forward… Second Report on ccmo Task Fulfilment period 2004 – 2008). In order to alleviate the structural increase in workload at the ccmo, an expansion of the ccmo secretariat was promised. The min-ister stated he attached particular importance to appointing an oversight staff member. However, he felt it was still too early to approve the ccmo’s request for expanding the staff to include a training coordinator.With regard to the second self assessment, the minister commented on, among other things, the ccmo’s call for expansion of its authority. The ccmo has observed that the field of medical research is developing swiftly. Within the current system, the government is unable to anticipate these development with sufficient speed. This means the government runs the risk of lagging behind in certain matters. The ccmo therefore proposed being given the authority to draft directives for sponsors and investigators, allowing new developments to be addressed swiftly. This authority should be limited to aspects relating to review. In his letter, the minister stated he felt this request was reasonable.
During the reporting year, the ccmo contributed to the discussion between the ministry of vws
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Quality control within the MREC and the CCMO oversight system
accredited mReCs are themselves responsible for safeguarding and where possible improving
the quality of reviews. Promotion of expertise among committee members and secretarial staff
is a key element in this process. additionally, all accredited mReCs have a quality system including
Standard operating Procedures (SoPs) in which all internal processes are defined.
the CCmo, as regulator, is responsible for monitoring the quality of accredited mReCs.
In march 2010, the CCmo announced it was developing a new method for continuous assessment
of quality of both substantive review and the administrative process within accredited mReCs.
this continuous oversight is a supplement to other forms of oversight performed by the CCmo.
the CCmo’s oversight task can be divided into roughly three categories:
– A priori oversight (assessment of regulations, expertise and independence of members, etc.)
– for cause oversight (based on incidents, reports, signals etc.)
– continuous oversight (monitoring of quality and continuity of the improvement process).
these three forms of oversight are complementary. the a priori oversight and for cause oversight
are already performed by the CCmo (see: Review committees, page 65 and: the CCmo as
regulator, page 66–67). Further interpretation of continuous oversight continued in 2010.
the nature of continuous oversight differs from that of for cause oversight. In for cause oversight,
a rule-based approach is mainly used, while continuous oversight primarily follows a principle-
based approach.
Continuous oversight is therefore primarily focused on the relevant principles of medical ethics
review, identifying problem areas and stimulating self reflection within an mReC. It is less focused
on defining and upholding regulations. Continuous oversight uses a problem-oriented approach
as proposed by malcolm Sparrow in his book ’the regulatory craft’ (Washington DC, 2000).
the underlying principle is identifying and defining key problem areas. In addition to analysing
the problem, performing interventions and monitoring the effect, communicating findings to all
accredited mReCs is a key component. this way not only the mReC being investigated, but all
mReCs can learn from the findings. the problem-oriented approach within continuous oversight
is part of a package of quality improving measures and initiatives. the goal is to improve the quality
of substantive review and the underlying working processes within accredited mReCs. Serious
shortcomings may come to light within an mReC during continuous oversight. the CCmo will
then inform the committee that a for cause process will be initiated.
over the past years, the quality of accredited mReCs was examined at association level by
the nvmReC via an audit system. the chairs of accredited mReCs indicated they did not want
two largely overlapping systems in effect during the chair meeting of april 2010. based on this
meeting, the nvmReC decided no longer to attempt to relaunch its ‘old’ audit system and is
working on a new form of auditing: intervisitation. the CCmo and the nvmReC regularly
consult with each other in order to keep each other up to date on quality improvement processes
and, where necessary, to coordinate them. a clear demarcation of mutual responsibilities is
the key principle.
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Committee
Members
Prof ID de beaufort, PhD Ethicist
Professor of medical ethics, erasmus university of Rotterdam (member till 1st october)
Prof jH beijnen, PhD Hospital pharmacist
Professor of analytical medicinal product toxicology, utrecht university
gjjW bours, PhD Nursing scientist
nursing scientist, maastricht university
Prof lm bouter, PhD Methodologist and deputy chair as of 1st September
Professor of epidemiology, Free university of amsterdam
Prof aF Cohen, mD, PhD Deputy chair and pharmacologist
Professor of clinical pharmacology, leiden university
Prof jCj Dute, llm Health lawyer
university professor, university of amsterdam (member per 1st august, former deputy member)
Prof jKm gevers, llm, PhD Deputy chair and health lawyer
Professor of health law, university if amsterdam (member till 31st august)
Prof R de groot, mD, PhD Paediatrician
Professor of Paediatrics, Radboud university of nijmegen
Prof jCjm de Haes, PhD Medical psychologist
Professor of medical psychology, academic medical Centre, amsterdam
Prof mj Heineman, mD, PhD Embryo expert
Professor of obstetrics and gynaecology, academic medical Centre, amsterdam
Prof gH Köeter, mD, PhD Chair and physician
Retired Professor of lung diseases (pulmonology), umC groningen
Prof e van leeuwen, PhD Ethicist
Professor of medical ethics, umC St Radboud, nijmegen
Prof mm levi, mD, PhD Physician
Professor of internal medicine, academic medical Centre, amsterdam
Prof jPj Slaets, mD, PhD Physician
Professor of geriatrics, university of groningen
Prof ba oostra, mD, PhD Fundamental scientist/molecular geneticist
Professor of molecular genetics, erasmus mC, Rotterdam
m vos-van gortel, ma Member on behalf of human subjects involved in research
Former member of the Council of State
Deputy members
Prof a de boer, PhD Pharmacologist
Professor of pharmacology, utrecht university
Prof DDm braat, mD, PhD Embryo expert
Professor of obstetrics, gynaecology and reproduction medicine, umC St Radboud, nijmegen
Prof jjm van Delden, PhD Ethicist
Professor of medical ethics, university medical Centre utrecht (as of 1st june)
Prof j Denollet, PhD Medical psychologist
Professor of medical psychology, tilburg university
jHHm Dorscheidt, PhD, llm Health lawyer
university tutor health law, university of groningen (as per 1st august)
Prof Hj guchelaar, PhD Hospital pharmacist
Professor of clinical pharmacy, leiden university medical Centre (as of 1st june)
Prof jDF Habbema, PhD Methodologist
Professor of medical operations research, erasmus university Rotterdam
Prof jPH Hamers, PhD Nursing scientist
Distinguished Professor of nursing and care of the elderly, maastricht university
Sje Horstink-von meyenfeldt, llm Member representing the human subject involved in medical research
member of the Council of State
Prof Ha moll, ma, PhD Paediatrician
Professor of Paediatrics, erasmus medical Centre, Rotterdam (as of 1st june)
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Prof C mummery, PhD Fundamental scientist/cell biologist
Professor of developmental biology, leiden university medical Centre
Prof P vermeij, PhD Hospital pharmacist
Retired Professor of clinical pharmacy, leiden university medical Centre
Prof mb vroom, ma, PhD Physician
Professor of Intensive Care medicine, academic medical Centre amsterdam (member until 31st December)
Observer on behalf of the Ministry of
Sport, Welfare and Sport
Rm den Hartog-van der tholen, ma Policy maker
Department of Public Health, sub-department ethics (till 1st august)
ml vos, ma Policy maker
Department of Public Health, sub-department ethics (from 1st august)
Advisors
advisor of ethics in reproductive medical research
Prof gmWR de Wert, PhD Professor of ethics of reproductive medical science and genetic research
advisors gene therapy
Prof CH bangma, mD, PhD Professor of urology, erasmus university Rotterdam
Prof ajm berns, PhD Distinguished Professor of experimental genetics of genetic conditions, university of amsterdam
Prof Fg grosveld, PhD Professor of molecular cell biology, erasmus university Rotterdam
advisor immunology
Prof Cjm melief, PhD Professor of immunohaemotology, leiden university medical Centre
advisors xenotransplantation
Prof FHj Claas, PhD Professor of immunogenetics of transplantation, leiden university medical Centre
Prof Fg grosveld, PhD Professor of molecular cell biology, erasmus university Rotterdam
Prof aDme osterhaus, PhD Professor of virology, erasmus university Rotterdam/erasmus medical Centre Rotterdam
legal health advisor
Prof gRj de groot, llm Distinguished Professor Health insurance law, Free university of amsterdam
Office
mDm (monique) al, PhD Secretary for medical affairs/staff member quality oversight (employed as of 1st april)
Dl (Dymph) van Drie-van den boom, mSc. Staff member communication
Ctm (Cecile) brekelmans, mD, PhD Secretary for medical affairs
mjH (marcel) Kenter, PhD executive director
e (eveline) Kooij, ma administrative assistant (employee legal affairs as of 1st november)
SH (Simone) Korevaar, m.eng Coordinator information management
mK (monika) Krystoporska management assistent
mC (marjanka) luijerink, PhD Secretary for medical affairs (employed as of 16th December)
a (annemarie) mast employee information management (employed until 1st july)
Rj (jim) terwiel, llm Secretary for legal affairs
em (Isabelle) van veldhuizen-Polman, llm Secretary for legal affairs
KRj (Kaate) vanmolkot, PhD Secretary for medical affairs
t (trinette) van vliet, PhD Secretary for medical affairs
Pjm (Paula) vossebeld, PhD Secretary for medical affairs
KS (Kirsty) Wilson bSc.Hons. Coordinator operational management and quality
PC (nance) Wüts-de groot administrative assistant
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Presentaties en publicaties CCMO 2010
Presentaties
title presentation meeting name organised by location date speaker
Dna and gene therapy Rotary Club Delft Rotary Delft 1st February mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker abbott Hoofddorp 8th February mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker lundbeck amsterdam 24th February mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker Sanofi-aventis gouda 2nd march mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker mSD Haarlem 4th march mjH Kenter
medical research with human subjects good research practices Rug groningen 23rd march gH Köeter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker Roche Woerden 29th march mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker astraZeneca Zoetermeer 29th march mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker eli lilly Houten 30th march mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker b-mS Woerden 6th april mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker janssen Cilag tilburg 19th april mjH Kenter
CCmo public trial register CbI’s Clinical trial Registriesand
Results Databases Conference
CbI alington (uSa) 27th april mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker amgen breda 6th may mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker Wyeth Hoofddorp 11th may mjH Kenter
CCmo-future strategy – upgrading Wmo to 2.0 Presentation guest speaker nefarma Houten 25th may mjH Kenter
Reporting adverse reactions to the mReC – building
on the Potemkin villages or on the trust in clinical
research?
PPn Symposium PPn breda 1st june mjH Kener
the industry as client of the mReC – CCmo future
strategy
Penthecilia Penthicilia Rotterdam 3rd june mjH Kenter
assessment of cell therapy studies in the
netherlands
Workshop Current problems on
Regulatory approval of atmP in
europe
Regenerate –
european
network for
Regenerative
medicine
berlin 25th june Pjm vossebeld
Reviewing medical research – searching for the
scapegoat
Send off symposium Henk ‘t Hart umCg groningen 28th october mjH Kenter
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title presentation meeting name organised by location date speaker
medical research with human subjects in the
netherlands and the role of medical Research ethics
Committees
meeting with japanese CRos Penthecilia Den Haag 20th September mjH Kenter
monitoring the quality of reviewing end of year meeting nvmetC nvmetC utrecht 3rd november mDm al
CCmo-future strategy – upgrading Wmo to 2.0 end of year meeting aCRon Soest 3rd november mjH Kenter
Research involving human subjects in the
netherlands and the role of mReCs
RvZ-lunch meeting RvZ Den Haag 15th november mjH Kenter
the role of the medical ethics committees lunch meeting KnCv Den Haag 22nd november gH Köeter
Scope of the Wmo meeting of the FSW Deans FSW Deans utrecht 25th november Ctm
brekelmans
Reporting and processing Saes and SuSaRs mReC course vumc vumc amsterdam 29th november mDm al
Quality policy within the mReC secretariat mReC course vumc vumc amsterdam 29th november mDm al
Reviewing multicentre research mReC course vumc vumc amsterdam 29th november mjH Kenter
upgrading Wmo to 2.0 – Future strategy mReC course vumc vumc amsterdam 29th november mjH Kenter
tgn1412 case: unlucky or system faults? mReC course vumc vumc amsterdam 29th november mjH Kenter
Publications
author title journal
mjH Kenter mReC’s, testing on animals and first-in-man studies tge 20 nr 3, p 102-3
Ctm brekelmans Patient safety in clinical interventional research ntvg, in press
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Research with medicinal productsPhase i Human pharmacological: first administration to humans, usually to a small number of
healthy volunteers. Tolerance and safety are examined, generally through dose escalation. Pharmacodynamics and kinetics are also often assessed.
Phase ii Explorative therapeutic: research into the efficacy of the treatment in question in (a small number of) patients. Also verification of the mechanism of action in patients or healthy volunteers and of the safety of short-term use.
Phase iii Confirmatory therapeutic: tests in medical practice of the final dose for usability and effectiveness in larger groups of patients. Comparison with an existing medicinal product or placebo. Long and short-term safety are also examined.
Phase iv Post-marketing research and research related to the area of indication the medicinal product is accredited for. These studies are not required for marketing authorisation purposes, but are important for optimising the use of the medicinal product.
Other research in which medicinal products are used: frequent studies are conducted in which medicinal products are used, but in which the objective is something other than for the phase I through iv research described above. The primary goal is not further research into the medicinal product, but a medicinal product is necessary to achieve the goal.
Abbreviations used
abr General Assessment and Registration Form (national application form)
aml Acute myeloid leukaemiabcb Central Review of Medical Research Involving Human
Subjects Decreeca Competent Authoritymeb Medicines Evaluation Boardccmo Central Committee on Research Involving Human Subjectsctfg Clinical Trials Facilitation Groupcro Contract Research Organisationdsmb Data Safety Monitoring Boardema European Medicines Agencyeu European Unionfdafmwv
Food and Drug Administration Federation of Medical Scientific Societies
hpv human papilloma virusic intensive careit Information technologyigz Health Care Inspectorateimpd Investigational Medicinal Product Dossierivf in-vitro fertilisation
luv Local feasibility statementmrec Medical research ethics committeemds Myelodysplastic syndromenk-cell natural killer-cellnvmrec Netherlands Association of mrecspif Research subject informationrivm National Institute for Public Health and the Environmentsae serious adverse eventsop Standard Operating Proceduresusar suspected unexpected serious adverse reactionumc University medical centrevhp Voluntary Harmonisation Procedurevrom Ministry of Housing, Spatial Planning and
the Environment(n)vwa (new) Food and Consumer Product Safety Authorityvws Ministry of Health, Welfare and Sportwbmv Special Medical Procedures Actwmo Medical Research Involving Human Subjects ActWob Government Information (Public Access) Actwzl Human Tissue Billzbo Independent Governmental Body
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CCMO
Central Committee on Research Involving Human Subjects
Postal address Post box 16302, 2500 bh The Hague, the Netherlands
Visiting address Parnassusplein 5, 2511 vx The Hague, the Netherlands
Telephone + 31 (0)70 340 6700
Fax + 31 (0)70 340 6737
E-mail [email protected]
Internet www.ccmo.nl
Colofon
Text and data ccmo secretariat
(Final) editing Marcel Kenter (ccmo) and Hedwig Ramirez Londoño-Neggers
English Translation Marcel Kenter, Kirsty Wilson (ccmo) and Wilkens
Design Total Identity, The Hague
Photography Hedwig Ramirez Londoño-Neggers, Utrecht
Printing Komplot bv, Rotterdam
April 2011
The Central Committee
on Research Involving
Human Subjects (CCMO)
ensures the protection
of research subjects who
participate in medical
research by reviewing
such research based on
applicable legislation
and taking into account
the progress of medical
science.
Research involving human subjects 2006 – 2010
Central Committee on Research Involving Human Subjects