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5. Clinical research methods and good clinical practice

5. Clinical research methods and good clinical practice

5.1 Introduction


The Medical Research Involving Human Subjects Act (WMO ) covers medical scientific research in which people are subjected to interventions or have to follow established behavioural rules. The main purpose of the act is to protect research subjects (patients and healthy volunteers) against the risks and burdens of biomedical research involving human subjects without unnecessarily hampering the progress of medical-scientific research.

All clinical researchers, including PhD students doing research covered by the WMO, are obliged to follow the foundation course Legislation and Organization for Clinical Researchers (BROK course). The aim of this course is to provide clinical researchers with knowledge of the laws and regulations covering clinical research and their practical consequences. The course is completed by sitting an official national examination for the certificate of the NFU (Nederlandse Federatie van Universitair Medische Centra). The AMC and the VUmc provide the BROK course on a regular basis.

 BROK course NFU, see:
https://nfubrokacademie.nl/



In line with the WMO, this chapter explains the requirements for clinical research methods and good clinical practice in all stages of the study.

5.2 Clinical research methods and good clinical practice


It is good practice when planning a research project to formulate the goal of the research transparently, following a critical analysis of the available literature and any other data that are available. In the case of clinical research involving subjects, the goal should comprise particulars of the sample to be taken, the intervention, diagnostic test or aetiological factor, and the outcome measures that will be used. An appropriate research design should be chosen, and the actual number of participants in the study should be ascertained, as this almost always turns out to be smaller than originally hoped for or expected. Precise formulation of the research question effectively selects the design of the project. Proper planning is absolutely required for a number of reasons: a researcher who knows what he/she wants and why, and who is able to formulate a clear motivation and design, has a greater chance of having his/her research proposal accepted by a grant-giving body. When starting out on a project, the researcher does not yet know the answer to the question, but it is essential for him/her to envisage what type of answer it could be. A researcher who cannot surmise what the answer may be is not asking the right research question.

For the reasons given above, a protocol summary should be drafted in the design phase of the research project containing the following elements:

  1. Rationale. Study background and hypothesis (if applicable).
  2. Objective. The main and secondary objectives of the study.
  3. Study design. For example, randomized controlled trial, case-control study, etc. In this paragraph attention should also be paid to the sample size calculation (the minimal number of subjects needed to confidently answer the main study question).
  4. Study population. For example, healthy human volunteers, 18-55 years old.
  5. Treatment (if applicable). For example, one group receives twice daily a 10 mg tablet of product X and the other group receives twice daily a placebo tablet. It also could be a surgical intervention or any other intervention.
  6. Investigational product. This paragraph is applicable to research on the effects of any product (e.g. medicinal product, food product, medical device or other).
  7. Non-investigational product. This paragraph is applicable for any other product that is used in the study. For example rescue medication, or challenge agents or products (e.g. medicinal product or chemical compound) used to assess study endpoints.
  8. Methods. A description and operationalization of the main study parameters/endpoints (e.g. the percentage change in the number of events from baseline to endpoint, or the difference in genetic profile between patients and controls). This paragraph also details the procedures subjects will undergo (e.g. the amount and number of blood samples, the number of site visits or questionnaires that have to be filled in).
  9. Safety reporting. Clinical researchers are required to report serious adverse events through the web portal ToetsingOnline to the Medical Ethics Committee that approved the protocol. When the research is determined to be high risk, a data and safety monitoring board (DSMB ) is required to monitor the safety of the participating research subjects.
  10. Statistical analysis, including power analysis, how missing data will be handled, and how data will be presented and analysed.
  11. Ethical considerations. A description of recruitment and informed consent procedures. If applicable, a risk-benefit analysis can be given. If a non-therapeutic study is carried out with minors or incapacitated persons, it should be specified whether the risks are negligible and the burden minimal, and why the study is group related (i.e. can only be done using these patient groups).
  12. Administrative aspects. Data should be handled confidentially and, if possible, anonymously. The handling of personal data should comply with the Dutch Personal Data Protection Act (De Wet bescherming persoonsgegevens ).
  13. Structured risk analysis. This consists of a number of steps to determine the direct risks for the research subjects in the study.

Summary of the research protocol.
This summary is derived from the revised template published in 2012 by the Central Committee on Research Involving Human Subjects (CCMO). See www.ccmo.nl

5.2.1 Obtaining approval

Research covered by the WMO and/or the Embryos Act must be submitted to an accredited Medical Ethics Committee (MEC) for approval before it can be conducted. Studies are subject to the WMO if they meet the following criteria:

  • It is medical scientific research.
  • Research subjects are subjected to procedures or are required to follow rules of behaviour.

Examples of clinical research that does not entail subjecting research subjects to procedures or require them to follow rules of behaviour, and is therefore not subject to the WMO, are retrospective studies on patient records and prospective research with patient data.

The MEC reviews research protocols in accordance with the rules laid down in the WMO. The MEC can only provide positive judgement of a research protocol if (Article 3 of the WMO):

  • The scientific research will contribute to new insights in the field of medicine.
  • There is no simpler or less burdensome alternative (e.g. ideally no incapacitated study participants).
  • The significance of the study is proportionate to the inconvenience (burden) and risk to which the research subject will be exposed.
  • The study meets the scientific criteria for research.
  • The study is to be carried out by or under the supervision of qualified investigators.
  • Any payment made to the research subject must not have been a decisive factor in his/her decision to take part in the study.
  • The protocol states the extent to which the scientific research might benefit the research subject or, in the case of group-based studies, the group to which the research subject belongs.

Research that is subject to the WMO cannot be carried out without a positive decision from the MEC. In some cases (e.g. for experimental interventions such as gene therapy) the Central Committee on Research Involving Human Subjects (CCMO) acts as the MEC.
See 'Besluit centrale beoordeling medisch-wetenschappelijk onderzoek met mensen' .

The protection of research subjects is the key issue in the WMO. Therefore, the law prescribes that:

  • Research subjects must be given written information about the study.
  • An independent expert who is not directly involved in the study must be available to give research subjects information.
  • Research subjects must give their written consent prior to taking part in the study.
  • Insurance must be taken out to cover any damage suffered by research subjects as a result of the study (liability insurance does not suffice).

The law imposes requirements on how the study must be reviewed, and additional requirements on research involving minors (persons under the age of 18) and incapacitated adults. MECs must follow these legal rules when reviewing studies. Consult the WMO for the full text.

After giving a positive decision, the MEC must still be informed of the following aspects: start and end dates of the study, protocol amendments, and amendments of other essential documents like the patient information. In the case of studies that are subject to the WMO, all serious adverse events (SAEs) and serious adverse device effects (SADEs) should be reported through the web portal ToetsingOnline . Suspected unexpected serious adverse reactions (SUSARs) should be reported through the web portal ToetsingOnline in the case of trials of medicinal products.

 'Besluit centrale beoordeling medisch-wetenschappelijk onderzoek met mensen'.
MEC / WMO

5.2.2 Additional requirements applicable to trials of medicinal products


For clinical research with medicinal products, an additional marginal review is necessary, in addition to the review by the MEC. This second review of whether there are grounds for non-acceptance concerning the study, is performed by the Competent Authority (CA). The CA examines whether there are motivated objections to the study. To this end, it checks the European database (EudraVigilance ) for previously reported side-effects of the medicinal products that may lead to unacceptable risks to the study subjects.

In a trial with medicinal products for which the MEC is the reviewing ethics committee, the CCMO will act as the CA. If the CCMO is the reviewing ethics committee, the minister of health, welfare and sport will act as the CA. The investigator has to submit the same documentation package to the CA as to the MEC in order to obtain a statement of no objection. For details, see the CCMO website .

The CA remains involved after the approval(s). The investigator/sponsor is obliged to notify the CA in the following cases: substantial amendments, SAEs (serious adverse events) and SUSARs (suspected unexpected serious adverse reactions) in the case of investigator-initiated studies through the web portal ToetsingOnline , annual safety report, end of study, and submission of the final study report.

Other obligations for interventional trials with medicinal products are:

  • Studies and end results must be registered in the EudraCT database (European Union Drug Regulating Authorities Clinical Trials), which is the European database of all clinical trials. A request for a EudraCT number can be arranged via the EudraCT website .
  • Planning and conducting the research should be in line with the ICH Good Clinical Practice (GCP ) guideline for trials with medicinal products.
  • Manufacturing of the investigational medicinal product (IMP) should be in line with the European Union Good Manufacturing Practice (EU-GMP) guidelines . This is also mandatory for placebos.

5.2.3 Manufacturing of study medication


In studies that with medicinal products as IMPs - either products under investigation (nonregistered) or medicinal products with a marketing authorization (registered) - the products (or 'study medication') must be manufactured, labelled and packed in compliance with the EU-GMP guidelines. To manufacture IMPs, a licensed GMP-manufacturing facility is required and a qualified person has to be appointed and registered at the Dutch health authority. The VUmc has an EU-GMP manufacturing licence for the packaging and labelling of study medication and for the production of radiopharmaceuticals. The AMC does not have a GMP licence.

The IMP, including placebo and comparator medication, should be labelled according to the EU-GMP annex 13 guideline . The label should provide at least the following information:

  • Name, address and telephone number of the sponsor or investigator
  • Pharmaceutical formulation and number of dose units
  • Batch number and/or production code
  • Trial reference code
  • Identification number of trial subjects
  • Name of investigator
  • Instructions for use
  • The words 'Uitsluitend bestemd voor gebruik in klinisch onderzoek'
  • Storage conditions
  • The words 'Buiten bereik van kinderen houden' (when used outside the hospital)
  • Expiry date or retest date.

Labels must be approved by the MEC.



5.2.4 Investigational medicinal product dossier


The investigational medicinal product dossier (IMPD) contains all the information about an IMP with regard to the active pharmaceutical ingredient (raw product), other compounds, the production process, quality control of the product, stability studies and clinical pharmacology. A template is available on the website of the CCMO . It is also obligatory to have an IMPD for the placebo and comparator medication. If the comparator is a registered drug, however, a summary of product characteristics (SPC) is sufficient (i.e. an IMPD is not needed). The SPCs of registered products can be downloaded from the website of the Medicines Evaluation Board (College ter Beoordeling van Geneesmiddelen - CBG ) or the European Medicines Agency (EMA ). The IMPDs must be approved by the MEC.

5.2.5 Storage and distribution of study medication


According to the Dutch Medication Law (Geneesmiddelenwet ), only pharmacies and wholesalers of medication may store drugs. Investigators may store medication only with the pharmacy's authorization. A prescription issued and signed by a physician is required in order to distribute study medication to the patient. Study medication transactions (receipt and distribution) are registered on drug-accountability forms. The investigator is responsible for the drug-accountability of returned medication. For all these issues, the pharmacy should be contacted at an early stage. It is recommended to make an agreement with the pharmacy and to document the arrangements.

EudraCT
https://eudract.ema.europa.eu/
Good Clinical Practice (GCP)
http://www.ccmo-online.nl/hipe/uploads/downloads_cato/richtsnoer%20GCP%20mrt%202003.pdf
EU Good Manufacturing Practice (GMP)
http://ec.europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf
College ter Beoordeling van Geneesmiddelen (CBG)
http://www.cbg-meb.nl
European Medicines Agency (EMA)
http://www.ema.europa.eu/ema/

 

5.2.6 Registration of the trial


Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions in order to evaluate the effects on health outcomes should be registered in a public protocol registry; this also applies to early phase uncontrolled trials (phase I) in patients or healthy volunteers. This is both a recommendation of the WHO and the policy of the International Committee of Medical Journal Editors (ICMJE ). If in doubt, registration is recommended. Studies can be registered with the Netherlands Trial Register , Clinicaltrials.gov or Current Controlled Trials . The Netherlands Trial Register and the CCMO have agreed to explore a merger of the Netherlands Trial Register and the CCMO register. The submission of the study protocol should be arranged prior to the start of the study, that is, before the first patient has signed the written informed consent.

International Committee of Medical Journal Editors (ICMJE)
http://www.icmje.org
Netherlands Trial Register
http://www.trialregister.nl/trialreg/index.asp
Clinicaltrials.gov
http://www.clinicaltrials.gov
Current Controlled Trials
http://www.controlled-trials.com

5.2.7 Data management


Before starting the research, a number of activities must be planned regarding the data management. Essential steps in data management are: developing a case record form (a paper or electronic document designed to record all the information for an individual study subject required by the study protocol), building a database, defining a procedure for data entry, defining and programming validation checks to ensure the consistency of the dataset, and, if applicable, setting up a randomization procedure, web questionnaire and/or logistic module. In clinical studies with medical products, the database must permit data to be changed in such a way that these changes are documented; it must also prevent the deletion of entered data (i.e. it must maintain an audit trail). It is also necessary to set up and maintain a security system that prevents unauthorized access to the data. There should always be an adequate backup of the data.

5.2.8 Monitoring


At the AMC, all investigator-initiated studies with medicinal products or medical devices, and studies with a high risk level, should be monitored. At the VUmc, monitoring is mandatory for all mono-centre investigator-initiated studies and all high-risk multicentre studies. The purpose of study monitoring is to verify that the rights and wellbeing of human subjects are protected, that the reported research data are accurate, complete and verifiable from source documents, and that the conduct of the study is in compliance with the currently approved protocol/amendments, with GCP and with the applicable regulatory requirements. In general, onsite monitoring should be carried out by an independent monitor before, during and after the trial.

In line with international recommendations, the Netherlands Federation of University Medical Centres (NFU) recommends that clinical research projects should be categorized according to the level of risk that they pose to the research subjects, investigators and the health service. The three levels of risk are: negligible, moderate and high. Accordingly, monitoring procedures in terms of frequency and intensity should be adapted to reflect the degree of risk. This recommendation has been adopted by both the AMC and the VUmc.

 Revised NFU guidelines.
In 2012 the Netherlands Federation of University Medical Centres (Nederlandse Federatie van Universitair Medische Centra; NFU ) developed guidelines on the quality control of medical research with human subjects. These guidelines can be downloaded as a PDF file.

5.2.9 Doing the research


Patients can be enrolled in a study only after the researcher has planned the clinical study, been granted funding, obtained approval from the MEC, received the notification of no objection from the CA (if applicable), and received the hospital board's formal approval. It is also necessary to register the study in a public registry before enrolling the first patient.

An overview (the enrolment log) must be kept of all eligible and consenting research subjects. A subject identification list must also be maintained by the researcher. This document is a confidential list of the names of all enrolled subjects along with their allocated study numbers. It allows researchers to establish the identity of any subject, if necessary. Subject study numbers should be used instead of identifying information. When study data are to be transferred to a party outside the hospital (e.g. pharmaceutical industry, physicians at other hospitals, other institutions), only subject study numbers may be used. Any subjects who are screened but are found not eligible to participate must be documented on a screening log.

A document containing instructions for data entry should be created. The data must be processed digitally in an error-free manner and checked (digitally) for completeness, correctness and consistency. Data analysis planning begins before the researcher has collected all the data. The statistical analysis plan should be drawn up and approved by a statistician.

For clinical studies with medicinal products, the MEC, CA and the EudraCT database in London should be informed after the last patient has received the last treatment according to the study protocol. A specific 'declaration of end of study' form is available on the EudraCT website . The requirements for EudraCT are valid only for clinical studies with medicinal products (both nonregistered experimental products and marketed products).

When a clinical study lasts longer than one year, the investigator should at least once a year submit a summary of the progress of the trial to the MEC by completing the 'annual progress report' template available on the website of the MEC or the CCMO. This report should be submitted within 60 days after the first approval in the first country of the European Economic Area has been obtained.

The MEC must always be informed of the end of the study by completing the 'end of study report' available on the website of the MEC or the CCMO . For studies with a shorter duration, the annual progress reporting may coincide with the reporting of the end of study.

For clinical research with medicinal products, once a year throughout the study or upon request, a complete overview of all safety information that became known from the study and, if applicable, from all other studies with the same medicinal product performed by the same investigator, must be submitted together with a critical overview and a statement regarding the risk/benefit ratio to the MEC and the Competent Authority (CA). This is called the 'annual safety report'. Within one year after the end of the study, the investigator should submit the 'summary report' with the results of the study to the  MEC and the CA.

5.2.10 Statistical analysis plan


After finalizing the protocol, the statistical analysis plan (SAP) should be drawn up and dated, approved and signed by the study group and a statistician. The SAP should contain a detailed description of the following:

  • Study objectives and design, including primary and secondary outcome measures.
  • The sample size calculation and power considerations.
  • If applicable: randomization procedure, including methods and logistics.
  • Study populations: which participants will be included in the analyses (intention to treat versus per protocol considerations).
  • List of relevant sample, patient and/or procedural characteristics that will be tabulated.
  • All statistical methods to be used to estimate effect sizes and/or to test the study hypotheses regarding the outcome measures, including pre specified subgroups.
  • The safety parameters and how they will be tabulated.
  • If applicable: the timing and stopping rules of interim analyses/safety analyses.

Data validation, cleaning and analysis should be performed in line with this plan and begin during data collection. When deemed necessary based on a review of the data/blinded data, the SAP may be formally updated. If changes involve sample size considerations or changes in primary outcome definitions, the protocol should be amended and the MEC should approve the amendment. These kinds of amendments are only possible as long as the study is on-going. Each deviation from the original statistical plan should be recorded in the SAP and noted in the final study report. Once all data have been collected, validated and cleaned, the database can be locked and the SAP finalized. When applicable, the blinding can be broken and the final analysis be performed.

All data analyses should be performed by persons who are sufficiently trained in the required statistical methods. When data types and/or the amount of data prevent the medical researcher from performing the necessary statistical analyses on his/her own, collaboration with epidemiologists or biostatisticians should be sought to ensure that the study conclusions are based on valid analyses.

5.2.11 Reporting on the research


Articles and any abstracts for conferences should be drafted. They must accurately reflect the original topic in the protocol and include additional analyses wherever such is useful, necessary and/or of interest. The researcher should state honestly where the question preceded the data and where post factum speculations take over. More and more journals demand transparent and full reporting of the essential components in the design and conduct of the research. Various checklists can be used to establish whether an article contains adequate information on every point. For example, there are the CONSORT guidelines for randomized controlled trials, and the STROBE and STARD guidelines for observational and diagnostic accuracy studies.

After reporting the findings, the researcher should archive all essential investigator documents (including data files, statistical syntax, etc.). The NFU recommends archiving essential documents for at least 5 years in the case of a study with a negligible risk, and for at least 15 years in the case of a study with a moderate or high risk. For investigator-initiated clinical studies with medicinal products, essential documents should be retained for at least 15 years, irrespective of the risk level of the study. These guidelines have been adopted by both the AMC and the VUmc.

 Guidelines for health research reporting, see:
http://www.equator-network.org/resource-centre/library-of-health-research-reporting
Study documentation (AMC), see:
http://www.amc-cru.nl/klinischonderzoek.aspx?panel=ARC
Study documentation (VUmc), see:
http://intranet/afdelingen/thema/crb/6979188/7103445/7091925/

5.3 Research support


The Clinical Research Unit (CRU) supports clinical research at the AMC. The CRU provides methodological support to researchers who are writing grant proposals or starting new clinical research projects. Its helpdesk can answer questions related to statistics. The CRU website provides detailed instructions on how to plan, execute and report clinical research. The website also provides various statistical tools (e.g. Wiki Biostatistics and the e-learning course Practical Biostatistics) and a set of standard operating procedures for clinical research can also be found in Kwadraet. With regard to data management, the CRU offers a range of products. ICT specialists and data managers can build GCP-proof databases, design and construct data warehouses, and set up randomization procedures. The CRU can also provide monitoring services and help researchers to set up a data safety monitoring board. For further details, see the CRU intranet site .

The Clinical Research Bureau (CRB) at the VUmc offers an infrastructure by providing guidance and advice mainly on investigator-initiated studies to ensure quality compliance. The services offered by the CRB include:

  • Training and education for research staff.
  • Monitoring of investigator-initiated studies that are subject to the WMO.
  • Data safety monitoring board in the case of high risk studies.
  • Advice and guidance regarding several legal aspects and supporting the contracting process for clinical trial agreements.
  • An intranet site providing advice and instructions on how to plan, execute and report clinical research according to GCP.

CRU
For more information about the AMC Clinical Research Unit, see
http://www.amc-cru.nl/welkom.aspx (intranet)
http://os1.amc.nl/wikistatistiek
http://www.elearningbiostatistics.com

CRB
For more information about the VUmc Clinical Research Bureau, see
http://intranet/afdelingen/thema/crb/ (intranet)

For information about biostatistical consults in VUmc see https://www.vumc.nl/afdelingen/EB/consultatie/

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