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Planning

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Once the problem formulation is completed and you know what questions are to be answered and what data need to be collected and analysed, the planning of your clinical study starts.

It is possible to get guidance on the planning process from Clinical Studies Sweden’s regional nodes or from specialists at your university if you are a researcher at a higher education institute.

The design and method of the study are important

There are many different methods for answering a research question, and the choice of design and method is something that will later on be of great importance for the scientific value of the study.

SBU scrutinises methods in health and medical care systematically, and has published a handbookexternal link, opens in new window describing how various study designs are valued scientifically.

ICH guidelines have been produced as a guiding document for planning medicine studies, but can also be of help when planning other types of therapy studies. ICH guidelines E9 and E10external link, opens in new window contain information on factors such as blinding, choice of control group, the difference between a confirmatory and exploratory purpose and the importance of outcome measures.

When you have decided what type of data to collect in order to answer the research question, you also need to decide how to collect the data. One way is to construct a case report form, CRF, and you can read more about this below. You should also consider how data collected (completed CRF, surveys, samples, images, register data, etc.) shall be marked up, and whether, once collection is completed, there is a link between the data collected and the identity of the study participant. If it is desirable to have such a link, the basic rule is that data shall be marked in such a way that only a person with access to a code key can identify the person who has provided the data. If there is a plan for how to collect data, mark it and to which persons the data will be available, then it is also easier to describe your data management to study participants, public authorities, personal data officers and other relevant persons who need information during the course of the study.

A research plan is necessary for ethical review applications, and functions as a handbook

Clinical studies carried out in Sweden require approval from the Etichal Review Authority. The ethical review application shall be accompanied by a complete and detailed research plan (also called a research protocol). The research protocol also forms the basis for an application for approval to any other public authorities (see the section on “Special rules for medicines and medical technology”) and shall function as a handbook, so that all parties involved can ensure uniform implementation, but also to make it possible after completion to follow how study data was generated.

The research protocol/plan must include:

  • the scientific question including specific goals and the purpose of the proposed project
  • a survey that summarises previous research results within the research area
  • a project description accounting for the design, selection of study participants, calculation of population size, procedures, methods and definition of primary and secondary effect variables
  • a brief description of the project’s significance to the research area

The website of the Ethical Review Authority includes guidelines for how the research plan shall be designed (in Swedish, pdf, 10kB).external link, opens in new window

Statistical analysis plan

For open studies, a statistical analysis plan (SAP) shall be in place before the study starts, for blind studies before the database has been locked (further information on statistical analysis is available in the Analysis step). An SAP shall include:

  • detailed definitions of analysis populations
  • analysis variables
  • general description of the analyses
  • exact analysis methods for each analysis variable

Information to study participants before consent

Before a study participant consents to participate in a clinical study, they shall be given access to all the information that a person may reasonably need to know in order to decide whether or not to take part in a research project. Guidelines for how information to study participants shall be designedexternal link, opens in new window is available on the website of the Ethical Review Authority.

The information to the study participants shall also be designed to comply with the information requirements in the Biobanks in Medical Care Act (SFS 2002:297) and the General Data Protection Regulation (EU) 2016/679. Biobank Swedenexternal link, opens in new window has produced a biobank guide (in Swedish) where you can read more about the information to be given to study participants specifically on biobank samples. If the study needs to be reported to the Medical Products Agency, there are further requirements on the information to be given to the study participants.

Find out what insurance cover is available for the study participants

The research principal for a clinical study shall ensure that there is insurance to cover any injury that may arise in conjunction with the implementation of the study. You will need to find out what insurance cover there is for the participants in your study, and check whether supplementary insurance needs to be arranged. The application to the Ethical Review Authority shall state whether the Swedish Patient Injury Insurance is valid, or if separate insurance needs to be arranged for the project.

Study budget for all the costs in the project

The funding of the project needs to be secured during the planning phase. There are a large number of Swedish and international research funding bodies, and researchers can also apply for grants and scholarships for which calls are published within the healthcare regions or by HEIs in Sweden, the Nordic countries or the EU.

In order to carry out a clinical study, you should plan for resources in terms of time, money and personnel. A study budget is a calculation of all the costs in the project. The list of costs shall include items such as personnel, training, applications, agreements, data handling, programming, study medicines/medical devices, laboratory samples, statistical analysis, biobanks and administration. One item in the budget is monitoring, which is mandatory for studies involving medicines and for studies of medical devices that need to be reported to the Medical Products Agency. The budget should be followed up regularly during the course of the project.

Is a health economics evaluation of the study needed?

You should also consider whether to add a health economics evaluation to your study. Such an evaluation discovers whether a medical intervention is cost-effective, that is to say whether there is a reasonable relationship between cost and effect as measured in improved health and increased quality of life, or Health Related Quality of Life (HRQoL).

In SBU’s handbook Assessment of methods in healthcare (pdf, 1796 kB), you can read more about health economics evaluation. The Dental and Pharmaceutical Benefits Agency, (TLV), has information about health economics evaluation on its websiteexternal link, opens in new window.

Specific rules for medicines or medical devices

There are specific rules to attend to when you are planning a study that includes medicines or a medical device.

Specific rules for medicines

A trial protocol is required for the application to the Medical Products Agency

For most clinical studies using medicines, authorisation from the Medical Products Agency is also required. The Medical Products Agency’s website has a test to help you determine whether or not your study requires authorisation from the Medical Products Agency (pdf, 154 kB, in Swedish)external link, opens in new window.

A trial protocol must be appended to the application to the Medical Products Agency. For medicine studies involving several clinics, the trial protocol forms the basis for uniform implementation and shall include all the information needed to ensure the participating clinics conduct the study correctly. On its website, the Medical Products Agency provides information on how to conduct clinical trials with medicinesexternal link, opens in new window.

A template for study protocols (including help text) is available here (in Swedish).external link, opens in new window

Allocating roles and responsibilities in accordance with Good Clinical Practice

Good Clinical Practice (GCP)external link, opens in new window is an international ethical and scientific quality standard for designing, conducting and reporting on clinical studies using medicines or medical devices. The purpose of GCP is to safeguard the rights, safety and well-being of the study participants. For medicine studies, GCP is defined by the International Conference on Harmonisation (ICH)external link, opens in new window, which includes US, European and Japanese medicine authorities.

Common questions about GCP on the European Medicines Agency’s websiteexternal link, opens in new window

More on the allocation of responsibility in the Medical Product Agency’s regulations on clinical medicine trials on human subjects (pdf, 96 kB, in Swedish)external link, opens in new window

According to GCP, there are a number of roles with varying responsibility to allocate when planning to carry out a clinical study using medicines.

A process overview for studies using medicines is available here.external link, opens in new window

The sponsor is the physical person or legal entity responsible for starting, organising and/or financing the study. In some cases, an individual can be both the sponsor and the principal investigator, and is then the person who both initiates and leads a clinical study. The role thus includes the obligations of both the sponsor and the principal investigator.

The sponsor has overall responsibility for the implementation of the study, and is responsible for issues such as:

  • ensuring there are written instructions for work, quality control and quality assurance
  • ensuring instructions are complied with
  • ensuring the study participants are guaranteed financial protection by means of insurance or otherwise

The sponsor may delegate all or parts of its tasks to an individual person, a company, an institution or an organisation, but the sponsor retains responsibility for ensuring the study is conducted and reported according to the applicable authorisations and rules.

A template/checklist for sponsorship responsibilities is available here.external link, opens in new window

The clinical investigator shall be a registered medical doctor or dentist and shall have the qualifications in the form of the education, training and experience required to take responsibility for the implementation of the study and the health and safety of the study participants, including documented training in GCP.

Some of the tasks of the clinical investigator are:

  • to provide the prerequisites for recruiting the agreed number of study participants and to set aside sufficient time to implement the study
  • to appoint qualified personnel who can help in the implementation of the study and also monitor delegated personnel in order to safeguard all processes
  • to take responsibility for delegated personnel receiving suitable training on the study
  • to ensure information on the study is provided, and that consent to participate is obtained according to the applicable rules
  • to draw up procedures for saving all study documentation and to allow monitoring and audit
  • to allow monitoring and audits

The clinical investigator has overall responsibility for the study, but may delegate tasks on condition that the delegation is done in writing. For this reason, a signature and delegation list must be drawn up and kept updated in the event of any personnel changes during the course of the study. A task must first be delegated before it may be executed by any person other than the clinical investigator.

If there is more than one clinical investigator at a trial site, the sponsor may appoint one of them to be the principal investigator.

A template/checklist for clinical investigatorresponsibilities is available here.external link, opens in new window

The monitor is a person appointed by the sponsor, whose responsibility it is to monitor the development of a clinical study, by carrying out tasks such as:

  • ensuring on location that the study is conducted, documented and reported according to the protocol, GCP and applicable public agency requirements
  • submitting a written report to the sponsor following each visit to the study site and to report on other study-related communication

In order to enable the monitor to monitor a study, he or she needs to have scientific and/or clinical prior knowledge, and also knowledge about:

  • the product being tested
  • the protocol
  • study participant information
  • the sponsor’s procedures
  • GCP
  • regulatory requirements

Set up systems for data collection, data processing and data storage

Data on the study participants in a clinical medicine study shall be collected into a data collection form, a Case Report Form (CRF). You can choose between setting up the system in paper format or electronic format. Electronic CRF (eCRF) may constitute the foundation for the database that is created for analyses, while paper CRF need to be converted into electronic data at a later stage. The material must be saved and be readable for at least ten years after the study has been concluded and reported.

You also need to write plans for data handling (Data Management Plan, DMP) and data validation (Data Validation Plan, DVP).

Specific rules for medical devices

Design of a medical device study

The design of a medical device study shall be based on the research question or hypothesis to be answered or tested. The study should be planned in such a way that the data collected is of good quality and can be used to answer the question involved. The question and study design can vary depending on what the purpose of the study is, but also depending on the development stage the medical device is at. You can read more about different study designs and statistical aspects in the Analysis section.

In addition to considering scientific aspects, you also need to ensure that the design that is best from a purely scientific viewpoint is also ethically and practically feasible. It is also a good idea to consider how the study design impacts on the quality of the data collected. A complex study design may require greater educational efforts for users and personnel, or a comprehensive plan for monitoring, to avoid failings in data quality compared to a design that largely follows the normal healthcare procedures.

Medical device aspects on ethical review

In addition to the requirements set by the Ethical Review Authority on the written information to be given to study participants, there are specific requirements on information to the participants in a medical device study. ISO 14155, Item 4.7.4 has recommendations for the information to be included.

When it comes to insurance for study participants, there are also circumstances that are specific for studies involving medical devices. If the studies are conducted as part of the healthcare principals activities, the patient insurance the healthcare principal is obliged to have is valid. On the other hand, there is no equivalent to the Medicinal Products Act (SFS 1992:859) covering medical devices.

Does the study need a permit from the Medical Products Agency?

In addition to being approved by the Ethical Review Authority, some studies involving medical devices must also be notified to the Medical Products Agency. Products that already have CE-marking and that will also be used in the study within the framework for the manufacturer’s intended use are not covered by the notification duty. Nor do studies of products of own manufacture according to the Swedish National Board of Health and Welfare’s regulation SOSFS 2008:1 (in Swedish)external link, opens in new window need to be notified to the Medical Products Agency. Clinical studies involving in vitro diagnostic products may in some cases require a permit.

Studies that need to be notified include:

  • all clinical studies involving medical devices that are neither CE-marked nor own production products
  • all clinical studies involving CE-marked medical devices when the plan is to use the product in a way that is not covered by the intended use

Contact the Medical Product Agency for advice if needed.

Medical device studies abroad

If you plan to conduct a clinical study involving medical devices in another country, you must inform yourself about the applicable legislation in that country. The European Clinical Research Infrastructure Network, ECRIN, has summarised information on regulatory requirements for many European countriesexternal link, opens in new window. The US Food and Drug Administrationexternal link, opens in new window is the regulatory authority for medical devices in USA, and China Food and Drug Administrationexternal link, opens in new window is the Chinese equivalent, just to mention some.

An adapted clinical investigation plan is needed for notification to the Medical Products Agency

If you need a permit from the Medical Products Agency for a clinical study involving medical devices, you will need to adapt your research protocol before submitting the notification. The research protocol for a clinical trial involving medical devices is called a clinical investigation plan, or CIP. ISO 14155, Annex A, has detailed information on what it needs to include. There is also a guidance documentexternal link, opens in new window on the EU Commission’s website describing how the national authorities assess the contents of the clinical investigation plan. The requirements on the contents of a clinical investigation plan are more comprehensive than the Ethical Review Authority’s specification for what must be included in a research plan, and therefore the more detailed clinical investigation plan shall be appended to the application for ethical review. An identical version of the clinical investigation plan shall be appended to the notification to the Medical Products Agency.

Important parts of the clinical investigation plan are the description of the data to be collected, which statistical considerations form the basis for the study design, and how data is to be analysed. Other important parts are a description of the study population, the procedures the study participants are expected to undergo, how informed consent is obtained, and a risk-benefit assessment relating to study participation.

In addition to the clinical investigation plan, a number of further appendices shall also be included in the notification to the Medical Products Agency. Information about mandatory appendices and their content is available in the notification formexternal link, opens in new window and associated instructions on the website of the Medical Products Agency.

Constructing a data collection tool

For a study involving medical devices that needs a permit, there must be a CRF, either in paper format or as an electronic system. An electronic CRF (e-CRF) can form the foundation for a database created for analyses, while a paper CRF needs to be converted into electronic data at a later stage. Irrespective of format, a CRF shall be constructed as a number of questions or tick-boxes that the study personnel fill in as the study participants answer questions or undergoes various investigations that generate measurement values. Data from the patient notes can also be filled in in a CRF. Annex C of ISO 14155 has an example of what a CRF may include.

If you use an e-CRF, there are specific requirements for system functionality and security. For example, an e-CRF must have a “logging function” to register who makes any changes to input data. The requirements on electronic systems in a studying involving medical devices are shown in ISO 14155, Item 6.8.3. You are also responsible for how the electronic processing of sensitive personal data is done, and you must know whether the electronic system entails personal data being processed abroad, or in any other operation than that of the research principal.

Remember that all the data collected in a CRF must be described in the clinical investigation plan, which must be approved by both a ethical review board and by the Medical Products Agency. No other data may be collected.

Allocating roles and responsibilities

According to ISO 14155, there are a number of roles with varying responsibility to allocate when planning to carry out a clinical study involving medical devices that requires a permit.

The manufacturer is the person responsible for construction, manufacture, marking, instructions, packaging and who states the designated purpose of a medical device, and who thereafter releases the device on the market in their own name. It is the manufacturer who shall CE-mark the product, irrespective of who has carried out the practical manufacture.

The sponsor is the individual or organisation responsible for starting and implementing a clinical study requiring a permit. It is common for the sponsor to also be the manufacturer of the medical device, but it is not a requirement.

The sponsor has overall responsibility for the implementation of the study, and is responsible for issues such as:

  • planning and implementation of the clinical study
  • communication with regulatory authorities
  • quality assurance and control
  • any contracting of subcontractors for tasks and functions

A full description of the sponsor’s role and responsibility is available in ISO 14155, Section 8.

The principal investigator is the person responsible for the implementation of a clinical study at a clinic. If the study is conducted at several clinics, there shall be a principal investigator at each site. The principal investigator shall have documented education and experience within the area the medical device is to be used in. The competence needs for the principal investigator shall be assessed based on the area of use of the device.

The principal investigator’s tasks include:

  • leading the work on the study at the clinic
  • ensuring that informed consent is obtained from study participants according to applicable rules and the clinical investigation plan
  • ensuring that the study is conducted according to the clinical investigation plan
  • being responsible for ensuring the study participants receive the medical care necessary during and after the implementation of the study
  • implementing safety reporting
  • ensuring that reliable data are generated

The principal investigator has overall responsibility for the study at the clinic, but may delegate tasks on condition that the delegation is done in writing to a person with suitable education and experience. A signature and delegation list must be drawn up and kept updated in the event of any personnel changes during the course of the study. A task must first be delegated before it may be executed by any person other than the principal investigator.

A full description of the principal investigator’s role and responsibility is available in ISO 14155, Section 9.

The monitor is a person appointed by the sponsor, whose responsibility it is to make independent checks that the study is conducted according to the clinical investigation plan and other applicable regulations. The monitor shall carry out the checks by visiting the clinics participating in the study, scrutinising the work and informing about recommended measures to improve the work on the study. After the visit, the monitor shall write a report to the sponsor.

In order to enable the monitor to monitor a study, he or she needs to have scientific and/or clinical prior knowledge, and also knowledge about:

  • ISO 14155
  • the device being tested and how it is to be used
  • the clinical investigation plan
  • the approved procedure for obtaining informed consent
  • the sponsor’s procedures
  • regulatory requirements

A full description of the monitor’s role and responsibility is available in ISO 14155, Section 8.2.4.

Collaboration between business, universities and healthcare

Clinical studies can be carried out at the initiative of healthcare, but it is also common for a company or an academic researcher to have an idea for a new or changed medical device.

When the medical device sector and healthcare collaborate in the development of medical devices, for example by conducting a clinical study together, the collaboration rules (in Swedish)external link, opens in new window shall be complied with.

When planning a clinical study in collaboration with healthcare, you should be aware that specific roles with a certain type of competence must be appointed. Read more about roles and liabilities in the section above. In addition to the competence that has to be recruited to fulfil the requirements of ISO 14155, the main rule is also that the person listed as the researcher responsible in an ethical review application shall have a doctoral degree. The researcher responsible in an ethical review application is often the same person as the principal investigator in the study. For a multi-centre study, the researcher responsible in an ethical review application is the person responsible for the trial site in the region from which the ethical review application is sent.

For help with contacting clinic that may be interested in implementing your planned study, you can use the service for coordinated feasibilities at the regional nodes.

Drawing up contracts and managing financial agreements

If the clinical study is implemented as commissioned research, that is to say some principal other than healthcare takes the initiative for the study, then a contract shall always be drawn up between the sponsor and the clinic or operation conducting the study. The contract shall regulate the allocation of responsibility for the study and any financial agreements. The healthcare principal will often require compensation for the additional costs the implementation of the study will entail for the operation. Financial agreements relating to commissioned research shall also be reported in the ethical review application.

If the healthcare principal takes the initiative for the clinical study, it is still recommended that a written agreement between the researcher and the operational manager is drawn up, governing aspects such as how additional costs to the clinic shall be financed.

Further agreements may need to be signed, for example if the study requires any X-ray or pathology input or a sample handling procedure via a central laboratory.