Identifying the plan and describing the investigational device
The sections of a clinical investigation plan that say what is being studied and by whom identify the plan and the people responsible, describe the investigational device and separate its intended purpose from its indication, set out how the device is accounted for, introduce the disease area and the rationale for the study, justify the design, and state the risks and benefits.
Plan identification and the people responsible
The plan must be identified by a study title, a reference number, and a version or date. It should carry both a version and a date, as in Revision 1.0, 22 February 2016, and some plans use lettered revisions such as Revision A, B and C. Where the plan has been amended, it must include a summary of the revision history, for instance that amendment 1 was made to include the device iteration and amendment 2 to adapt to new guidelines. The header and footer should carry the version number, the page number and the total number of pages. The total lets a reader be sure that all pages are there.
The plan must then name the people and places involved:
- the sponsor's name and address, and its local country representative where one is required
- the name, address and professional position of the principal investigator, who is the lead investigator at a site, and of the coordinating investigator, who is the principal investigator taking responsibility for the study
- the addresses of the investigational sites
- the names and addresses of other institutions involved in the investigation, such as a data safety monitoring board or an echocardiography core laboratory
The list of investigational sites can be kept separate from the plan, provided the plan references it.
The investigational device, its intended purpose and its indication
The device section of the plan must:
- describe the device and its intended purpose
- give details of the manufacturer of the device, which is often not the sponsor, since several device companies do not manufacture their own devices
- specify the name or number of the model type, including software versions and any accessories
- state the purpose of the device in the proposed investigation, and the population and indication it is intended for
- describe the device, including any materials in contact with tissues or body fluids
- state the training and experience needed to use the device
- describe the medical or surgical procedures involved in using the device
This material is sometimes already written in the clinical investigator's brochure, or, for a commercially available product, in its instructions for use or in earlier study protocols.
Intended purpose and indication can easily be confused. For a coronary stent, the intended purpose is to improve minimal lumen diameter in the coronary arteries, and the indication is de novo stenotic coronary artery lesions.
The plan can address training even when no specific training is required. For a drug-eluting stent, for example, it can state that the stent may only be used by a board-certified cardiologist, since implanting it is no different from implanting other drug-eluting stents, and that there are no specific training requirements.
Device accountability
Device accountability describes how the device will be traced during and after the investigation, for example through lot, batch or serial numbers. It is needed only for an investigational device not approved for commercial use, or for a commercially available device used outside its label, so the section can be skipped when a commercially available product is used within its indication.
Accountability shows that the location of the investigational device is known at all times. Its rationale is to ensure that no patient outside the study receives a study device, or at least to detect it when one does, so that corrective measures can be taken. It does happen that non-study patients receive study devices. Accountability is very complex and time-intensive, but very important.
The records are split between sponsor and site. The sponsor keeps records of the physical location of the investigational devices, and the principal investigator or the site keeps records of their receipt, use, and return or disposal. Access to investigational devices must be controlled, and they must be used only in the investigation and according to the plan. The plan often also states that they should be kept separate from commercial devices.
The introduction
One experienced writer finds that ISO 14155 puts too little emphasis on the content of the introduction, which the standard spreads over several paragraphs. In that writer's view, the introduction should contain a summary of the disease area and its key publications, previous data on the device, if there are any, and a rationale for conducting the study. Other study protocols may give an idea of how to structure it.
The introduction might be copied one to one into the clinical study report, so it is worth writing a good one. A writer who writes a good introduction may also be asked to help with the publication next time.
Justification for the design
The plan must justify the design of the investigation. The justification evaluates the results of the relevant preclinical testing carried out to justify using the device in humans, and the clinical data relevant to the proposed investigation. This is usually already summarised in the introduction.
Risks and benefits
The risk and benefit section names the anticipated clinical benefits, the anticipated adverse device effects, the residual risks of the device identified in the risk analysis report, the risks of participating in the investigation, possible interactions with concomitant medical treatments, the steps that will be taken to control or mitigate the risks, and the risk-to-benefit rationale.
For a product that is already CE marked, and so approved for commercial use, the risks usually come from its instructions for use and are copied across. For an unapproved product, they can usually be taken from the clinical investigator's brochure or the risk management plan.
The writer is sometimes asked to provide the risks, for instance when working for a start-up or for inexperienced people, and should agree only if very confident in the disease area. Otherwise, the writer can suggest a literature review of the disease area and come up with a list of suggested risks, which then requires confirmation by a physician. The list can also draw on information about similar products found online, such as published instructions for use, and on other protocols.