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Clinical Investigations

Once you have completed your technical file, which includes a very detailed clinical evaluation plan, it feels as though you have reached the peak of a mountain. Now, you know what clinical data you need to collect and what endpoints to test.

Great, but don’t stop for too long to take in the view because you will soon realize there are further peaks to climb before you can reach the summit. One of those is the clinical investigation.

The planning and initial phase of a clinical investigation can be overwhelming. Using an experienced clinical project manager to plan and conduct the study will make the difference between a well-organized proactive study and one that is constantly reacting to problems and struggling to adhere to regulations.

Let’s look at some key aspects of a clinical investigation where the required effort is often underestimated, resulting in long delays right from the beginning of the project:

  • Essential document preparation
  • Contract negotiations
  • Submission for ethics and, if applicable, competent authority approvals

Core essential documents are the foundation of the study

Ethics committees and competent authorities will vary slightly on the documentation that they require for submission. For the purposes of this discussion, the focus will be on core documents required for all clinical investigations. The clinical investigation plan (CIP) defines the entire study. The patient informed consent form (ICF) describes the study to the patients and enables them to give their consent to participate. The investigator brochure (IB) or Instructions for Use (IFU) provides all the technical information regarding the device, and the case report form (CRF) is the blueprint for your database where the study data will be recorded and stored.

The clinical investigation plan requires considerable effort to create, and various people will need to contribute or at least review the document. The author, of course, has the primary job of writing the document, but the study statistician needs to be involved from the start to help with the design, methods, and sample size calculation. Reviews and input from the data manager will facilitate a synchronized case report form, and input from the Principal Investigator or other medical experts will ensure that the schedule of visits and details of the procedures are relevant to the specific therapeutic areas. Coordinating the input from all these busy people is a task in itself; therefore, enough time must be allowed for their written input and reviews. Waiting on input from one person can stall the entire project.   

The informed consent form will be scrutinized by the ethics committee, so don’t rush through the creation of this document. Most ethics committee sites provide useful templates but don’t misjudge the amount of study-specific information that is needed. It must be written in a language that is easy to understand and describes all the procedures and risks of the study without being too long. Some ethics committees will enforce the allowance of a maximum number of pages. And remember that changes to the CIP will almost always require parallel changes to the ICF.

The investigator brochure or instructions for use provide the information to justify that the device is safe to test on patients. As stated in the beginning, your technical file should be complete at this point. It will provide all the proof of required testing, demonstration of compliance with applicable standards, risk analysis and mitigation efforts, etc. However, compiling and summarizing the information into an understandable document – the IB - requires time. Additionally, the IB generally requires graphical depictions, which can also take a considerable amount of time.

The case report form must mirror the data described in the clinical investigation plan. The data manager should be aware in advance of possible measures and results that could be problematic during data collection. A well-designed CRF will facilitate the data collection from the sites and safeguard the quality of the data.  

Start contract negotiations as soon as possible

While essential documents are being created, the Project Manager may assist the sponsor with the site contracts. This is a lengthy process that always takes longer than anticipated. The contracts spend weeks with the legal departments of each entity and can bring a study to a complete stop if agreements cannot be reached. Some ethics committees want a fully signed contract included with the submission, while some sites may require ethics approval before they will finalize the contract – know the details of each site so you can prepare accordingly.

Submission ……. and approval

Finally, you submit the documents for approval and are making progress. This is definitely a milestone of the initial study phase but remember to allow sufficient time for the approval process.

Although some ethics committees have time limits for their response and yours, it is important to plan for enough time and assume at least one update or response to their questions or requests for changes. Multiple sites will add further complexity.

The key is knowing as much as you can about the process to prepare so that you’re not surprised by additional requests or someone’s holidays that will affect your timelines. As always, clear communication with everyone involved is crucial.

Once the submission is in, you can just relax until you get the approval – NO, of course not! In the meantime, there are plenty of other documents, logistics, and vendors to organize.


Do you have any questions about this article or do you need support? Contact us for a non-binding consultation.
Julie Tantau, AuD
Head of Clinical Operations - E-Mail