With increasingly diverse requirements to fulfil in order to support regulatory submissions and compliance post-approval, this has created a strain as organizations are trying to achieve this with the same, or reduced, human and financial resources. This creates the need to look carefully at how best a company, from multi-national billion dollar companies to small start ups, can utilise their service providers to ensure the regulatory needs of each market are met.
A successful clinical investigation requires a robust clinical strategy but as is well known, in order to gain approvals to begin the study, the devil is always in the details. In order to cast aside the devil from the details it is important to be able to access existing relationships with: Regulatory Authorities, including Notified Bodies in Europe; Clinical Key Opinion Leaders (KOLs) and Ethics Committees.
Experienced Clinical Research Organisations (CROs) can benefit companies when planning clinical strategies and development activities particularly when key team members from Research, Development, Marketing and Senior Leadership are involved in discussions. For these team members to have a voice “at the table” with Regulators and KOLs can ensure that the project is well supported both from a human and financial resource perspective. Also discussions on whether activities are required or not are restricted to those where there are less well defined requirements, particularly in the case of new and novel technology.
Once these requirements have been agreed then these should be captured in the Clinical and Regulatory strategy documentation to ensure that the design inputs match the design outputs that will be used to support the different submissions for the clinical investigation.
Globally there is continued learning and improvement to what is considered “state of the art” from a clinical, regulatory and technical perspective, therefore the clinical and regulatory strategy should be regularly reviewed with your chosen CRO for those countries where the clinical investigation is planned to be conducted.
Establishing a fool-proof contingency plan to ensure cost effectiveness during unplanned longer studies
Industry is challenged everyday with increasing demands for clinical data with the need to reduce operating expenditure to ensure delivering value to shareholders to allow for further investment in research, development and infrastructure improvement. Here it is important to look at how you can ensure that each clinical investigation is delivering the best return on investment through each product life-cycle. But with today’s regulatory requirements and experiences with significant recalls of medical devices, can any longer term studies be considered to be “unplanned” with respect to what is required to fulfil the needs to demonstrate patient safety?
In the post-approval phase of a product’s lifecycle there have been requirements to perform clinical investigations for both pro-active post market surveillance (PMS) and Health Technology Assessment (HTA) studies. These are not new requirements from a Regulatory Authority perspective but measures have needed to be put into place so that the industry are accountable if they do not consider these requirements in their clinical and regulatory strategies. How can the studies be designed to meet the endpoints of both clinical performance and cost effectiveness?
It should be remembered by a company that they are required to be the expert in their particular device and therefore if Regulatory Authorities require a longer-term clinical investigation to be performed it will be of benefit to the company and to patient safety. A Regulatory Authority does not want clinical activities to be performed if they do not benefit improvements for patient safety. Generally, justifications and rationales that are founded on good science, clinical data and what can be achieved within the clinical community, are well received and listened to by Regulatory Authorities. Preparing these justifications and rationales well results in robust and valuable discussions between all stakeholders and will deliver the best result for the company, the clinical community and overall patient safety.
Key points which should be considered in the planning phase of a longer term clinical investigation are:
- What is achievable within the clinical community?
– Are the proposed follow up activities still in line with clinical practice?
– Patient perspective
– Core lab facility needs
- Are the endpoints of the study commensurate with the life cycle of the product?
– Will there be a phase out of older products within the scope of the recruitment process of the clinical investigation and will it be possible to replace the product with newer, state of the art iterations without significant investment in resubmissions for each country and clinical site?
- There should be regular critical reviews of the data to ensure desired endpoints continue to be met as more is learn about the longer-term clinical performance of a product.
Providing best practice ideas for coping effectively with administrative overload in order to meet specified deadlines
There is no magic formula for dealing with the administrative burden that comes with performing clinical investigations in a highly regulated industry sector. Success comes from having clear and well-communicated endpoints, excellent project management, continued communication on progress and good team and personal discipline.
For the whole team, internal and external team members all need to have clearly defined roles and responsibilities to which they are accountable. Teams need to be well supported and have a regular forum where any potential issues can be raised and decisions can be taken to ensure these issues are resolved quickly, so a steering committee with representatives for each functional group/outsourced team is essential.
Each task and document needs to have defined timelines and the consequences for the overall project should be communicated and understood if the timeline for each task or document is not achieved. One major difficulty in any project is obtaining signatures for sign off so that the next steps in a project can begin. Many times the people required are not in the same country, time zone and have other priorities. Also the fun part of the work has been completed and this last part is the tedious, administrative part. To compensate for this and keep the momentum and energy high to achieve task closure, it is beneficial to assign for each document a ‘document owner’ who is accountable for obtaining signatures and will dedicate a specific day for signatures. In order to keep momentum and motivation for this tedious but essential part of a task closure, allocate two points in the day for a status update to the project leader to support the document owner in obtaining signatures.
Every time a deadline is achieved the efforts and achievements for all the team members needs to be recognized and how this benefits the project goal should be reinforced. Eventually document reviews and sign offs become something that is seen as ‘more fun’ rather than a time-consuming bureaucratic task.
Once a clinical investigation is underway clinical data monitoring is another activity that can result in an administrative overload if not managed effectively. It is of benefit to decide with your CRO that a data review is performed when each data set is uploaded into the study database and any queries are then followed up quickly with the clinical site so any potential issues can be resolved in a short period of time and are not left to scheduled site monitoring visits.
Overcoming barriers faced during patient recruitment in order to cope with the requirements of increased number of patients now needed for clinical studies
The clinical investigation has been approved both from Regulatory Authorities and, where required, Ethics Committees. The investigators are trained, the site initiation visits completed and now all that is left is to recruit patients into the study. Patient recruitment and the need for increasing numbers of patients and studies is a very important consideration for a successful clinical investigation. There are certain cultures that have a strong ethic to support healthcare research and performing studies in these countries will naturally have a lower barrier to patient recruitment.
When planning a clinical investigation and considering the optimum strategy for patient recruitment it is beneficial to review published clinical studies with similar patient populations and determine the following:
- Which centers were involved in these studies?
- Which were the highest recruiting centers and why?
- Which CROs were involved with these studies?
– How did they manage patient recruitment?
– What were the challenges for patient recruitment?
– What lessons were learnt in patient recruitment?
- What is the referral pathway for patients in each country?
Taking these factors into account will ensure that the clinical investigation is well set up to meet the increasing needs for clinical data to support the Regulatory and HTA requirements of a global market.