1- Choosing the countries where the study will be taking place; choosing the centers in these countries that may be interested and qualified to participate

The first thing to do when preparing a clinical trial is to determine the location in which the study is going to take place. The pathology you are studying may have a specific geographical distribution. The marketing strategy may require that a clinical trial is performed where the compound or device will be sold. The choice of the countries will have a significant impact on the CRO selection. The competencies of the sites will determine the amount of training and supervision that one will need to budget. In some cases, a coordinator will need to be allocated to sites without resources.

2- Selecting the internal collaborators; what are the important characteristics of the staff?

Building the sponsor team should be planned with a long term dynamic view. According to the sponsor team composition, the selected CRO will need to be staffed to match the sponsor organization. Someone in the team should have a very solid and recent knowledge of the pathology and its therapeutics, however, not everyone needs be a specialist of the therapeutic area. I often think of what Montaigne the French philosopher wrote in the first chapter of the Pedagogical Considerations in his famous Essays: "You must choose a good leader who has a head well made rather than well filled". I always prefer someone enthusiastic and curious; willing to work hard and ambitious, as to someone very experienced who has lost the energy to defend a point of view with passion. I think that it is important that I am surrounded by people with a broad spectrum of interests, who are able to speak about other topics than just related to pharmaceutical research as this can evoke solutions not otherwise imagined. I also believe that "cross pollinization" can happen when some analogies can be drawn from other fields of interests, and that this gives us ideas for how to resolve issues in our professional environment.

3- Preparation of budget, plan for compound development and regulatory considerations

Very seldom the sponsor develops a budget in advance for a specific project. We usually wait for the CROs to send us the bid budget which therefore tells us how much our projected ideas cost. I think this is not a good plan. One must have a very good idea of what things cost in order to start elaborating a project that is realistic and with equal depth to the company’s pocket. The study should insert itself perfectly within a global development plan and each question asked in the CRF should participate to the same goal: getting the drug or device approved by the legal authority. The CRF should be reviewed carefully to be absolutely sure that it contains only essential questions to which we need the answer in order to get the agency’s approval. The sponsor should understand the regulatory environment of the therapeutic area, have good relationship with agencies, and be familiar with the way in which to process an IND with this specific department. There are as many processes as there are countries therefore, timelines for submission need to be carefully analyzed with the help of the CROs in order to organize the work in meaningful steps.

4- Protocol Development; reality check with the future centers and P.Is

Often medical teams write a beautiful protocol that is strongly focused on internal consistency but once it is tested in the field, it reveals itself impossible to implement. The process described can be too different than the current practice that evolves continuously. or the different steps required may not be in the usual sequential order used in the everyday practice, just to name a few issues. It is important that the protocol is built with constant feedback not only from a practicing Doctor but also from a P.A. and the nurse’s point of view. In some countries, hospitalization can be longer for the same pathology or symptoms because the structure of the health care reimbursement is different. Procedures are often not exactly the same and standard care may not be similar in each part of the world. The protocol needs to take all of this into account to make a plausible path to follow.

5- Choosing the vendors; the "reverse model".

Selection of the vendors is critical for the success of any project; however, we rush the process and use a method that is frustrating for everyone and rather inefficient. CROs are contacted a couple weeks before we need a proposal and each rush through their algorithms without a deep understanding of the request and the preferences of the sponsor. They produce something standard, packed with safety buffers to temper their lack of true understanding of what the sponsor has in mind. Another method is to have a continuous dialogue with a few selected CROs. I meet every Thursday, for a one on one meeting, with the Director of BD or the VP of Operation, or Regulatory from a small group of CROs that I find efficient and well organized. I explain what we have in mind for the future, our development plan, our current mindset, our errors, the paths we have explored without success, and others that have brought fresh ideas and promising openings. We discuss future trials, logistics which bring about an exchange of ideas. During that time, we rarely speak formally of the budget, but sometimes the BD Director will evaluate the cost of an idea to get some reality checks in the thought process. Eventually I will be introduced to a great manager whose personality fits with the team I currently work with… we give ourselves some time to develop a relationship and to ensure we are talking the same language. As a foreigner who left his country, customs and language, I find it extremely important to assure a common ground with the people I will eventually work closely with for the several years that take a project from beginning to end. After this process, a timeline is decided and the CRO proposes the main players who will be involved in the project. We meet and discuss the overall project and evaluate the dynamics to see if the relationship will work. At the end of this process, we ask for a formal bid. At this time there are very few points that are not clarified. The competing CROs give us similar budgets as the true costs of the project are precisely calculated and all buffers are removed because the unknown factors are now limited. We no longer select a CRO based on budget alone, but based on personalities, competencies of individuals and methods proposed by the companies. It does take time and personal involvement, but for me, it is well worth the investment.

6- Bid review: A- budget analysis B- the work to perform and method used

When I ask CROs to propose a budget, I give them a budget grid template to complete, and in addition, I ask them to provide their standard proposed grid. I compare the grids and see how they transfer the information from one to the other. The proprietary grid I provide makes it easier for us to compare bids between CROs, however, I do not want to eliminate a CRO who has not been able to fully convert their grid into ours, hence the reason why I request their own grid. Once the money part has been analyzed, we ask questions regarding the process they are going to use and the people involved, their geographic location and the amount of time they will invest every week on the project. We give our feedback, our preferences, we share the ideas generated by their bid.

7- The oversight or "real time audit"

Once the project has been attributed to selected vendors, the work starts immediately. Regulatory starts preparing their EC and MOH submissions, centers are contacted or re-activated, paperwork takes place, and medication is prepared etc. As soon as the first subject is enrolled at a site, I ask that an "early audit" take place to verify the competency of the monitor, the quality of the staff at the research center, that the protocol is unfolding smoothly, and that the parts are moving together well. This process is repeated at a few other sites in different countries and is repeated again in the middle of the study enrollment. If necessary, this still allows time to adjust a part of the process that was not adequately planned. Rather than having an audit after database closure, I prefer to invest our resources in early detection of protocol deviations, process malfunction or staff inadequacy, as we have a better chance to correct this early and raise the quality of the data collected. It is important that this oversight is done by an independent party; preferably a company specialized in this kind of work, not a potential competitor of the CRO engaged in the work.