What did this big pharmaceutical company do? They organized a web cast for investigators, invited the CRO team to it, thanked everyone for their interest, time, and contribution, showed the self-evident curves, and simply stated that the drug had failed in that study. When they realized one web conference was not enough: not everyone interested was able to attend, they organized one more… What is more, they continue treating patients who remained on study after the database lock. That is the difference.
Despite all the importance of negative results of clinical trials there is a bias towards publishing positive ones. To reduce consequences of such a bias, Helsinki declaration now requires publishing negative results of any clinical trial as well as positive ones: “Negative and inconclusive as well as positive results must be published or otherwise made publicly available.” The fact that a negative result of a project is as important as a positive one is the key and unique feature of project management in clinical trials. It constitutes the basis of philosophy of project management in clinical trials and makes every project and every managerial effort meaningful.
Project targets
Project targets include scope, quality, timelines, and cost. Traditionally, it is thought that the client may fix only three out of the four targets maximum. For example, if the client defines scope, quality, and timelines of the project, they may not define its cost – it is to be defined by the CRO. Or, alternatively, if the client says what scope, timelines, and cost they would like to have, they may not dictate what quality should be like.
In clinical trials, in fact, none of the four targets may be really fixed by any of the parties including the client because of the following main reasons:
CROs make assumptions regarding scope better, but there is always room for creepy scope to say nothing about big scope changes at the sponsor’s request;
– Ideal quality is constantly tried to be achieved;
– Timelines are very much dependent on people and organizations including sites, Competent Authorities, Ethics Committees, and so on;
– Only CRO can define the cost.
Scope
Scope means the volume of work to be performed to complete the project successfully and associated effort. It depends on many variables including but not limited to:
1. Therapeutic area and indication;
2. The number and list of countries;
3. The number and list of sites;
4. The number of patients to be enrolled;
5. Screen failure rate;
6. Full service versus clinical part only;
7. The number of vendors.
Normally these macroparameters are defined by the sponsor, but the problem is that originally they are not always defined correctly, especially in conjunction with timelines and quality (cost is defined by the CRO). Often the CRO has more experience in the given therapeutic area and indication and is able to assess better, for example, the number of sites necessary to complete patient enrollment on time. The CRO Project Manager’s capability to challenge the sponsor’s assumptions wherever needed is a trait of professionalism: the Project Manager is not supposed to be a “say-yes-to-all” person. Of course, different specialists and subject matter experts help the Project Manager in defining the project scope and challenging the client’s assumptions – clinical trials are a team game.
Quality
Perfectionism is a feature of our industry. Although absolute quality in all aspects of a clinical trial is never achievable, we continue spending a lot of time and resources to reach it. I think the new edition of GCP, ICH E6(R2), devoted to risk-based quality management should help to overcome this pathological feature to a significant degree.
In addition to this, from the managerial standpoint we should rather think about the level of quality requested by the client than about ideal quality (which, by default, requires unlimited resources and time, which we never have).
Timelines
Timelines have major impact on cost, because there are a lot of parameters directly dependent on time. At the same time, normally timeline decrease or increase does not lead to proportionate decrease or increase in cost.
For example, if timelines are shortened by two times due to treatment and follow-up duration decrease, which is typical of premature study completion due to the lack of efficacy and/or safety concerns, the cost will not become twice smaller. The reason for this is that set-up and closure, which are much more labor intensive and costly, remain intact and they are more important cost-drivers for the study as a whole than treatment and follow-up.
Cost
The cost of a project in clinical trials if outsourced to a CRO is defined solely by the latter. Different methods are used by different CROs for that, but the idea is one and the same: to express the volume of work in discrete units, for which price is known. After this is done, it is just a matter of multiplying the number of units by their cost.
In reality the sponsor very often chooses the CRO that offers the lowest cost, which is a very questionable approach due to the following reasons:
1. Some CROs tend to underbudget to have a competitive advantage, which leads to a drastic cost increase throughout the course of the trial.
2. The cost is only one project target – there are three more as we have discussed and all of them are interrelated. So if a lower cost CRO is selected, there is a higher probability that quality will be lower and timelines will not be observed…
The cost is paid to the CRO based on the sponsor-CRO contract. There are the following main types of contracts:
1. Fixed price contract, which is also usually milestone-driven. The cost of a study is fixed upon agreement at the beginning of the study and may be subject to change only if there is a real change in scope – additional countries and sites, increased number of patients, unplanned protocol amendments, and so on. The CRO is paid upon achieving milestones, which may be site activation driven (first site activated, 50% of sites activated, last site activated, etc.), patient recruitment driven (first patient in, 50% of patients enrolled, last patient in, etc.), subject visits driven, data driven (last page verified, database locked, etc.) Fixed price contracts are a bit tricky though. Whether the CRO spends less or more effort on the study, the contract is not recalculated. The point is that the second situation (the CRO spends more) is easily tolerated by the vast majority of sponsors, but the first one (the CRO spends less) is harder to accept psychologically, and the sponsor may ask to recalculate the budget. Whether to do it or not is the CRO’s decision.
2. Unit-based (unitized contract) – the whole budget is divided into units. Once a unit is completed, the CRO is paid for it. An example of a unit may be one monitoring visit or, say, 10 monitoring visits performed.
3. Time and material type of contracts came from construction. In this case CRO is paid simply based on the effort spent according to timesheets.
4. Mixed contracts. For example, the contract may be fixed price milestone-driven with some units – usually monitoring visits or site audits – introduced.
Building blocks of project management in clinical trials
Building blocks of project management in clinical trials are no different from those in any other area. They are planning, organizing, motivating, and controlling.
Planning
“Who fails to plan, plans to fail.” It is impossible to overemphasize