To Alexander Murzin
and Julia Smolina,
List of Abbreviations
AE — Adverse Event
CRA — Clinical Research Associate
CRO — Contract Research Organization
CTMS — Clinical Trial Management System
EDC — Electronic Data Capture
EU — European Union
FDA — Food and Drug Administration
IXRS — Interactive Voice/Web Response System
NA — North America (n)
PM — Project Manager
I am now hearing more and more often that Project Managers in Clinical Trials exist only to calculate the project money. This is not true: Project Managers do a lot of things in clinical trials and their primary role is definitely not to be a “calculator”.
This is why I decided to write this book. It represents a summary of my experience and the most essential knowledge I have gained on this way. I tried to say that Project Management is first of all about its spirit and only to rather a limited degree — about money.
This book is also to share my thoughts about clinical trials and project management. I hope that at least some of them will resonate with yours.
I have tried to make the book an easy reading to the extent that is possible for this topic and not to bore you with overcomplicated schemes and diagrams. You will find only several simple tables added for the sake of illustration in the part devoted to goal setting.
Philosophy of project management in clinical trials
The axiom I use in my professional day-to-day life is that all principles of project management do apply to project management in clinical trials. No exceptions.
Eventually every organization, even if it originally proceeded on the assumption that the usual, general project management has nothing to do with project management in clinical trials, turns to the ABCs of project management…
But despite the fact that from the process point of view everything that has been created for project management in general applies to project management in clinical trials in particular, there is a huge gap between the two indeed. This gap is rather philosophical than anything else.
Let’s have a look at the definition of a project: “Project — a temporary endeavor undertaken to create a unique product, services, or result.” (PMBOK Guide, 5th edition, PMI, 2013). A positive, tangible, and lasting for some period of time result is meant in this definition. But a negative result is quite an acceptable result of a project in clinical trials and, what is more, it has a positive overall impact unlike a negative result of a project elsewhere.
Imagine a project of constructing a bridge or building a space shuttle fails. What does that mean? Usually a disaster!
But what if we have a look at an unsuccessful attempt to create a vaccine against a cancer, an antibiotic for an infectious disease treatment, or exon-skipping therapy for a rare genetic disorder treatment? They are very straightforward in telling the entire scientific society: “Do not go this way. We have been here and have been unsuccessful. Try another, your own way.”
Each failed study is a step to development of effective and safe treatment of a disease or condition. For example, immunotherapy of cancer had been unsuccessful for decades until we got nivolumab and pembrolizumab. But these two look more like a miracle rather than a usual treatment now: millions of thanks to those who consecutively failed but never gave up.
So if everything was done correctly and a clinical trial failure is supported by data of a high quality, that is fine. What is more, it is beneficial for the industry as a whole. The problem is that it is not always interpreted this way. And to explain why we need to consider two types of sponsors in clinical trials. I call them high-stake and low-stake ones.
A typical representative of a high-stake sponsor is a small biotech company. Basically all they have is a molecule, which is a drug candidate. Just candidate — they have nothing to sell on the market yet. Consecutively, they do not have their own money: they are constantly trying to find investors. To attract money this way they promise that some milestones — first regulatory approval of the study, first patient in, last patient in, database lock — will be met on time. And that is one of the first things for a CRO PM to learn about their high-stake sponsor — what their internal milestones are.
In addition to shortage of money high-stake sponsors normally have shortage of everything else — human resources, experience, processes and procedures, IT infrastructure… The US Food and Drug Administration even has a special program to support such sponsors — small businesses, as they call them.
And please add a high turnover rate to all these factors. As a result, such companies do not have what I call corporate memory. In the middle of a trial they do not know what key decisions have been made by them themselves or their predecessors and are very often prone to challenge them, which is not always a good idea in an ongoing trial.
They are constantly overloaded and distracted. It is hard for them to observe timelines for study-related documents like plans, budgets, and so on. One of the most frequent requests you can hear from them begins with the words “Could you please re-send?..” — an e-mail, a document, and so on.
To realize the real pressure they are under and to respect these people and what they do are real keys to building successful working relationship with them for a CRO manager rather than to discuss kids and pets as normally recommended by books devoted to business communication…
And since the stake is that high and pressure is incredible for such sponsors, negative trial results may drive a strong emotional reaction in such a sponsor, which is absolutely understandable.
There was a phase III oncology study for a high-stake client where Progression Free Survival was the primary endpoint. That double-blind trial comprised two groups — the control group was administered the standard of care regimen, and the main group — standard of care regimen plus the novel agent. After the database lock and statistical analysis it turned out that there was no difference in Progression Free Survival between the two groups. Literally, their curves simply coincided.
It was a kind of shock for the sponsor, although, to be honest, 85% of all phase III trials fail, and it is not secret to anyone. Such general information does not help much in a concrete situation. The CRO was suspected of enrolling not right patients. It was a bit weird accusation, because each and every subject on the study had been approved by the sponsor Chief Medical Officer. In the end the sponsor requested to exclude some patients from analysis. Those subjects were not treated heavily enough before inclusion into the trial according to the sponsor’s idea.
After several rounds of discussion those “not treated heavily enough prior to study patients” were excluded from analysis. It resulted in one interesting thing. The curves continued coinciding in exactly the same way. If the drug works, it works. If it does not, it does not, and nothing can be done about it.
The other type of sponsor is low-stake ones. A typical representative is a pharmaceutical giant. They also have a lot of internal pressure: milestones, financial reports, and so on. It is also important to understand from the very beginning what your counterpart’s pain is. But the key differences are they already have registered product (s) to sell and to have money from and each molecule they develop is normally not the only one. They do have a pipeline. And if a given molecule fails in a given indication, it is painful, but it is not a tragedy.
I have an example of rather a small, high-stake sponsor that was purchased by a big pharmaceutical company on the verge of database lock for one of the products that was developed in oncology. The primary endpoint was Progression Free Survival as well. Upon the database lock it turned out that the graphs for the main and control groups do coincide.
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 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 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.
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 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.
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.
“Who fails to plan, plans to fail.” It is impossible to overemphasize the importance of planning in project management in general and in clinical trial project management in particular.
What normally prevents people from planning is lack of time. Planning insufficiency leads to further lack of time. The vicious circle is created.
So it is vital to put aside e-mail, switch off the phone, seat with stakeholders and start planning. Those who will fulfill the plan should be involved in planning. It is not only a matter of respect, but also a matter of validation of assumptions and engagement — people prefer to realize plans that were created with their participation.
There are a lot of excellent tools for scheduling including MS Project and many others with detailed guidance on how to use them, so let’s not waste time on this topic.
I recollect my conversation with a professional leading start-up activities in a country. His boss promised to the client without prior consultation with him that a submission will be performed in a much shorter period of time than it could be done at all. As a result the promise was not kept and the start-up lead was somewhat demotivated. But what is more important, he did not even try to shorten the timelines for this submission because of his disengagement.
But even if a plan in a clinical trial is written, it is only used as a collection of rules and norms in the vast majority of cases. It does not serve its main purpose — setting goals.
Let’s take the essential part of an enrollment plan for a mock study as an example (as per scenario, the very last sites are activated in February and March):
What is so good about this enrollment plan? The numbers differ from month to month. If your tool shows the same enrollment in August as in April (given one and the same number of active sites), there is something wrong about it. The list of reasons for different intensity of enrollment includes but is not limited to:
1. Seasonality of the disease: it is easier to enroll patients with community acquired pneumonia during winter period, with the flue — during epidemics of this disease (February-March normally) and so on.
2. Holiday seasons:
— Christmas and New Year — end of December — very beginning of January in the vast majority of countries, beginning of January (about 10 days in a row) in some countries (Russia, Ukraine);
— Periods of long national holidays like at the beginning of May in Russia, Ukraine, and Bulgaria;
— High holiday season (July and August) in Europe.
3. Site tiredness: centers that enroll for more than a year tend to become tired of a study and loose or shift their focus. At the same time, opposite examples are also possible, when while enrolling sites become more trained, proficient in a study and enroll better and better month by month with no signs of tiredness.
But we need to return to our enrollment plan itself. We might have a good plan, created lege artis, with involvement of all stakeholders, using the latest predictive technologies, but not working. Where is the disconnect?
The problem is that a plan does not translate into concrete goals for country teams. To do so we need to take our projections for the next month, for February, for example: