Exactly What Does a Principal Investigator of a Trial Do?

Exactly What Does a Principal Investigator of a Trial Do?

By Milton Packer, MD

Most observers do not understand what the academic leaders of a clinical trial really do. To many, the steering committee simply takes its marching orders from industry sponsors. Some believe that every trial is designed by the sponsor; the academic leaders rubberstamp it; every analysis is directed by the sponsor; the principal investigator dutifully presents the intended results; the sponsor writes the paper; and the academic leaders sign their names to it.

Conspiracy theorists love this story. It fulfills their wish to envision the world as an evil place that is controlled by those in power and money. To be sure, the world may be an evil place that is controlled by power and money, but the conspiracy theorists will find little to feed their frenzy when it comes to large-scale clinical trials of drug therapy in cardiology. It is possible that the story that I fabricated at the start of this essay happens among the vast numbers of clinical trials that are carried out each year. But I just wouldn’t know.

I have led or served on the leadership committee of more than 30 large-scale clinical trials. The trials have been sponsored by both industry and the NIH. The vast majority of these trials yielded results that were a major disappointment to the sponsor, but all of the trials provided critical information that advanced the science of cardiovascular medicine.

The role played by the academic leadership is complicated. We know from the start that we have no financial power. Our ability to design, execute, analyze, and report the results of a clinical trial in a fruitful and unbiased manner stems from seven intriguing features of our involvement.

First, our collective experience over many decades has taught us the paths that are wise as well as those that are foolish. If you assemble 6-10 incredibly experienced and clear-thinking experts in a room, their shared knowledge dwarfs any talents that either the NIH or industry sponsor has in house. Our sponsors know this, and that is why they ask for our help.

Second, every trial poses a substantial reputational risk to the leadership committee. If the trial is poorly designed; if the wrong patients are enrolled; if the data collection is woefully incomplete; if the endpoints are unpersuasive; and if the results are presented in a biased manner, the cardiology community will notice — and it will take us to task for these errors. Reputations are built over decades, but they can be destroyed in minutes.

Third, the academic leadership designs the entire trial and fashions the entire protocol — from start to finish — including the statistical plan and the case record forms. We take this responsibility seriously, and we are uniquely qualified to do this. To be sure, the sponsors are fully engaged; they ask lots of questions, offer many proposals, and make many suggestions; and they may push back on various issues. But it is not in their interest to interfere with our work.

Fourth, the academic leadership knows that the sponsor has a budget that governs the work. But we may not know exactly what that budget is. There is always some financial flexibility on the part of the sponsor. So if we can make a strong argument, we have a good chance of having the idea funded. If our thinking process is weak, the sponsor should rightfully ignore it.

Fifth, the academic leadership forms a partnership with the sponsor. That means that the relationship needs to be effective; it must be respectful; it needs to be a happy and active interchange; and it must be firmly based on principles of integrity and trust. Otherwise, nothing useful gets done.

Sixth, the academic leadership and the sponsor speak with different voices to different audiences. We speak to our colleagues in medicine and to our patients. The sponsors speak to Congress, to their shareholders, to regulatory agencies, and to payers. Because the audiences are different, the messaging is never identical, but it needs to be consistent.

Seventh, in my experience, the executive committee drives every analysis that we show or publish. We develop every word of every presentation or scientific paper — every slide, every figure, and every table. The sponsors have a legal obligation to review our work and ensure that it is accurate. But we are the sole determinant of the data interrogation and interpretation as well as the messaging and the tone. Anyone who has ever worked with me knows that there has never been an exception to this rule.

For the record, I have been (and will continue to be) a very strong and vocal advocate for data sharing. Anyone who wants to check on my work is strongly encouraged to do so. If I have made a mistake, I will acknowledge and fix it.

Worried about conflicts of interest? So am I. My consulting fees are linked directly to the time I spend, and they are limited to my work on drugs or devices for indications that are under development. If anyone thinks that I should work on a 5-year clinical trial for free, they must think that my expertise and efforts are worth nothing. I have no financial interest in the results of any trial; I hold no equity interests; and I do not accept speaking fees for giving a presentation about any product for an approved indication from its manufacturer.

Why does the process work? Why do sponsors agree to these terms? Every trial thrives on a balance of powers. The sponsor controls the funds, but the academic leaders are in control of what we say and what we do.

That is our main negotiating strength. If we are uncomfortable, we can say so — often loudly. And if we are really uncomfortable, we can walk away — and if necessary, we may not do so silently.

Essentially, the trial is governed by a social contract that endures for 5-10 years. Those who know the reputation of the academic leaders of a trial know what they should expect from the trial. We fail only if we do not live up to our own standards. And with every trial we do, those standards become higher.

Nevertheless, the relationship is not always a smooth one.

Have I been asked to accept a poor design for a clinical trial? Yes.

Have I been asked to accept a data collection process that I did not have faith in? Yes.

Has anyone ever suggested that an improper analysis be shown instead of a proper one? Yes.

Have I been offered “help” in writing a manuscript or making a presentation? Yes.

In each of these examples, my answer has always been no. And I deliver that response calmly and firmly in a short one-word answer. My delivery (and personal history) ensures that the person asking the question will not ask it again.

What happens when the sponsor is unhappy with me? Well, that happens all the time. It is part of my job to make the sponsor unhappy. But the relationship is not adversarial. I am not making anyone unhappy because I dislike or distrust them. It is simply because I like the trial (and I respect the patients who contribute to it) much more than I care about the sponsor’s comfort.

Have I ever failed to be persuasive? Have I ever felt the need to walk away from a trial that was being done improperly? The answer is yes. But the sponsor knows that I do not bluff. If the matter is of such importance that the issue becomes a deal-breaker, I let the sponsor know the seriousness of my position. And they need to hear it only once.

When I have felt really uncomfortable, I have removed my name from papers; I have resigned from trial committees; and I have publicly severed ties with sponsors.

So the arrangement is a simple one. When a sponsor asks us to help, they know what to expect. And they also understand what we expect. And let me assure you, there are many academic leaders who embrace the same philosophical and operational principles as I do. If you understood our collective experiences, I am confident that you would be very favorably impressed.

If you doubt what I am saying, it means that you have never seen a first-rate executive committee in action. Those who cast aspersions indiscriminately on all industry-sponsored trials do so out of willful ignorance. And they forget that — like it or not — it is industry (and not the NIH) that is responsible for nearly all new drug and device development. And it is industry that financially supports the pivotal trials that lead to the approval of new treatments in medicine.

So have you wondered what the academic leadership of a trial really does? Now you no longer need to ask.

This article was published by MedPage Today.

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