Is FPI the most counterproductive milestone in Clinical Research?

Approximately two and a half decades ago when I was first exposed to, and began working in the clinical research world, I was fortunate enough to begin working on a study that was already underway and churning along, primarily focused on finishing and analyzing the relevant data needed for submission. It was a large, pivotal phase 3 program and despite the importance of the project and compound to the company, I don’t recall experiencing any undue stress or urgency in the work. Shortly thereafter, I started on a new phase 2 study that was in the planning stage which unveiled to me, perhaps unfortunately, the lauded “First Patient In” (FPI) milestone and all the associated baggage that came along with it.

It was not a particularly pleasant revelation, but I was too young in my career and na?ve in my knowledge base, to question the importance of the target, and so I joined the ranks of the frantic to move heaven and earth to ensure that milestone was met. As I progressed through my career jumping from CRO, to Sponsor, to management consulting, this same urgency and importance around FPI followed without regard to organization, vendor, sponsor, therapeutic focus or time. And despite many industry speeches and opinion articles to the contrary, the same reverence around this milestone persists and is pervasive to this very day. So, I thought it might be helpful to re-open pandora’s box and pose a simple question, why? Why is so much weight placed on this milestone and what impact does it have on the people tasked with meeting a date assigned to it? And while we are being inquisitive, we might as well ask the follow-on question, Is it worth it?

However, before addressing these questions, and unpacking the operational importance and emotional impact of FPI, it may be beneficial to explore the origin and metamorphosis of the milestone itself. 

From whence we began

FPI starts off innocently enough as a seed of an idea that is placed on a Gannt chart or project plan months, or even years in advance of when it will actually occur. It is often defined by people who will inevitably have very little direct impact on, or responsibility for, meeting that date (beyond tracking to it). It is planned long before protocols are written, vendors identified, equipment purchased and logistics considered. A lay person may look at this date and innocently proclaim “This date looks like a prospective plan to me”. Except it’s not, is it? Once that date is set, it carries with it some invisible weight and gravitas imparted by no one in particular but inexplicably respected and revered by all. So, the date is set and the work begins to meet it. At first everyone is excited and collegial, with the terms like “partner”, “collaboration” and “synergy” being invoked as amicable discussions and numerous meetings ensue where team members deliberate the development of the various components that make up a clinical trial. 

Alas, there is one key problem, and it is not in the milestone itself, but rather the generally accepted principle that FPI is a solid terminus and thus immovable without severe consequence. With a solid terminus, woe be to those whose responsibilities lie towards the end of that terminus and whose work is dependent on those who precede them earlier in the timeline. The story is one we know all too well. The earlier work stretches out for any number of valid reasons; discussion, indecision, new analyses, new assessments, KPI feedback, regulatory feedback etc. And as the activities earlier in the timeline extend out beyond their original schedule there is no accepted consequence resulting from this comportment on the date for FPI. Instead, expectations just shift onto the people and activities downstream whose allotment of time to perform their work is continuously condensed like a compactor piston slowly pushing towards the wall, yielding the same end result: “enormous pressure”.

Enormous pressure leads to anxiety. Anxiety leads to frantic acts. Frantic acts lead to strained relationships, lapses in judgement, mistakes and poor morale. That term “partner” that was used earlier on in the project in now muttered with a note of disdain and resentment. Culpability is tossed around and pointed in all directions replete with flurries of e-mails sent copying the world and emergency contentious meetings scheduled to strongly re-convey that the FPI date is at risk, cannot be missed, and future relationships and business hinge on meeting this milestone.

And so, after all of this damage and strain has seeped into the veins of various groups and organizations, we approach the earlier question of “why”. But, before addressing “why”, perhaps the more appropriate question to ask first is “So what?” So what if we have to shift the FPI date to accommodate tasks that took longer than we planned for 1 year ago? So what if we need to shift a few weeks to make sure that all parties have enough time to deliver their work at a level of quality that the study deserves?  

Arriving at Why?

The question of “So what” appropriately leads into elucidations of why.  So, why is FPI so important? Well, let’s explore some of the common arguments we hear as well as those that are well known, but unspoken:

Common arguments:

1)    “We have announced to Wall Street that we will be starting the study and our stock price depends on it” (applicable only to publicly traded companies, by the way):  I know a few analysts on Wall Street and get access to daily analyses from many more and I have yet to see any analyst recommend a sell or hold option based on one trial not getting to FPI on the exact date they said they would. Analysts, like ourselves, care more about where you end than where you begin, and consequently stock price is impacted by, data, potential for success and market dynamics, not a few weeks delay in starting a trial. Next time you see a press release announcing the start of a trial, read the forward looking statement at the end to get a sense of why analysts might shy away from basing their forecast on the attainment of this milestone.

2)    “We are in competition with XXX company and need to be first to market”: Ok, that is a very valid argument for finishing your trial on time, and to finish one needs to start. But, when I was consulting, we used to ask our clients to run a metric on how long it took them to get from FPI to 15th patient enrolled. And then again how long it took them to enroll 50% of the target. More often than not, the timeframe from FPI to either of those other targets was excessively long, highlighting the false imperative of rushing to get the first subject in. There are a number of factors and variables that contribute to getting to database lock and topline results, and yet none seem to garner nearly as much importance and focus as FPI. Perhaps they should.

3)    “We will lose potential patients and excitement about participating in the trial if we don’t start on time”: People participate in clinical trials because they need or want to, not because their neighbor down the road is doing it, or because there was a press release that went out a few weeks ago. We can always do another press release, or ad campaign, but if those methodologies are so effective, then how come they don’t work as well when we are in the middle of recruitment?

The unspoken reasons: Actually, there is only one!

1)    “Our bonuses are tied to this milestone”. And there it is. No one says it, but everyone knows it, and financial incentive is a very strong motivator in both a positive and negative sense.

Rocketing towards inevitability

Eventually at some point in the timeline, perhaps after being delayed, we enroll our first subject and what is the outcome? There is a perfunctory celebration which may last a few hours or even a day, but the wounds of the endeavor are deep and persist for much longer. Which begs the question “Was it worth it”?

The answer I will leave up to you to determine. Yes, putting a date and target on something and labeling it as critical helps us overcome our predisposition to procrastinate, and the avoidance of procrastination is a good discipline to instill. However, if procrastination is the problem, perhaps there is a better way of addressing the underlying behavior that leads to it rather than resorting to the same suboptimal methods employed for years.   When the scales are brought forth, did meeting a specific date outbalance, or even balance out against, all the stress, pain, anxiety, damaged relationships that resulted? 

Consequence is inconvenient

Meeting an FPI milestone has not resulted in recruiting patients in meaningful numbers any faster and is certainly not a barometer on stock price. After decades of this practice perhaps it is time to change our strategy and avoid tying FPI to people’s bonuses and instead focus on merit and effort as benchmarks for monetary reward. Yes, Biopharma and med device companies are different from other industries especially given the strict regulatory environment in which they operate, but they are not that different to where the notion of consequence should be discarded. I like to draw analogies between the construction and clinical trials as operationally they are very similar.  Both industries are focused on building something tangible, involve multiple parties and stakeholders and demand significant effort and cost. So, let’s explore the analogy and substitute “move in date” for to “FPI”.

A construction project begins with an idea that is translated into a plan developed by architects, months or even years in advance. Permits are secured to allow construction to begin.  Contractors secure materials and sub-contractors are hired to complete various portions of the job, with each job having a reasonable allotment of time to ensure that the job is done safely, correctly, to code, and with a high level of quality.

·      If the plumber takes a few extra days than was planned we don’t shorten the allotment for the electrician to make up for the plumber’s delay.

·      If the drywall takes a few extra days to get up, we don’t tell the painter he has to get his job done in half the time.

·      If the client changes their mind and wants to add a second story or even just another bathroom, their house will not be ready at the original planned date and certainly not at the same cost.

This direct relationship between cause and effect is universally ingrained in almost all business and industry. Why, when it comes to something as important as healthcare and the development of treatments and cures, do we turn a blind eye and ignore this relationship in favor of chasing an arbitrary date. It is a practice that seems to do far more harm than good.

Last minute heroics are no substitute for poor planning and indecision, just ask the people on the ground who are forced to meet these dates to give you an honest answer, and see what they say.

“Rushing never saved the time that planning did.”

                                                               Ben Parris