Why Founders Underestimate Protocol Design

One of the first questions I ask founders has nothing to do with their technology.

It isn’t about sensitivity, specificity, engineering, AI, or clinical performance.

I ask a much simpler question: “Who designed your protocol?”

When the answer is, “We did,” they’re usually expecting that to be the right answer.

Instead, I start asking a very different set of questions. Who is this study supposed to convince? What commercial decision will it change? What evidence are you collecting today that de-risks your next study?

That’s usually when the conversation changes.

Not because the founders aren’t smart. Most are incredibly smart. They’ve built innovative technologies, navigated FDA requirements, raised capital, recruited advisory boards, and convinced investors to believe in an idea that didn’t exist a few years earlier.

This has nothing to do with intelligence. The problem is that protocol design isn’t just a scientific exercise. It’s a business decision with long-term consequences, and most companies don’t recognize that until the study is already underway.

The Most Expensive Document in Your Company

Founders often assume they’re creating a research document. In reality, they’re making decisions that will shape reimbursement, market access, provider adoption, future financing, publication strategy, commercialization timelines, and sometimes whether the company ever gets another opportunity to generate evidence.

I hear people say all the time that a poorly designed study might require another million-dollar trial later. Sometimes that’s true. But here’s what I see more often: many startups never get the chance to spend another million dollars.

If the first evidence-generation program fails to answer the questions that matter most to payers, providers, investors, or health systems, the company may never reach the next funding milestone. That’s why I find myself saying some version of this almost every week: Before you spend the money, make sure it’s the right study.

Where Founders Usually Go Wrong

If I’m being candid, the mistake usually isn’t about saving money or maintaining control. It’s confidence.

Founders are problem solvers. They assume protocol development is another problem they can solve internally. So they copy protocols from published literature. They ask respected KOLs to draft the study. They rely on an academic medical center. They ask Regulatory or Medical Affairs to lead the effort.

On the surface, all of those approaches sound reasonable. And every one of those groups brings valuable expertise.

The problem is that each is looking through a different lens.

Academic investigators naturally optimize for scientific rigor and publication. Regulatory teams optimize for regulatory requirements. Medical Affairs teams think about clinical credibility. None of those perspectives are wrong. They’re simply incomplete.

Very few people in those conversations are asking:

Will this evidence change payer behavior?

Does the comparator reflect how care is actually delivered?

Are we collecting information that supports adoption?

Are we embedding data that de-risks the next evidence-generation investment?

Will this study help us move from FDA clearance to reimbursement?

That’s where evidence strategies begin to drift.

Version 10 Wasn’t the Problem

I reviewed a protocol recently that was already on Version 10. Everyone involved believed they were making it better. They weren’t. They were polishing the same fundamental mistake.

The company already had 510(k) clearance. Yet they were preparing to invest in another study focused almost entirely on clinical validity and comparative performance. There were virtually no market access endpoints. No meaningful assessment of workflow and implementation barriers. No payer-relevant evidence. Nothing designed to strengthen future reimbursement discussions.

The protocol wasn’t poorly written. It simply answered the wrong question.

Nobody had stepped back and asked whether the study was designed to support the company’s next commercial milestone. That happens more often than most founders realize.

Clinical Success Does Not Automatically Become Commercial Success

This is one of the biggest misconceptions I encounter. If a technology performs well clinically, many founders assume adoption will follow naturally.

Healthcare doesn’t work that way.

Providers ask different questions than regulators. Payers ask different questions than providers. Hospital value analysis committees ask different questions than either. Investors care about something different again.

Nothing happens in a vacuum. An endpoint influences the reimbursement story. A comparator influences payer confidence. A data source influences credibility. A workflow assessment influences adoption. A treatment burden measure influences implementation.

Every protocol decision has downstream consequences. If those decisions are made without considering commercialization, the study may still be scientifically successful while falling short where the company needs it most.

Every Study Should Do Two Jobs

This is one of the biggest mindset shifts founders can make.

Most teams think about the study immediately in front of them. That’s understandable. But every prospective study should accomplish two things. First, it should answer today’s question. Second, it should reduce uncertainty around tomorrow’s investment.

That might mean collecting healthcare resource utilization data before building an economic model. It might mean including patient-reported outcomes that become valuable in future payer discussions. It might mean evaluating workflow or implementation barriers that help shape the next pivotal study. Or it may simply mean learning enough about recruitment, adherence, site performance, or real-world variability to avoid making expensive assumptions later.

Those data are often inexpensive to collect while a study is already underway. They become extraordinarily expensive once the opportunity has passed. This is where companies unknowingly leave value on the table.

What Most Founders Don’t Realize

One of the most rewarding parts of my job is watching the moment when a leadership team realizes evidence generation is much broader than protocol writing.

Recently, after one of these discussions, a CEO said something that stuck with me:

“When you say you’re a strategic CRO, I finally understand what that means.”

That wasn’t because we suggested a different CRF or a different statistical test. It was because we reframed the entire purpose of the study. We started talking about commercialization. Reimbursement. Future studies. Investor milestones. Evidence sequencing. Risk reduction.

The protocol became part of a much bigger strategy.

Most founders are genuinely surprised by how many decisions are being made before the first patient is ever enrolled. Not because they lack expertise, but because nobody has shown them how those decisions ripple through commercialization years later.

Why This Matters Now

Today’s medtech companies are under enormous pressure. Funding environments are tighter. Investors expect efficient capital deployment. Payers continue demanding stronger evidence. Health systems scrutinize adoption decisions more carefully than ever.

Every evidence-generation investment has to work harder.

Companies can no longer afford studies that answer only one stakeholder’s questions. Protocols need to generate commercially actionable evidence. They need to support reimbursement. They need to support adoption. They need to create confidence for future investments. Most importantly, they need to reduce, not increase, commercialization risk.

TTi’s Perspective

At TTi, we don’t believe founders should stop being involved in protocol development. Quite the opposite.

Founders bring the vision. Clinical investigators bring scientific expertise. Medical Affairs brings clinical insight. Regulatory brings regulatory perspective. What we add is a commercialization lens that is often missing.

We help companies pressure-test whether the study they’re planning is actually the study they need. Sometimes that means changing endpoints. Sometimes it’s comparator strategy. Sometimes it’s adding pragmatic elements, real-world outcomes, workflow measures, healthcare resource utilization, patient-reported outcomes, or implementation data that strengthen future evidence plans. Sometimes it’s simply asking questions nobody else in the room has asked.

Most protocols aren’t poorly written. They simply answer today’s question while overlooking the decision the company will have to make next.

That distinction can determine whether a promising technology becomes a commercially successful one.

Remember:

Evidence is only valuable if it changes the next decision.

– Dr. April