From Delays to Amendments: The High Cost of Getting Clinical Trial Protocol Design Wrong
Clinical trial success hinges on a strong foundation, and that foundation is protocol design. It’s the blueprint that guides everything from study startup and patient enrollment to data collection and final analysis.
But what happens when that blueprint for conducting the trial — one that details the methodology, objectives, and ethical considerations — needs to be redrawn mid-build?
The answer is simple: costs go up, timelines slip, and recruitment stalls. And in some cases, promising therapies are delayed or derailed altogether.
While some clinical trial protocol design amendments are necessary, a growing body of evidence suggests that many are avoidable. Amid tighter budgets and rising operational complexity, sponsors and CROs can’t afford to miss the mark and incur these added costs.
The Direct Costs of Clinical Trial Protocol Amendments
A study from the Tufts Center for the Study of Drug Development (CSDD) put real numbers to a long-understood problem. According to their analysis, the median direct cost to implement a substantial amendment was $141,000 for a Phase II protocol. That figure ballooned to $535,000 for a Phase III protocol.
These figures account for protocol re-writes, re-submissions to regulatory bodies and institutional review boards (IRBs), re-consent of patients, updated training for study teams, and delays to clinical operations.
For multi-site, multi-country clinical studies, that number climbs even higher.
When sponsors or CROs realize that an eligibility criterion is too narrow or that procedures are too burdensome, they may find themselves back at the drawing board — and under pressure to do it fast.
The Indirect Costs To Account for in Trial Amendments
While the direct financial impact is steep, the indirect costs of protocol amendments carry their own weight:
- Delays in First Patient In (FPI): Each amendment can push FPI back by weeks or even months, particularly when site activation has already begun.
- Enrollment Bottlenecks: Protocols that are misaligned with real-world patient populations, whether due to overly strict inclusion/exclusion criteria or excessive visit schedules, struggle to hit enrollment targets. Each week lost to low accrual is a week lost in the market.
- Patient Retention Risks: Complex or rigid protocols can discourage patients from staying enrolled. If mid-study changes are required to address dropout trends, it’s often too late to recover the full cohort.
- Staff Burden: Re-training, re-consenting, and re-engaging patients takes a toll on already stretched site staff. These disruptions can also erode goodwill between sponsors and clinical research teams.
- Reputational Impact: A clinical trial perceived as poorly designed or difficult to execute can strain sponsor-site relationships and make future collaborations more difficult.
As Research Protocols Grow More Complex, Amendments Are on the Rise
Between 2015 and 2023, the average number of amendments per protocol increased by nearly 60%, according to additional findings from Tufts CSDD.
That rise parallels another trend: protocol complexity. Modern protocols often include:
- More endpoints
- Greater use of digital tools and data capture systems
- More frequent assessments
- Narrower eligibility criteria
- Global site footprints
These design choices often serve a purpose, from improving scientific rigor to regulatory alignment. But they can also introduce friction that isn’t apparent until a clinical trial protocol moves from paper to practice.
Not all protocol amendments are bad, of course. A new safety signal may require added screening procedures. A faster-than-expected enrollment curve may justify expanded eligibility. Shifting regulatory guidance may necessitate procedural adjustments.
But as one industry leader put it, the biggest culprit for protocol amendments is that “protocols are not optimized from the start to account for unseen realities.”
Realistic Examples of Clinical Trial Design Pitfalls
These examples show how subtle missteps can snowball into costly amendments:
Over-Restrictive Criteria in a Cardiovascular Study
A Phase II heart failure study excludes patients with mild diabetes and chronic kidney disease — two common comorbidities in the target population. Sites find that the majority of real-world patients don’t qualify, and enrollment stalls. An amendment later expands inclusion, but several weeks of recruitment momentum are lost.
Vaccine Protocol Misses Seasonal Timing
A respiratory vaccine study targeting older adults launches in late spring — after flu season has peaked and RSV activity has dropped. Sites struggle to find interested and unvaccinated patients, and enrollment lags behind projections. A revised protocol adjusts the seasonal screening window, but the trial loses critical calendar time.
Technology Overload in an Immunology Trial
An autoimmune disease study requires patients to use a connected device, log daily symptoms in an app, and complete weekly surveys. Participants quickly become overwhelmed by the digital workload. The app does not send reminders/notifications, and the patients miss entering critical data. Sites report frequent data gaps and rising dropout rates. The sponsor streamlines reporting requirements, but not before patient engagement is compromised.
High Patient Burden in a Dermatology Study
A vitiligo trial requires patients to attend bi-weekly visits for imaging and biopsies, with no travel support offered. Many potential participants live over an hour away or have daytime work conflicts and, as a result, retention drops early. The protocol is amended to include home visits and travel stipends, but several high-quality candidates have already withdrawn.
How a Site Can Support Clinical Trial Protocol Design
Many of these costly amendments can be avoided with early, site-informed protocol input.
At Remington-Davis, we’ve supported 630+ trials across therapeutic areas, from dermatology and immunology to metabolic and respiratory disease. And in that time, we’ve seen firsthand how early engagement with experienced sites can help sponsors build better protocols from the start.
Before a study launches, our experienced team, including board-certified physicians and seasoned research staff, reviews the protocol through the lens of practical execution. We raise flags on overly narrow criteria, burdensome procedures, or unrealistic timelines.
We assess whether the study design is appropriately chosen based on the research objectives and hypothesis, an often-overlooked driver of protocol performance. We ensure protocols clearly define interventions being tested, including dosage and administration routes, and provide well-described methods for monitoring participant safety and reporting adverse events. And, we advocate for protocols written in clear and concise language to avoid misinterpretation by sites, patients, and IRBs.
With a 97% patient retention rate, we know how to keep participants engaged. We can advise on visit schedules, transportation challenges, and real-world accessibility to avoid unnecessary hurdles.
Think of us as not just a site, but a strategic partner. We work closely with CROs and sponsors in the planning phase to ensure your protocol works scientifically and operationally as well. Our consultative approach helps reduce trial friction before it begins.
We know the cost of getting clinical trial protocol design wrong is high. That’s why we make it a point to help you get it right from the start.
When you’re ready to connect for your next clinical trial, we’re here.
Frequently Asked Questions
How does a protocol amendment impact the trial’s statistical analysis plan?
Protocol amendments, especially those that alter endpoints, enrollment criteria, or visit schedules, may require updates to the statistical analysis plan. Even seemingly minor changes can affect power calculations or introduce bias if not handled carefully. Collaborating with a site early on can help reduce the number of changes that impact data integrity downstream.
Can protocol design influence patient safety beyond the obvious?
Yes, protocols that are overly burdensome or poorly aligned with patient realities can introduce safety risks. For example, if visit windows are too tight or procedures are overly complex, patients may miss assessments or stop reporting adverse events. Patient safety starts with feasibility: if patients can’t reasonably comply, safety oversight is compromised.
How does informed consent affect protocol design optimization?
Complex protocols often lead to complex consent forms, which can overwhelm patients and increase the risk of dropout or non-compliance. When a site is involved in the early stages of design, they can help ensure that consent documents are not only compliant, but understandable and manageable for the average participant. Clear communication supports both ethics and enrollment.
How do changes to primary or secondary objectives affect regulatory approval?
Substantial changes to primary objectives or even how they’re measured can trigger protocol amendments that require re-approval from IRBs and regulatory agencies. This delays the study, and also affects how results are interpreted and influences whether the trial is deemed successful. Aligning your study objectives with feasible execution reduces the likelihood of major rework.
Do adaptive clinical trials reduce the risk of protocol amendments?
Yes, when done well. Adaptive designs in clinical trials build flexibility into the protocol from the start, reducing the likelihood of unplanned amendments. However, Quality by Design (QbD) principles should still guide protocol development to guarantee consistency and feasibility across sites.