How to Cut the Negative Impact of Protocol Amendments

Social distancing laws in response to the COVID-19 pandemic forced dramatic changes to procedures for the collection, monitoring, review and analysis of clinical data in trials. Regulators have responded with an appropriate degree of flexibility but some CROs initially struggled to manage the impact on clinical trials.

How Protocol Amendments Can Impact Clinical Research

The onset of social distancing guidelines amidst the COVID-19 pandemic prompted significant upheavals in the procedures governing the collection, monitoring, review, and analysis of clinical trial data. While regulators have displayed flexibility in response, many Contract Research Organizations (CROs) initially grappled with managing the resulting disruptions in clinical trials.

What is a protocol amendment in clinical research?

Protocol amendments are more common in clinical trials than you might think. A 2017 article by the Tufts Center for the Study of Drug Development (CSDD) found 59% of clinical trials have at least one protocol amendment (PA). The Phase II studies reviewed in the Tufts research had on average 2.7 amendments per protocol while the rate was higher for Phase III studies at 3.6 amendments per protocol. Our experience is that 79% of clinical trials have at least one protocol amendment.

Why should this matter? Protocol amendments have a major impact on CRF design, which typically lead to delays and system downtime for CRF updates, and ultimately increased costs for sponsors. It’s important also to highlight the frustration experienced at sites due to their inability to enter data during system downtime, which leads to backlogs in data entry.

Protocol amendments surveyed by the Tufts research cost on average $141,000 each for Phase II trials, while Phase III PAs were $535,000 per amendment. More significantly, the opportunity cost from delayed trials are far higher. Studies with protocol amendments take on average 6 months longer from protocol approval to last patient first visit than others. Furthermore, they were 90 days longer from last patient last visit to database lock, according to the Tufts research.

Implications of Protocol Amendments

The impact of protocol amendments extends beyond mere procedural adjustments.

CRF Design Updates: They can have a major impact on CRF design, which typically leads to delays and ultimately increased costs for sponsors. It’s also important to highlight the frustration experienced at sites due to their inability to enter data during system downtime, which leads to backlogs in data entry.

Financial Implications: They can also be costly for trials. The Tufts research paper revealed that protocol amendments cost on average $141,000 each for Phase II trials. Phase III PAs were much higher at $535,000 per amendment. This cost is without including any financial problems caused by delayed trials.

Time Delays: Studies with protocol amendments take on average 6 months longer from protocol approval to last patient first visit than others. Furthermore, they were 90 days longer from last patient last visit to database lock, according to the Tufts research.

How to reduce the impact of protocol amendments

Whilst some protocol amendments can be avoided, the majority are required in response to external, unforeseeable changes such as new safety information. Working with a CRO proficient in minimising the impact of protocol amendments on trial timelines is crucial. Aixial specialises in leveraging technology and expertise to optimise efficiency, offering flexible processes, protocol development services, meticulous database design, and a highly experienced data team to navigate protocol amendments effectively.

When planning a clinical trial, it’s common for sponsors to overlook or underestimate the possibility of protocol amendments. The COVID-19 outbreak has highlighted some of the rigidness many industry clinical trial protocols implement, but we have remained focused on being agile and flexible to minimise the impact of protocol amendments on your trial.

Aixial Group’s commitment to flexibility and efficiency in Clinical Research

We are a CRO that specializes in leveraging technology and experience to optimize efficiency, particularly by being more agile and flexible than other CROs in multiple ways:

We have flexible processes that can adapt to change easily. Many of our clients come to us with bad experiences of working with large CROs with rigid procedures embedded into their large internal structures.
We offer protocol development services, using our expertise to set the original protocol with the most flexibility while maintaining safety standards and a focus on delivering the right endpoints for your study.
We plan database design carefully at the outset of your trial. This takes specialist skill but enables changes to be made mid-study much more easily.
Our 140-strong data teams are highly experienced. There is practically no challenge that we haven’t come across previously or that we can’t handle.

Our average experience:

Lead Data Managers: 12+ years
Biostatisticians: 15+ years
Senior Statistical Programmers: 10+ years

We communicate and work in partnership with sponsors and sites to solve problems through teamworking. That’s why our 2019 client survey rated us as 4.7/5 for communication 2019 client survey results
We maintain the team, we don’t swap and change. We stay familiar with the study so we can respond more quickly to unexpected changes. The team you meet before you work with us is the same team you work with after your project commences.

When planning a clinical trial, it’s common for sponsors to overlook or underestimate the possibility of protocol amendments. The COVID-19 outbreak has shown the inflexibilities of much of the clinical trials industry, but we have remained focused on being agile and flexible to minimise the impact of protocol amendments on your trial. This includes key steps in planning and developing the protocol from the onset, such as:

Therapeutic and functional review and input.
Early feasibility assessments to obtain critical feedback from investigators and site personnel on the patient population, eligibility, and overall design versus SOC.
Early Regulatory Affairs (RA) involvement for a proactive review and feedback to streamline the approval process and mitigate potential regulatory hurdles.
Flexible protocol language that allows for an adaptive design based on emerging data from the study.