By Angus Henderson

Biotech sponsors operate in an outsourced model, relying heavily on CROs and other vendors to execute clinical trials. Theoretically, this setup allows small, resource-constrained teams to focus on strategy while service providers handle the operational heavy lifting. But it’s rarely that simple.

Startup biotechs are like the Millennium Falcon: agile, fast, capable of incredible things, but held together by the sheer force of will of its crew of heroic rebels; they move quickly and stay lean, but they’re also responsible for keeping every part of the ship running, even in hyperspace. Big Pharma’s Star Destroyer may be less maneuverable but is powerfully equipped and fully staffed by dedicated Clone Troopers. Under ICH E6 (R3), both ships are being asked to navigate more complex oversight expectations, but only one has to do it with a skeleton crew.

While sponsor oversight was included in ICH E6 (R2), the requirements were less stringent. E6 (R3) closes that gap with more explicit, auditable, risk-based responsibilities across all functional areas. However, for biotechs, where bandwidth is already stretched, oversight often becomes a balancing act between staying informed and managing competing priorities.

You’ll have made every effort to select the right vendors and initiate your study: submissions, approvals, site activations and then recruitment finally starts. It’s never as fast as you’d like, but the metrics look reassuring, don’t they?

The reality is, without structured oversight, critical risks can go unnoticed until they become full-blown issues. The challenges for smaller sponsors are to make that oversight meaningful without drowning in process and avoiding the temptation of just throwing more SOPs at the added responsibilities introduced by E6 (R3). With greater oversight expectations, more risk-based responsibilities, more decisions to document, and more need to stay hands-on, the question is: how do you do all that and fly compliant and in control — and still have time to defeat the Empire?

The Force Is Strong — But The Team Is Small

Most early-stage biotechs operate a team of a small number of functional leads often supported by external consultants. This lean model creates the opportunity for broader, more varied roles and close cross-functional collaboration — the essence of why many of us enjoy working in this environment. Partnering with (often large) CROs is a crucial part of this model, with the vision of a seamless, high-functioning team. This enables biotechs to scale flexibly and stay focused on their core scientific strategy. Study team members often wear multiple hats (managing vendors, troubleshooting systems, and tracking project delivery, as examples) all while trying to maintain strategic alignment and momentum. It’s a workload that can easily become increasingly reactive, especially when working to the rhythm and complexity of a larger organization. The Millennium Falcon crew is suddenly less nimble when docked to their vendor’s well-equipped space station.

Governance meetings and CRO reports may offer a sense of structure but rarely tell the whole story. Updates are typically framed around vendor priorities and workflows (understandably, they still have a job to do), which can give sponsors a one-sided perspective. With limited bandwidth, it’s easy for the sponsor’s attention to be pulled toward whatever seems to be the CRO’s issue of the moment.

Over time, this constant operational noise can make it harder to stay close to the clinical science, which is at the core of the study. Critical gaps can go unnoticed simply because no one is looking in that direction. This isn’t about capability; it’s about capacity. The risk isn’t that sponsors don’t understand the issues, it’s that they may not have time to engage with them early enough to shape decisions, spot issues, or course correct. Oversight then becomes as much about protecting scientific objectives as it is about ensuring GCP compliance.

Even the most capable teams across biotech can run into these issues. Operating in an outsourced model with limited internal resources requires constant balancing between execution and oversight (the light and dark side of the Force, perhaps). And that’s exactly what the new ICH E6 (R3) guideline will put to the test.

E6 (R3): This Is the Way

E6 (R3) increases expectations for every sponsor, whatever its size. In practice, it calls for more clarity, more focus, and more adaptability in how trials are overseen, and it explicitly demands a quality by design (QbD) approach built into trials from the start. The guideline expands the sponsor’s responsibilities into areas like risk-based quality management, documenting decisions, and proactive issue detection. However, each of these puts more on the sponsor’s plate, and the trial doesn’t get any simpler.

One of the clearest shifts in R3 is its added specificity to oversight obligations. Under R3, sponsors must now document oversight as a continuous, risk-based, proactive activity across all functions, including vendor subcontractors and, ultimately, the trial sites and investigators. For lean teams, this creates an awkward paradox: the more outsourced you are, the more oversight you are responsible for. This may not sound new to those who engaged with indirect oversight responsibilities under R2, but under R3, these expectations become explicit, auditable, and non-negotiable. Back on the Millennium Falcon, the trusty old R2 unit gave the crew a map and a mission. The upgrade to E6 (R3) installs a navigation system but disables the autopilot. You need to know where you’re flying, why you’re going there, and how to prove you didn’t drift off course.

Under R3, it’s no longer enough to accept what’s reported. Sponsors are expected to look deeper, document their own decisions, and challenge assumptions where needed. Small biotechs also face the added complexity of dealing with CRO processes designed with Big Pharma clients in mind (many sponsors feel “biotech-specialized” CRO units are often more marketing than substance). But before sponsors can meet these new expectations, they need to ask a more basic question: Are we seeing what matters?

These Aren’t The Metrics You’re Looking For

Usually lacking in-house clinical systems, smaller sponsors rely on a patchwork of home-grown solutions (Does anyone else have a burgeoning collection of Excel trackers?) supplemented by static vendor metric reports, which can give a false perspective without context. Informed sponsor oversight and assurances of quality, as required by E6 (R3), demand more than passive consumption of metrics. Dashboards and reports can support decision-making, but only if sponsors are confident in what the data represents and how it was generated and can evaluate what’s missing.

Sponsors should step back and ensure they’re targeting the areas of highest risk (and at the right time) rather than just whatever the CRO happens to report. They should also be clear about what effective delivery looks like for the study, keeping clinical objectives in focus and ensuring that data quality is maintained throughout, not just checked at the end. If oversight is reduced to ticking boxes and meeting timelines, it misses the point.

Oversight shouldn’t be about constantly rechecking CRO outputs; it’s about shaping how and where sponsor input adds value. This means defining expectations, leading the conversation, and making sure the right people are interpreting what’s being shown. Oversight doesn’t just happen in documents; it’s a leadership behavior. However, defining oversight is only half the challenge. Resourcing is the other.

Oversee The Oversight, You Must

More important than a slick dashboard is having the right people in place to take meaningful action when the hyperdrive goes offline at the wrong moment. Oversight isn’t just about processes; it’s about people, especially when they are thin on the ground. Small biotech teams rarely have the luxury of in-house expertise across every function. For specialized areas like statistics or regulatory, we often rely on external consultants, with other functions outsourced to the CRO. But this fragmented model can make it harder to identify risks early — a critical expectation under E6 (R3) — and to maintain consistent oversight across the study life cycle. And who oversees the oversight when you’ve outsourced the expertise?

Problems come when oversight turns into box-ticking admin or a mound of paperwork, both of which make it easy to lose sight of the bigger picture. This isn’t just inefficient — it’s risky. E6 (R3) doesn’t offer exemptions for small biotechs. Instead, they must risk assess their oversight activities and prioritize. If you’re spending your day chasing documents, are you still watching the science? 

Fixing The Hyperdrive: The Biotech Path Through E6 (R3) Oversight

Oversight can no longer be a background activity; it should be built in by design as part of day-to-day study management and persist throughout the study’s life cycle. This means conducting up-front risk assessments and tailoring oversight plans accordingly.

Sponsors should set oversight expectations up front in the study plans and use this to frame the CRO-sponsor relationship. Sponsor calls should provide a forum for balanced dialogue, not just CRO status reporting, and sponsors should take an active role in shaping the agenda. With so much information flowing in, sponsor project managers mustn’t simply accept being overwhelmed. They should work with the CRO to ensure updates are focused, relevant, and aligned with the study’s priorities. Could we borrow a common practice from our GMP colleagues and introduce service level agreements for critical services (not to replace oversight, but to set expectations)?

Each outsourced function should have a designated sponsor-side owner: someone responsible for reviewing outputs, challenging assumptions, and ensuring the work aligns with the trial’s priorities. Whether that’s an internal lead or a contracted expert, no area should be left without a point of accountability. In many cases, these hats will fall to the project manager, and this exercise will quickly expose capability gaps. Proactively identifying and filling those gaps is how sponsors can avoid blind spots, ensuring that attention is paid not just to operational milestones but also to scientific credibility.

If internal expertise is limited, sponsors may need to think differently about how they resource oversight. One option is fractional engagement of experienced functional leads, individuals who can provide critical input at key moments, without the weight or cost of full-time roles. Used well, this kind of resourcing allows teams to stay focused on the science, without losing control of the delivery.

Teams should begin implementing their E6 (R3) strategies now, even before the new guidelines are officially enforced. Regulators and partners expect to see this approach in action. (For example, lack of oversight of CROs is a frequent theme in the FDA warning letters to sponsors.) The goal is to build a culture where quality oversight is part of everyone’s job, not an extra task.

E6 (R3) Readiness: Five Oversight Strategies

1. Prioritize oversight by design.
2. Assign sponsor-side ownership for every function.
3. Tailor oversight to risk and complexity.
4. Set the oversight agenda with vendors.
5. Document the decisions (and the rationale).

A New Hope (For Sponsor Oversight)

If E6 (R3) is ushering in the era of Quality by Design, then is it time we talked seriously about oversight by design? That means building oversight intentionally, not retrofitting it around your service providers. It means deciding up front where the sponsor’s judgment matters most and what it needs to see to be confident in trial delivery. This doesn’t mean inventing something new, just defining what matters most and putting sponsor judgment where it counts.

Sponsor oversight isn’t a document to be filed; it’s a way of working. Under E6 (R3), biotechs can no longer afford to assume that vendor expertise guarantees quality. Oversight must be structured, risk-based, and continuous, even when resources are tight.

The small biotech model still flies, but some odd noises are coming from the engine room that need attention. By focusing on high-impact areas, embedding oversight into day-to-day operations, and being honest about where internal capabilities fall short, sponsors can meet regulatory expectations without drowning in admin.

And maybe — just maybe — bring a little balance to the Force.

About The Author:

Angus Henderson is a clinical development consultant supporting early-stage biotechs with clinical science and operations. He believes good oversight should be proactive, practical, and a bit more Yoda.