Investigator-Initiated Studies: What Review Committees Seek

More often, it loses momentum because the proposal does not yet show how an important clinical question can become a credible, ethical, and deliverable study without creating disproportionate patient burden.

That distinction matters. An investigator-initiated study review is not simply an exercise in ranking ideas. It is the point at which Medical Affairs must decide whether a proposed research question has enough scientific value, operational clarity, and governance discipline to justify asking patients, investigators, sites, and institutions to carry it forward. The committee is assessing the protocol, but it is also assessing the care pathway around the protocol: who will be asked to participate, what will happen to them, how safety will be managed, and whether the proposed endpoints can produce meaningful evidence rather than additional noise.

For our industry, this is where independence becomes practical rather than rhetorical. Investigator-sponsored research governance depends on proposals arriving through an unsolicited route, being reviewed by the medical function, and remaining separate from commercial or sales influence. A strong submission therefore needs to demonstrate more than enthusiasm. It needs to show that the question is scientifically defensible, the design is proportionate, the investigator is capable of assuming sponsorship responsibilities, and the study can be delivered without compromising ethical or regulatory standards.

The firewall: why independence comes before approval

The first criterion is procedural, but it shapes everything that follows: the request must be spontaneous and unsolicited.

An investigator-initiated study proposal should be directed to the medical department rather than generated, shaped, or solicited by a commercial function. This is not a minor administrative preference. It protects the purpose of the research and allows the review committee to consider the proposal on its scientific and clinical merits, rather than on its possible sales potential or commercial usefulness.

That separation can feel abstract until we consider the lived experience of the participants. A study is asking people to contribute time, data, biological samples, travel, treatment changes, or repeated assessments. If its underlying rationale has been influenced by commercial priorities, confidence in the evidence can be weakened before the first patient is enrolled. Independence is therefore part of patient protection, not only a compliance principle.

The medical review process should be able to answer several straightforward questions:

• Did the investigator or institution originate the scientific question independently?
• Was the proposal submitted directly to the medical department through the defined process?
• Can the scientific rationale stand on its own, without reference to projected sales or market opportunity?
• Is the proposed work distinct from promotional activity?
• Are the investigator and institution prepared to take responsibility for the study as sponsor-investigator?

The committee is not expected to treat every unsolicited proposal as suitable simply because it arrived through the correct channel. Independence is necessary, but it is not sufficient. A proposal can be entirely independent and still be scientifically underdeveloped, operationally unrealistic, or poorly aligned with the therapeutic strategy.

Independence is not a ceremonial barrier around the review process; it is what allows the committee to ask whether the study deserves to exist on clinical grounds alone.

This is also why the roles of Medical Affairs and field-based colleagues need to remain clear. Medical science liaisons may have valuable scientific conversations with investigators, but they should not solicit or write an investigator-initiated study proposal on an investigator’s behalf. The integrity of the process depends on preserving the distinction between scientific exchange and study sponsorship.

Scientific rationale: a compelling question is only the beginning

The committee’s next task is to understand whether the proposed study addresses a genuine evidence gap and whether the design can answer the question it poses.

A familiar therapeutic area does not automatically create a strong scientific rationale. Committees will usually look for a clear explanation of what is not known, why that uncertainty matters to clinical care, and how the proposed research would improve understanding. The most persuasive proposals connect the evidence gap to a meaningful endpoint or decision in the care pathway.

That connection is often where proposals become either clinically useful or merely interesting.

A study may propose to describe treatment patterns, compare outcomes, examine a subgroup, collect real-world data, or explore a patient-reported outcome. Each of these can be valuable. But the proposal needs to explain what clinicians, patients, or healthcare systems could do differently if the study produces a credible result. A technically impressive dataset that does not support a meaningful clinical interpretation may impose considerable patient burden without producing an equally meaningful return.

From strategic alignment to clinical relevance

Strategic alignment does not mean that the investigator must reproduce the company’s internal priorities. It means that the proposed work should sit within a defined therapeutic strategy and contribute to a question that has relevance for the development of medical understanding.

Review committees may consider:

• Whether the research addresses an identified unmet need or evidence gap.
• Whether the population is clearly defined and clinically relevant.
• Whether the intervention or exposure is appropriate to the research question.
• Whether the primary and secondary endpoints are capable of producing interpretable findings.
• Whether the proposed design is suitable for the question, rather than selected for convenience.
• Whether the study duplicates existing evidence without a clear justification.
• Whether the anticipated findings could contribute to scientific communication or improved care.

The primary endpoint deserves particular attention. In a protocol, it is easy to list several outcomes that sound valuable. In practice, each additional outcome can increase the burden of data collection, analysis, interpretation, and site execution. A committee will want to see that the primary endpoint is not simply the most convenient measure, but the outcome most closely connected to the central clinical question.

Secondary endpoints should support that question rather than create a long catalogue of potentially publishable observations. They may add context, illuminate patient experience, or help interpret the primary result, but they should not obscure the study’s central purpose.

This is where patient-centred thinking becomes operational. A questionnaire that is administered at every visit, a laboratory assessment that requires an additional trip, or a follow-up schedule that conflicts with ordinary care can all affect retention. The protocol should make clear why these activities are necessary and whether the evidence they generate justifies the patient burden they create.

The difference between a coherent protocol and a crowded one

A coherent protocol has an identifiable line of reasoning:

1. There is a defined clinical uncertainty.

2. The study population reflects the people affected by that uncertainty.

3. The design can address the question without introducing avoidable bias.

4. The endpoints reflect outcomes that matter to patients or clinical decisions.

5. The analysis plan is proportionate to the study’s objectives.

6. The expected result will be interpretable, even if it does not confirm the investigator’s hypothesis.

A crowded protocol often moves in the opposite direction. It accumulates exploratory objectives, additional subgroups, multiple endpoints, and extensive data collection in the hope that something useful will emerge. That approach can make a proposal appear ambitious, but it may weaken feasibility and dilute the scientific message.

The review committee is not looking for the largest possible study. It is looking for a study in which the scientific question, patient population, design, endpoints, and resources are aligned.

Investigator capability: experience is evidence of readiness

An investigator-initiated study is not only a scientific concept. It is a regulated undertaking, and the committee must assess whether the proposed investigator or institution can carry the responsibilities that come with sponsorship.

Standard review criteria may include active medical licensure and recent clinical research experience within the previous three years. These details are not intended to create a narrow hierarchy of investigators. They provide a practical indication that the proposed sponsor-investigator has recent familiarity with research conduct, participant protection, documentation, safety reporting, and the operational demands of a clinical study.

Recent experience is especially relevant when the proposal involves multiple sites, complex data collection, interventional procedures, vulnerable populations, or a demanding follow-up schedule. A strong clinical reputation may support the scientific rationale, but it does not by itself demonstrate readiness to manage a regulated study.

The committee may therefore look beyond the investigator’s title or publication history and consider the broader research environment:

• Has the investigator conducted relevant research recently?
• Is there evidence of experience with the proposed study design?
• Does the institution have appropriate research infrastructure?
• Are the site team and supporting departments identified?
• Can the investigator describe how recruitment, retention, monitoring, and safety reporting will be managed?
• Is there a realistic plan for data quality and protocol adherence?
• Does the team have access to the population it intends to study?
• Are the proposed responsibilities understood by the institution?

This is not a request for an immaculate research history. Investigators may be developing a new programme, moving into a different design, or working with an institution that has not previously led the exact type of study proposed. What matters is whether the submission recognises the gap and provides a credible plan to address it.

The investigator as sponsor

One of the most important points in evaluating investigator-sponsored studies is the legal and regulatory position of the investigator or institution. In an IIS, the independent investigator or institution serves as the legal sponsor-investigator and assumes full responsibility for the study’s regulatory conduct.

That responsibility includes, where applicable:

• Study design and protocol development.
• Regulatory submissions, including IND or CTA filings where required.
• Ethics committee or institutional review board submissions.
• Safety reporting.
• Maintenance of essential documentation.
• Protocol adherence.
• Oversight of participating sites and study personnel.
• Appropriate handling and reporting of study data.

The company may provide support within the approved arrangement, but that support does not transform the company into a co-sponsor or make it a shared holder of the investigator’s legal responsibilities. The distinction needs to remain visible throughout the review and contracting process.

A proposal may be scientifically excellent and still require revision if the investigator’s understanding of these obligations is unclear. The review committee is protecting the future study from a predictable failure mode: a promising protocol approved without sufficient recognition of who will actually carry the regulatory burden once the work begins.

Feasibility: where patient burden meets operational reality

Feasibility is sometimes treated as the least inspiring part of scientific review. In reality, it is where the proposal meets the lives of the people expected to participate.

A study may look reasonable on paper while creating a difficult care pathway. It may require visits that are not aligned with routine appointments, repeated assessments with limited clinical value, complex eligibility confirmation, or follow-up that is difficult for patients with mobility, work, caregiving, or financial constraints. These pressures affect recruitment first, but they also affect retention, data completeness, and the credibility of the final analysis.

For this reason, a committee will look at more than whether a site can technically conduct the protocol. It will consider whether the study can be conducted consistently and respectfully.

Questions of feasibility may include:

• Is the target population available in the proposed setting?
• Is the recruitment assumption realistic for the disease area and eligibility criteria?
• Do the visit schedule and assessments fit within ordinary care?
• Are there requirements likely to create avoidable travel or time burdens?
• Can sites manage the data collection with their existing personnel?
• Is the follow-up period sufficient to observe the proposed outcome?
• Are the study procedures proportionate to the expected scientific value?
• Does the protocol allow for predictable operational variation without compromising data quality?

These questions become especially important in studies that rely on real-world data. Real-world evidence is often described as closer to everyday practice, but that does not mean the data are automatically simple or complete. The proposal should explain how relevant data will be identified, harmonised, validated, and interpreted, particularly where clinical documentation differs between sites.

Budget is a scientific issue as well as a financial one

Review committees assess whether the budget is cost-effective, but cost-effectiveness should not be reduced to finding the lowest number. An underfunded study can be just as problematic as an unnecessarily expensive one. If the budget does not support adequate oversight, data management, safety reporting, or site coordination, the study may fail to deliver reliable evidence.

Trial oversight costs generally account for approximately 30 percent of total site and personnel budgets in investigator-initiated clinical trials. That proportion is a useful reminder that oversight is not an incidental administrative layer. It is part of the work required to protect participants and preserve data integrity.

A credible budget should connect each significant cost to a defined study activity. Committees may examine:

• Site and personnel requirements.
• Monitoring and oversight activities.
• Data management and statistical support.
• Safety surveillance and reporting.
• Regulatory and ethics submissions.
• Laboratory, imaging, or central assessment costs.
• Investigator and study team training.
• Archiving and essential document management.
• Publication or scientific communication activities.

The central question is not simply whether the requested amount is high or low. It is whether the budget reflects the actual obligations of the proposed study and whether the distribution of resources supports a safe, well-controlled care pathway for participants.

A concise view of the review dimensions

Regulatory accountability cannot be delegated away

A sponsor-investigator may use external support, including a contract research organisation, for specific operational tasks. Under FDA 21 CFR 312.52 and ICH Good Clinical Practice principles, certain sponsor obligations can be transferred contractually to a CRO. But the transfer of tasks is not the transfer of ultimate accountability.

This distinction deserves more attention than it often receives in early proposal discussions. A CRO may support monitoring, data management, site coordination, or other defined activities, but the sponsor-investigator remains accountable for the study’s regulatory responsibilities. Contract language should therefore identify what is being delegated, how performance will be overseen, and how issues will be escalated.

A review committee will be reassured by a proposal that treats delegation as a governance arrangement rather than as an escape from responsibility. It should be possible to see:

• Which activities will remain with the investigator or institution.
• Which tasks may be assigned to external providers.
• How the CRO or other provider will be selected and qualified.
• Who will review safety information.
• Who will make decisions when protocol deviations or data concerns arise.
• How the investigator will maintain oversight of delegated work.
• How essential records and regulatory communications will be controlled.

This becomes particularly important as Good Clinical Practice expectations continue to evolve. The finalisation of ICH E6(R3) in 2025 reinforces a broader movement toward proportionate, risk-based, quality-focused research conduct. The practical implication is not that every IIS must become more complex. It is that each study should be governed according to the risks that matter most for participants, data reliability, and the credibility of the result.

In the United Kingdom, the planned implementation of the UK Clinical Trials Regulation in April 2026 adds another layer of timing and operational awareness for teams preparing relevant studies. The precise route will depend on the study and jurisdiction, but the underlying principle remains steady: regulatory planning should begin with the protocol, not after approval has been granted.

What distinguishes a reviewable proposal from an approvable one?

A reviewable proposal gives the committee enough information to discuss it. An approvable proposal gives the committee confidence that the study can move into the next stage without requiring its central logic to be rebuilt.

That difference is often found in the quality of the submission rather than in the ambition of the research question. A proposal becomes stronger when it acknowledges uncertainty, identifies practical limitations, and explains how risks will be managed. It does not need to promise a definitive answer to every question in the therapeutic area.

In practice, the most persuasive proposals tend to do five things well:

1. They define the clinical uncertainty precisely.

The investigator explains what is not known and why the gap matters to patients, clinicians, or healthcare delivery.

2. They connect the design to the endpoint.

The methods are not presented as a collection of familiar research activities; they are chosen because they can answer the stated question.

3. They treat patient burden as a design variable.

Visit schedules, assessments, consent processes, and follow-up are considered in relation to lived experience and expected scientific value.

4. They demonstrate sponsor readiness.

The investigator and institution show that they understand regulatory responsibility, safety reporting, oversight, and protocol conduct.

5. They provide a credible operational and financial plan.

Recruitment, staffing, data management, monitoring, and oversight are resourced in a way that reflects the real work of the study.

None of these criteria requires the proposal to be commercially attractive. Indeed, commercial benefit cannot be the basis on which the company approves the work. The relevant question is whether the study has scientific validity, ethical acceptability, regulatory feasibility, alignment with the defined therapeutic strategy, and an investigator capable of delivering it responsibly.

The final test is what happens at the bedside

An investigator-initiated study review can appear to be a sequence of internal gates: scientific review, budget assessment, compliance review, and approval. But behind each gate is a person who may be asked to rearrange treatment, travel to a site, complete another questionnaire, undergo another procedure, or share information about a condition that already shapes much of daily life.

That is why our review criteria must remain connected to bedside reality. Scientific rationale is not complete until it explains why the question matters. A meaningful endpoint is not meaningful simply because it can be measured; it should help us understand an outcome that affects care, function, symptoms, safety, or a patient’s ability to live with their condition. Feasibility is not merely a site’s capacity to open a study; it is the possibility that patients can stay in the study without carrying an unreasonable burden.

For Medical Affairs, the responsibility is to preserve both sides of that equation. We must protect independence and compliance while keeping sight of the people whose participation makes the evidence possible. The strongest investigator-initiated studies are not necessarily the most elaborate. They are the ones in which the scientific question, the sponsor’s capabilities, the regulatory plan, and the patient’s lived experience fit together with unusual clarity.

That is ultimately what review committees seek: not a proposal that promises everything, but one that can responsibly deliver something meaningful.