Oncology clinical trials run under the same core regulatory framework as any other therapeutic area — Good Clinical Practice, informed consent, IRB oversight, adverse event reporting — but three things are operationally distinct in ways that shape how a trial is designed, monitored, and administered: tumor response is measured against a specific standardized imaging criteria set (RECIST), the endpoints that define trial success are largely unique to oncology (ORR, PFS, OS, DFS), and a meaningful share of U.S. oncology trials run through a federally funded cooperative group network (the NCTN) rather than purely through commercial sponsors and CROs. This guide covers those three areas specifically. For general trial phase definitions, IRB/informed consent process, or adverse event reporting mechanics that apply the same way in oncology as anywhere else, see CASRAI’s Clinical Trial Phases and Pharmacovigilance in Clinical Research guides.
Tumor Response Assessment: RECIST 1.1
Response Evaluation Criteria in Solid Tumors (RECIST) is the standardized method oncology trials use to determine whether a tumor has shrunk, grown, or stayed the same on serial imaging. The current version, RECIST 1.1, was published by an international working group (EORTC, the U.S. National Cancer Institute, and others) and is the de facto standard referenced in FDA guidance and the large majority of solid-tumor trial protocols.
The mechanics: at baseline, up to five target lesions (maximum two per organ) are selected and measured, with lymph nodes only countable as target lesions if their short axis is 15 mm or greater. On each subsequent scan, the sum of target-lesion diameters is compared against two reference points — the baseline sum and the smallest sum recorded at any point on study (the “nadir”) — to classify response into one of four categories:
- Complete Response (CR) — disappearance of all target lesions, with any pathological lymph nodes reduced to under 10 mm short axis.
- Partial Response (PR) — at least a 30% decrease in the sum of target-lesion diameters relative to baseline.
- Progressive Disease (PD) — at least a 20% increase relative to the nadir, with an absolute increase of at least 5 mm, or the appearance of one or more new lesions.
- Stable Disease (SD) — neither sufficient shrinkage to qualify as PR nor sufficient growth to qualify as PD.
Because RECIST assumes a tumor that shrinks in response to a cytotoxic mechanism, it can misclassify certain immunotherapy responses, where a tumor may appear to grow temporarily (pseudoprogression) before responding. Immunotherapy trials frequently use a modified variant, iRECIST, which confirms apparent progression on a follow-up scan before calling it PD, to avoid prematurely taking patients off an active treatment. For a research administration or clinical-trials-office team, the practical implication is that RECIST version and any modified variant must be specified in the protocol and applied consistently by trained, often blinded, independent central reviewers — inconsistent application across sites is a recurring finding in trial audits and monitoring visits.
Oncology-Specific Endpoints: ORR, PFS, OS, and DFS
Most therapeutic areas define trial success against a small number of endpoints specific to that disease. Oncology has its own recurring set, and understanding what each one measures — and what it does and doesn’t tell a reviewer — is central to how oncology trials are designed and how their results get evaluated by FDA:
- Overall Response Rate (ORR) — the proportion of patients who achieve a CR or PR by RECIST at any point during the trial. ORR can be assessed relatively quickly, in a single arm, without a control group, which is why it is a common basis for early or accelerated approval decisions in oncology, particularly in rare or heavily pretreated cancers.
- Progression-Free Survival (PFS) — the time from randomization until RECIST-defined progression or death from any cause, whichever comes first. PFS requires a control arm and longer follow-up than ORR but not as long as OS, and is FDA’s most commonly used surrogate endpoint for oncology accelerated and, in some cases, regular approvals.
- Overall Survival (OS) — time from randomization to death from any cause. OS is the most direct measure of clinical benefit in oncology and is generally considered the gold-standard endpoint, but it requires the longest follow-up and the largest trial, since death events in many cancers accrue slowly, especially as later lines of therapy after progression can extend survival independent of the study drug.
- Disease-Free Survival (DFS) (also called Relapse-Free Survival, RFS) — used specifically in the adjuvant/curative-intent setting, after a patient has had definitive treatment (surgery, often with radiation) with no detectable disease remaining: the time from randomization until disease recurrence or death. DFS plays the equivalent role in the post-surgical setting that PFS plays in the metastatic setting.
The common thread across ORR, PFS, and DFS is that all three are surrogate endpoints for OS: each is used because it is measurable sooner and in a smaller trial than a true survival endpoint, on the premise that the effect is reasonably likely to predict an eventual survival or cure benefit. That premise doesn’t always hold, which is precisely why FDA’s use of surrogate endpoints in oncology comes bundled with a post-approval verification obligation, covered next.
Why Oncology Leans Heavily on Accelerated Approval
FDA’s Accelerated Approval pathway — approval based on an effect on a surrogate endpoint reasonably likely to predict clinical benefit, conditioned on a required post-approval confirmatory trial — is used across therapeutic areas, but oncology has historically accounted for a disproportionate share of accelerated approvals of any single therapeutic category. The reason follows directly from the endpoints above: ORR and PFS are exactly the kind of surrogate FDA’s accelerated-approval regulation (21 CFR 314.510 / 601.41) contemplates, and many cancers — particularly rare cancers, later treatment lines, and pediatric cancers — don’t have patient populations large enough to power a timely OS-driven confirmatory trial before a full approval, making a surrogate-based accelerated approval, followed by a maturing confirmatory trial, the practical path to getting a drug to patients sooner.
For research administration purposes, this means an oncology sponsor’s accelerated-approval program carries the same post-2022 FDORA obligations covered in CASRAI’s Accelerated Approval entry — a confirmatory trial that must be underway, not merely planned, with its enrollment and completion timeline tracked as a compliance matter, not just a scientific one. Oncology’s other three FDA expedited pathways — Priority Review, Breakthrough Therapy designation, and Fast Track — and Orphan Drug designation for rare cancers are also disproportionately used in oncology, but operate the same way there as in any other therapeutic area; Accelerated Approval is the one pathway where oncology’s endpoint structure specifically drives its outsized use.
The NCTN Cooperative Group System
A substantial share of U.S. oncology trials, particularly publicly funded, later-phase, and comparative-effectiveness trials, run through the National Cancer Institute’s National Clinical Trials Network (NCTN) rather than through a single commercial sponsor. This is a structural difference from most other therapeutic areas, where large multi-site trials are typically sponsor- or CRO-run.
The NCTN consists of five NCI-funded U.S. network groups, each with its own scientific committees, statistical and data center, and disease-site focus, plus a Canadian partner group:
- Alliance for Clinical Trials in Oncology — formed from the merger of the American College of Surgeons Oncology Group, Cancer and Leukemia Group B (CALGB), and the North Central Cancer Treatment Group.
- ECOG-ACRIN Cancer Research Group — formed from the merger of the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN).
- NRG Oncology — formed from the merger of the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG).
- SWOG Cancer Research Network — one of the original cooperative groups, retained under its historical name (formerly Southwest Oncology Group).
- Children’s Oncology Group (COG) — the single NCTN group dedicated to pediatric cancers.
Canadian Cancer Trials Group (CCTG) participates as the network’s Canadian collaborating group. The current five-group U.S. structure dates to NCI’s 2014 cooperative group reorganization, which consolidated a larger number of legacy cooperative groups into these entities to reduce overlap and administrative burden. Together, NCTN trials run across more than 2,200 sites, spanning NCI-designated cancer centers, academic medical centers, and, through the NCI Community Oncology Research Program (NCORP), community hospitals and practices — which is how NCTN trials reach patient populations and geographic settings that a purely academic-center or purely commercial trial network typically doesn’t.
For a research administrator, the practical difference from an industry-sponsored trial is in funding and governance: NCTN trials are developed and peer-reviewed through the cooperative group’s own scientific committees and NCI’s Cancer Therapy Evaluation Program (CTEP) before activation, funded largely through NCI grants and cooperative agreements rather than a single sponsor’s trial budget, and require participating sites to have separate site-level agreements and NCI-specific regulatory documentation (e.g., CTEP registration) in addition to standard IRB and GCP requirements.
Institutional-Level Review: PRMS and the Scientific Review Committee
NCI-designated cancer centers are required, as a condition of their Cancer Center Support Grant (CCSG/P30) funding, to maintain a Protocol Review and Monitoring System (PRMS): an institutional layer of scientific-merit review that sits before, and separately from, IRB ethical review. The core of a PRMS is the Scientific Review Committee (SRC), which evaluates a proposed oncology protocol’s scientific merit, design, and accrual feasibility, and prioritizes it against other open protocols competing for the same patient population — a step that clinical trials outside cancer centers generally don’t go through, since non-oncology protocols typically proceed directly to IRB review. Research administrators supporting an oncology protocol’s activation timeline need to budget for this additional institutional review step; it commonly runs in parallel with, rather than after, IRB submission, but it is a real, separate gate that non-oncology trial activation at the same institution may not have.
Frequently Asked Questions
Is RECIST required for every oncology trial?
RECIST 1.1 is the dominant standard for solid-tumor response assessment and is expected by FDA in most solid-tumor trial protocols, but it isn’t universally mandated by regulation for every oncology trial. Hematologic malignancies (leukemias, lymphomas, myeloma) generally use disease-specific response criteria instead (e.g., the Lugano classification for lymphoma), and immunotherapy trials frequently use RECIST variants like iRECIST rather than unmodified RECIST 1.1.
What’s the difference between PFS and DFS?
Both measure time-to-event endpoints short of overall survival, but in different clinical settings. PFS is used in patients with active, measurable disease (typically the metastatic or advanced setting) and measures time to progression or death. DFS is used after a patient has completed definitive treatment with no detectable disease remaining (the adjuvant setting) and measures time to recurrence or death.
Why do so many oncology drugs get accelerated approval instead of regular approval?
Because ORR and PFS — endpoints that can be measured faster and in smaller trials than overall survival — are exactly the type of surrogate endpoint FDA’s accelerated-approval regulation is built around, and many cancer trial populations (rare cancers, later treatment lines, pediatric cancers) are too small to power a timely OS-driven trial. See CASRAI’s Accelerated Approval entry for the confirmatory-trial obligations that come with it.
Are NCTN cooperative group trials the same as industry-sponsored oncology trials?
No. NCTN trials are developed and scientifically reviewed through the relevant cooperative group’s committees and NCI’s Cancer Therapy Evaluation Program, funded primarily through NCI grants and cooperative agreements, and run across a network of academic and NCORP community sites. Industry-sponsored trials are developed and funded by a single commercial sponsor, typically through a CRO, though the two models increasingly overlap on trials where industry co-funds or supplies drug to an NCTN-run study.
