Oncology Live®
Vol. 23/No. 8
Volume 23
Issue 08

Pragmatic Clinical Trials Can Play a Key Role in Oncology

Pragmatic clinical trials “inform a clinical or policy decision by providing evidence for adoption of the intervention into real-world clinical practice.”

Maurie Markman, MD

Maurie Markman, MD

Cancer clinical research is characterized by several types of clinical trials. Phase 1 studies, for instance, are used to define the safety, pharmacokinetic profile, and optimal delivery approaches for antineoplastic agents. Phase 3 randomized studies directly compare the toxicity and efficacy of specific therapeutic strategies.

There is one form of clinical trial that has received limited attention and needs to become a greater component of our community’s focus. Pragmatic clinical trials “inform a clinical or policy decision by providing evidence for adoption of the intervention into real-world clinical practice.”1 These trials may inform issues that are highly relevant to practicing physicians and previously unaddressed by explanatory trials designed to “confirm a physiological or clinical hypothesis.”1 Such studies are likely to be conducted in a homogenous and generally quite non–real world patient population, often with the purpose of achieving regulatory approval of agents for subsequent commercial sale.

Pragmatic trials may address questions that have nothing to do with regulatory or commercial concerns. Rather, their investigators seek to learn the optimal approach to handling a common or vexing clinical matter in a large or limited group of patients. Examples of studies in which investigators explored a common population-based problem include the SOME trial (NCT00773448),2 which evaluated the clinical utility of routine screening for cancer in individuals who experienced a venous thromboembolism; a 3-group parallel study (ACTRN12618000930280)3 that examined the effectiveness of different online education approaches in managing the common and costly clinical dilemma of knee osteoarthritis; and a study to evaluate strategies to optimize smoking cessation efforts (NCT02328794).4

Alternatively, a pragmatic trial may examine a critically important but quite narrow subject. An example is NOR-DRUM (NCT03074656), which evaluated the value of therapeutic drug monitoring for patients with immune-mediated inflammatory disease receiving maintenance treatment.5

Turning to the cancer arena, there are many clinical topics where objective trial-generated data could be helpful in optimizing care. For example, what is the relative efficacy and toxicity of talc pleurodesis vs an indwelling pleural catheter in the management of a malignant pleural effusion?6 Or what is the benefit-to-risk ratio in regard to preserved cognitive function associated with whole brain radiation therapy plus radiosurgery vs radiosurgery alone in the treatment of individuals with a limited number (1-3) of metastatic brain lesions?7 These issues are unlikely to generate commercial support or be viewed as advancing cancer therapeutics, but they may be critically relevant to oncologists attempting to provide the best possible palliative care.

Similarly, pragmatic clinical trials may seek to find a simple, safe, and inexpensive strategy to prevent a serious treatment-related adverse effect. Relevant real-world examples of these issues include addressing hearing loss associated with cisplatin delivery in children,8 or resolving a highly contentious debate among oncologists regarding the potential role of secondary cytoreduction followed by hyperthermic intraperitoneal chemotherapy in platinum-sensitive recurrent ovarian cancer.9

For both of these examples, a pragmatic clinical trial has been conducted and investigators reported their results in high-impact oncology journals, an indication of the relevance of the concerns addressed and the importance of the data generated.

It is perhaps appropriate to consider a potential pragmatic clinical trial, that as far as this commentator is aware has not yet been initiated, to address a question relevant to gynecologic oncologists.

The FDA recently approved the use of a novel imaging drug, pafolacianine (Cytalux), for use during ovarian cancer surgery with the specific intent to permit the discovery of additional metastatic malignant lesions that may be resected prior to the subsequent delivery of cytotoxic chemotherapy.10 This approval was based on data from a phase 3 trial (NCT03180307) that revealed use of the proprietary intraoperative imaging strategy permitted the identification of additional lesions beyond those observed from direct visualization in one-third of the 109 patients available for analysis of efficacy.11 False positives were also noted, and approximately one-third of patients experienced adverse effects including nausea, vomiting, and abdominal pain.11

Regulatory approval was presumably provided based on the assumption that the removal of these additional nonvisualized lesions, resulting in a more complete surgical resection would be translated into a superior clinical outcome. The intent of highlighting the approval of this agent is not to present a formal discussion supporting or refuting its scientific basis or merit but rather to emphasize the opportunity for the development of a pragmatic clinical trial that directly tests this conclusion. Of course, multiple details would need to be considered—including study funding—but one might consider the prospective conduct of a registry-type, community-based study where detailed data on patients would be collected, such as tumor grade, unique histologic features, initial tumor stage, comorbidities, BRCA-mutation status, treatments received, and time to initial disease progression, among others.

The specific hypothesis to be addressed would be whether patients who have no gross macroscopic residual disease following the completion of primary surgical cytoreduction assisted by use of the imaging strategy experience superior progression-free survival compared with individuals who attained this state of no gross visible macroscopic residual disease without this new technology.

It is reasonable to assume the results of a well-designed study would be quite meaningful to clinicians and patients and subsequently would be published in a high-impact medical journal.


  1. Ford I, Norrie J. Pragmatic trials. N Engl J Med. 2016;375(5):454-463. doi:10.1056/NEJMra1510059
  2. Carrier M, Lazo-Langner A, Shivakumar S, et al; SOME Investigators. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med. 2015;373(8):697-704. doi:10.1056/NEJMoa1506623
  3. Bennell KL, Lawford BJ, Keating C, et al. Comparing video-based, telehealth-delivered exercise and weight loss programs with online education on outcomes of knee osteoarthritis. Ann Intern Med. 2022;175(2):198209. doi:10.7326/M21-2388
  4. Halpern SD, Harhay MO, Saulsgiver K, Brophy C, Troxel AB, Volpp KG. A pragmatic trial of e-cigarettes, incentives, and drugs for smoking cessation. N Engl J Med. 2018;378(24):2302-2310. doi:10.1056/NEJMsa1715757
  5. Syversen SW, Jørgensen KK, Goll GL, et al. Effect of therapeutic drug monitoring vs standard therapy during maintenance infliximab therapy on disease control in patients with immune-mediated inflammatory diseases: a randomized clinical trial. JAMA. 2021;326(23):2375-2384. doi:10.1001/jama.2021.21316
  6. Thomas R, Fysh ETH, Smith NA, et al. Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: the AMPLE randomized clinical trial. JAMA. 2017;318(19)1903-1912. doi:10.1001/jama.2017.17426
  7. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases. JAMA. 2016;316(4):401-409. doi:10.1001/jama.2016.9839
  8. Brock PR, Maibach R, Childs M, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med. 2018;378(25):2376-2385. doi:10.1056/NEJMoa1801109
  9. Zivanovic O, Chi DS, Zhou Q, et al. Secondary cytoreduction and carboplatin hyperthermic intraperitoneal chemotherapy for platinum-sensitive recurrent ovarian cancer: an MSK team ovary phase II study. J Clin Oncol. 2021;39(23):2594-2604. doi:10.1200/JCO.21.00605
  10. Voelker R. Lighting the way for improved detection of ovarian cancer. JAMA. 2022;327(1):27. doi:10.1001/ jama.2021.22960
  11. Tanyi JL, Chon HS, Morgan MA, et al. Phase 3, randomized, single-dose, open-label study to investigate the safety and efficacy of pafolacianine sodium injection (OTL38) for intraoperative imaging of folate receptor positive ovarian cancer. J Clin Oncol. 2021;39(suppl 15):5503. doi:10.1200/JCO.2021.39.15_suppl.5503
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