As most clinical trial professionals know, oncology is a unique therapeutic area that deals with the prevention, diagnosis and treatment of cancers. Oncology studies usually require more lengthy and intricate CRFs due to the nature of the therapeutic area, the nature of the tests and examinations performed and the type of data collected and required for the statistical analysis. Several additional factors contribute to the complexity of oncology studies including the large number of partially related diseases and the importance of disease sub-types and/or genotypes. [See “What makes oncology different from other therapeutic areas” by CROS NT’s Head of Statistical Consultancy, Thomas Zwingers]
CROS NT’s Clinical Data Management department looks at CRF design considerations for oncology studies.
The process for CRF design needs to be as standardized as possible so that CRF forms can be replicated from study to study. Having standardized CRFs not only promises the physician’s continued familiarity with the CRF, but also helps minimize the cost to the Sponsor.
Data collected for oncology clinical trial CRFs is more complex than data collected for other therapeutic areas. CRFs for cancer history consist of the date of diagnosis or data of metastasis. Depending on protocol specifics, the medical history page is more extensive and specific to the disease treatment. There can be other types of specific examinations included such as tumor assessment via CT scans or MRI scans, biopsies, ECOG and other cancer specific treatments.
The investigational study drug is usuallly administered according to the defined number of cycles in the protocol, and each cycle consists of a number of dosing days (e.g. Day 1, Day 8, Day 15, etc). The subject is usually required to attend clinic visits on the expected dosing days in compliance with the protocol time-window.
There will most likely be a a pre-dose and post-dose for ECG and Vital Signs collection, and the Adverse Events page will be infusion-related and always have a start/stop time. The Adverse Event page includes the “Common Terminology Criteria for Adverse Evenets” (CTCAE). The NCI Common Terminology Criteria for Adverse Events is descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE. The CTCAE displays Grades 1 through 5, with unique clinical descriptions of severity for each AE followed by a ranking system based on severity as follows:
- GRADE 1: Mild – asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
- GRADE 2: Moderate – minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL*.
- GRADE 3: Severe or medically significant but not immediately life-threatening – hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**.
- GRADE 4: Life-threatening consequences – urgent intervention indicated.
- GRADE 5: Death releated to AE.
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
**Self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for Grade selection. Grade 5 (Death) is not appropriate for some AEs and therefore is not an option.
In the design of Oncology studies, the Tumor Assessment CRF is where the tumor size is assessed and measured. Response Evaluation Criteria in Solid Tumors (RECIST) is designed to provide a set of criteria to evaluate the progression, stabilization or responsiveness of tumors. These tumors are measured as either ‘Target Lesions’ or ‘Non-target Lesions’ and have specific criteria in which they are evaluated such as ‘complete response’, ‘partial response’, ‘stable disease’ and ‘progressive disease’.
The responses for each individual lesion are combined into an overall response for each visit. At the end of the trial, the series of visit responses are evaluated to produce information that corresponds to an endpoint, such as the date of progression or the best overall response.
Standardizing CRFs allows for conformity in data collection across studies within the same indication which develops clinical trial value and adequacy. For solid tumor studies for instance, we know that the same variable will always be measured. There will always be a CT scan and MRI. Lymph nodes will be examined as well as blood samples.
A given endpoint term (eg, overall survival) used in an Oncology trial should always envelop the same set of events (eg, death by disease progression, death by Adverse Event, death from unknown cause), and, in turn, each event within that endpoint should be commonly defined across endpoints and studies.
As mentioned above, standardizing CRFs is not only cost effective and accepted by most Sponsors, oncologists and regulatory authorities, but the template can be used for clinical studies worldwide, thus increasing overall study efficiency.
As the center of excellence for clinical data, CROS NT’s data management team has extensive knowledge in the management of data generated in Phases I-IV and medical device trials. This strength enables CROS NT to improve speed, efficiency and cost effectiveness leading to flexible solutions for all phases of the drug development cycle. The team is expert in various data collection, reporting and visualization systems. Our senior data managers have extensive experience in CRF design and review.