Clinical Trial Background Issues

Overview

Clinical trials, also called research studies, test new or revised treatments in people with disease, in this case cancer. The goal of this research is to find better ways to treat cancer and help cancer patients.

Clinical trials test many types of treatment using:

We will discuss the various issues in clinical trial design. As in other areas of cancer research, clinical trial design is also changing. As the new information from genomics, proteomics and biomarker research makes its way into the clinical trial system; new design approaches are being developed. Advances in technology also provide new ideas for imaging, radiology and surgery to test. Clinical trial phases are described in detail later in this section.

PICO:

The acronym PICO is used by many clinical researchers stands for key elements used to organize clinical trial design. The four PICO letters stand for:

• Patients,
• Interventions,
• Comparisons, and
• Outcomes.

PICO Patient Issues

The first step in clinical trial design is to define the types of patients needed to participate in a trial (i.e., eligibility requirements). This sample represents the population of patients for whom the results will be applicable if the trial is completed successfully.

		Eligibility requirements can be both inclusionary (participants must have) and exclusionary (participants must not have). Participant eligibility criteria can range from general (age, sex, type of cancer) to specific (prior treatment, tumor characteristics, blood cell counts, organ function). Eligibility criteria may also vary depending on the phase of the trial. In Phase 1 and 2 trials, the criteria often focus on patient safety making sure that people who might be harmed because of abnormal organ function or other factors are not put at risk during the trial. Phase 2 and 3 trials often add criteria concerning disease type and stage, and number and type of prior treatments.

The more stringent the eligibility criteria, the easier it is to find a treatment effect. However, the less stringent the eligibility criteria, the more likely the result will be replicated in the real world outside of clinical trials.

There is much discussion about relaxing eligibility requirements as noted by biostatistician George Sledge, Division of Biometry, Duke University Medical Center, Durham, NC: "Phase III clinical trials in cancer should have much broader eligibility criteria than the traditional restrictive criteria commonly used. Adoption of less restrictive eligibility criteria for most studies would allow broader generalizations, better mimic medical practice, reduce complexity and costs, and permit more rapid accrual without compromising patient safety or requiring major increases in sample size."

Below is an example of eligibility requirements from a study on the NCI website.

"Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Inclusion Criteria: (must have)

• Subjects must have histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
• HER2-positive by FISH, CISH, or IHC 3+
• ECOG performance status 0 or 1
• Left ventricular ejection fraction greater than or equal to institutional lower limit of normal
• Adequate laboratory studies (hematological, chemistries and urinalysis)
• Life expectancy greater than or equal to 3 months

• Cohort A only:
  • Subjects must be either trastuzumab naïve or have had prior trastuzumab in the adjuvant setting only
  • Subjects must not have had a clinically significant drop in cardiac function during a prior exposure to trastuzumab
  • Subjects must have had no prior lapatinib therapy
  • At least 3 weeks from enrollment since prior chemotherapeutic agents, including taxanes, in the neoadjuvant or adjuvant setting
  • At least 3 months from enrollment since prior trastuzumab in the neoadjuvant or adjuvant setting
• Cohort B only:

• Subjects must have failed (due to disease progression or toxicity) trastuzumab in the first-line metastatic setting. Trastuzumab must be discontinued for at least 3 weeks prior to enrollment
• Subjects must have received prior chemotherapy as adjuvant therapy or for metastatic disease
• Prior chemotherapy treatment must be discontinued for at least 3 weeks prior to enrollment
• Subjects must have had no prior capecitabine
• Subjects must have had no prior lapatinib

Exclusion Criteria: (must not have)

• Inflammatory breast cancer
• Current or prior history of central nervous system metastasis
• Clinically significant cardiovascular disease
• Concurrent or prior (within 1 week before enrollment) anticoagulation therapy, excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (ie, less than or equal to 1 mg daily) for prophylaxis against thrombosis is acceptable while on study
• Subjects with a history of prior malignancy, except:
  • Malignancy treated with curative intent and with no known active disease present for greater than or equal to 3 years before enrollment and felt to be at low risk for recurrence by treating physician
  • Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
  • Adequately treated cervical carcinoma in situ without evidence of disease
  • Subjects with interstitial pulmonary disease
• For Cohort B only:
  • Current or prior history of long QT syndrome
  • Baseline ECG report of QTc interval of > 480 milliseconds
  • Severe chronic liver disease (Child Pugh C)"

You can see by the many criteria listed above why suggestions are being made to relax the eligibility requirements.

Not only do you limit the population of eligible patients by having such strict requirements but also the patients that meet these requirements do not often represent the typical patients seen in clinical practice. The more diverse the trial's population, the more useful the results could be to the general public, particularly in Phase 3 trials.