Glossary

Adaptive trial design—a trial with one or more decision points built into the trial design. How the trial proceeds following each decision point depends on the data observed up to that point. One of the more commonly used adaptive trial designs is one that stops early or continues later than expected based on results that indicate how effective the treatment under study is after a limited number of patients have been tested.

Amplification—a process resulting in an increase in the number of copies of specific genetic sequences within a genome. Amplification of some genes can cause some types of cancer.

Analytical validity—the accuracy of a test in detecting the specific entity that it was designed to detect. This accuracy does not imply any clinical significance, such as diagnosis.

Apoptosis—programmed cell death.

Bias—the systematic but unintentional erroneous association of some characteristics within a group in a way that distorts a comparison with another group.

BRCA—a gene that when mutated increases risk of developing breast cancer and/or ovarian cancer. Two BRCA genes have been identified and are known as BRCA1 and BRCA2. The acronym BRCA stands for “breast cancer gene.”



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Glossary Adaptive trial design—a trial with one or more decision points built into the trial design. How the trial proceeds following each decision point depends on the data observed up to that point. One of the more commonly used adaptive trial designs is one that stops early or continues later than expected based on results that indicate how effective the treatment under study is after a limited number of patients have been tested. Amplification—a process resulting in an increase in the number of copies of specific genetic sequences within a genome. Amplification of some genes can cause some types of cancer. Analytical validity—the accuracy of a test in detecting the specific entity that it was designed to detect. This accuracy does not imply any clinical significance, such as diagnosis. Apoptosis—programmed cell death. Bias—the systematic but unintentional erroneous association of some characteristics within a group in a way that distorts a comparison with another group. BRCA—a gene that when mutated increases risk of developing breast cancer and/or ovarian cancer. Two BRCA genes have been identified and are known as BRCA1 and BRCA2. The acronym BRCA stands for “breast cancer gene.” 0

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0 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS Clinical endpoint—characteristics or variables expected at the end of a clinical trial, reflecting how patients feel, function, or survive. After achievement of a clinical endpoint, a patient’s participation in the clinical trial ends. Clinical trial—a formal study carried out according to a prospectively defined protocol that is intended to discover or verify the safety and effec- tiveness of medical procedures or interventions in humans. Clinical utility—the physical and psychological benefits and risks of a given technique or test. Computed tomography (CT)—a radiographic technique that uses a computer to assimilate multiple X-ray images into two-dimensional, cross- sectional images or a three-dimensional image. Use of this technique can reveal many soft-tissue structures not shown by conventional radiography. De novo classification—a Food and Drug Administration classification of a device or diagnostic that is not equivalent to a legally marketed product. De novo classification is a way for a low-risk medical device to bypass the premarket approval process. Deletion—the loss of genetic material. Some cancers are triggered by the deletion of key genes, portions of genes, or their regulatory sequences. Diagnostic—an investigative tool or technique used in biological studies or to identify or determine the presence of a disease or other condition. Epidermal growth factor receptor (EGFR)—a receptor that is over- produced in several solid tumors, including breast and lung cancers. Its overproduction is often linked to a poorer prognosis because it enables cell proliferation, cell migration, and blood vessel development. Several new drugs recently approved by the Food and Drug Administration specifically target EGFR. Estrogen-receptor positive (ER+)—a tumor, either a primary tumor or a metastasis, that tests positive for estrogen receptors. Such tumors, often found in cancers such as breast cancer or uterine sarcoma, may be treated by hormonal therapy that decreases or blocks estrogen to prevent or slow tumor growth. Some tumors may also be progesterone-receptor positive (PR+) and may be treated with a different type of hormonal therapy. Genome—an organism’s entire complement of DNA, which determines its genetic characteristics.

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 GLOSSARY Genomics—the study of all of the nucleotide sequences, including struc- tural genes, regulatory sequences, and noncoding DNA segments, in the chromosomes of an organism or tissue sample. One example of the applica- tion of genomics in oncology is the use of microarray or other techniques to uncover the genetic “fingerprint” of a tissue sample. This genetic fingerprint is the pattern that stems from the variable expression of different genes in normal and cancer tissues. Global outsourcing—conducting a clinical trial outside the United States in an effort to save money. High-throughput system—any approach using robotics, automated machines, and computers to process many samples at once. Human epidermal growth factor receptor 2 (HER-2/neu)—a growth factor receptor that is used as a breast cancer biomarker for prognosis and treatment with the drug trastuzumab (Herceptin), which targets the pro- tein. The HER-2/neu protein is overexpressed in approximately 25 percent of breast cancer patients, due to amplification of the gene. Magnetic resonance imaging (MRI)—a method by which images are created by recording signals generated from the excitation (the gain and loss of energy) of hydrogen atoms in tissue when placed within a powerful magnetic field and pulsed with radio frequencies. Mass spectrometry—a method for separating ionized molecular particles according to mass by applying a combination of electrical and magnetic fields to deflect ions passing in a beam through the instrument. Microarray—a high-throughput tool for biological assays in which many different probes (sometimes 10,000 or more) are deposited on a chip surface (glass or silicon) for analysis. DNA microarrays are the most commonly used microarrays. Microdose study—a study employed in phase 0 clinical trials that uses imaging or other means to assess where in the body a compound is distrib- uted and for how long it remains in these sites. A microdose is defined as less than 1/100th of the dose predicted to yield pharmacological effects, and less than 100 micrograms. A microdose study is designed not to induce pharmacologic effects; rather, it can indicate whether an experimental drug reaches its target. Off-label use—the doctor-prescribed use of a drug for a condition or dis-

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS ease for which it has not been approved by the Food and Drug Administra- tion, or the use of a drug by a non-approved method. Pharmacodynamics—the study of the biochemical and physiological effects of drugs, the mechanisms of drug action, and the relationship between drug concentration and effect. Pharmacodynamics is the study of what a drug does to the body, as opposed to pharmacokinetics, which is the study of what a body does to a drug. Pharmacokinetics—the study of the metabolism of, or chemical changes experienced by, substances in an organism over time, such as drugs. Phar- macokinetics is used to determine how quickly and for how long a drug acts on its target. Phase 0 trial—an exploratory investigational new drug study (IND). The main purpose is to assess the likely therapeutic effectiveness of a compound, based on whether it reaches its target in people and how long it is active in the body. An exploratory IND study tests a new experimental drug on human subjects prior to a phase I clinical trial. Phase I trial—a clinical trial in a small number of patients in which the toxicity and dosing of an intervention are assessed. Phase II trial—a clinical trial in which the safety and preliminary efficacy of an intervention are assessed in patients. Phase III trial—a large-scale clinical trial in which the safety and efficacy of an intervention are assessed in a large number of patients. The Food and Drug Administration generally requires new drugs to be tested in Phase III trials before they can be put on the market. Positive predictive value—the probability that an individual with a posi- tive test has or will develop a particular disease or characteristic that the test is designed to detect. It is a measure of the ratio of true positives to the sum of true and false positives. Positron emission tomography (PET)—a highly sensitive technique that uses radioactive probes to image in vivo tumors, receptors, enzymes, DNA replication, gene expression, antibodies, hormones, drugs, and other com- pounds and processes. Premarket approval—a Food and Drug Administration approval process for a new test or device that enables it to be marketed for clinical use. To

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 GLOSSARY receive this approval, the manufacturer of the product must submit clinical data showing the product is safe and effective for its intended use. Premarket notification or 510(k)—a Food and Drug Administration review process that enables a new test or device to be marketed for clinical use without undergoing the premarket approval process. To qualify for the 510(k), manufacturers must provide documentation supporting the claim that their product is substantially equivalent to one already on the market, in terms of safety and efficacy. Proteomics—the study of the structure, function, and interactions of the proteins produced by the genes of a particular cell, tissue, or organism. The application of proteomics in oncology may involve mass spectrometry, two- dimensional polyacrylamide gel electrophoresis, protein chips, and other techniques to uncover the protein “fingerprint” of a tissue sample. This protein fingerprint is the pattern that stems from the various amounts and types of all the proteins in the sample. PSA test—a blood test that detects prostate-specific antigen (PSA). The PSA test was approved by the Food and Drug Administration in 1985 for prostate cancer recurrence, but it is now widely used as a screening test for prostate cancer. Qualification—the evidentiary process of linking an assay with biological and clinical endpoints that is dependent on the intended application. Randomization—randomly placing trial participants in different arms of a trial; for example, one arm may use a standard treatment while another uses a standard treatment plus a new drug. Sensitivity (clinical)—a measure of how often a test correctly identifies patients with a specific diagnosis. It is calculated as the number of true- positive results divided by the sum of true-positive and false-negative results. Specificity (clinical)—a measurement of how often a test correctly identi- fies the proportion of persons without a previous diagnosis. It is calculated as the number of true-negative results divided by the sum of true negatives and false positives. Surrogate endpoint—a biomarker that is intended to substitute for a clinical endpoint in a therapeutic clinical trial and is expected to predict

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS clinical benefit, harm, or lack thereof, based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Two-dimensional gel electrophoresis—a technique used to separate molecules from one another based on their isoelectric point, charge, and size. One-dimensional electrophoresis, in contrast, has fewer molecule- distinguishing capabilities, as it only separates molecules on the basis of their charge and size. Type 1 error—In statistics, the error of the “false positive.” In other words, concluding that a test result is positive when it is, in fact, negative is a Type 1 error. Validation—the process of assessing an assay or measurement performance characteristics.