PubMed · 54750
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1976-02-14. Editorial: How double blind?. https://pubmed.ncbi.nlm.nih.gov/54750/
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PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). RESULTS HYPOTHESIS: A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. PATIENT POPULATION: The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. INTERVENTION: Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. OUTCOMES: An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting: Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. TRIAL DESIGN: The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. CONCLUSION: Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward.
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Prevention studies, as distinguished from studies investigating treatments for established disease, present some distinct challenges. Perhaps the most extensive experience with preventive agents is in the area of infectious diseases; vaccines have been extremely effective in preventing many such diseases. Vaccines have been, and continue to be, studied in other disease areas such as certain cancers, but as yet have not achieved success outside of infectious disease prevention. One obvious and important feature of prevention studies is that they enroll healthy individuals; thus such studies require particularly high standards for the safety of those enrolled (and those who might ultimately receive the product being tested). Prevention studies often need to be quite large, as the types of diseases most important to prevent tend to be uncommon. Large studies usually require simplified approaches; to ensure high quality of data on the key variables it may be necessary to compromise on the amount of data collected, frequency of data collection, and other aspects of trial design. The reliability of randomization and blinding may be especially important in these large studies, as bias could easily overwhelm the small effects that are usually sought. Often, biomarkers thought to indicate developing but as yet subclinical disease, will be important to evaluate; whether such markers can serve as primary endpoints in prevention studies has been a contentious issue in many contexts. Studies in older populations, such as those at risk for Alzheimer's Disease, raise challenges such as accounting for competing risks, and considering potential interactions of preventive agents with multiple medications often used by the elderly.