Grades on this exam: 88 86 83.5 81.5 81 81 80 78 77 77 76 74 74 74 73 73 72 68 March 11, 2009 Page 1 of 4 HSEM 3708 - Spring 2009 - Exam 1 Name:___________________________________ ================================================================================= 1. Define the term 'clinical trial'. [7] A clinical trial is an EXPERIMENT carried out in HUMAN BEINGS with a HEALTH RELATED OUTCOME. Most clinical trials COMPARE two or more approaches to treatment or prevention. 2. Why are treatment assignments in clinical trials 'randomly' assigned? To try to ELIMINATE BIAS associated with treatment selection by either doctors or their patients. [7] To provide APPROXIMATE BALANCE on factors that may affect outcome, including factors that were not known in advance or measured. 3. Actually treatment assignments in most clinical trials now are NOT randomly assigned. They are assigned using the output of a computer program. The assignments are deter- mined by a formula. If you run the computer program twice, it will give exactly the same assignments. So it is not random at all, but completely predictable! a) How would you define the word 'random' ? Functionally, random means 'UNPREDICTABLE'. That is, if you are observing a random sequence of treatment assignments, you will not be able to predict with certainty what the next assignment will be. [5] b) Why is it OK to use a computer program to generate treatment assignments in a 'randomized' clinical trial? Because even though the sequence is not random, if you do not know the formula, you will not be able to predict a sequence of assignments. Clinical staff and their patients are not told the formula, so for them the treatment assignments are UNPREDICTABLE. [5] October 28, 2008 Page 2 of 4 PubH 7460 - Fall 2008 - Exam 1 Name:___________________________________ ================================================================================= 4. Recall the first clinical trial discussed in this class, on the use of dexamethasone for cerebral malaria. a) That trial had some defects which by today's standards might prevent its getting published. What were some of them? The study design was randomization in PAIRS, but the analysis was not a PAIRED analysis. The paired design could have permitted NONRANDOM assignment of patients. [4] The paper did not specify a PRIMARY ENDPOINT. The paper does not mention whether patients or their parents gave INFORMED CONSENT. There was no DATA AND SAFETY MONITORING BOARD. b) How might you redesign and analyze that trial if you had it to do over? 1. DON'T USE A PAIRED DESIGN. It does not have any advantages IN THIS STUDY over an unpaired design. [4] 2. Define a PRIMARY ENDPOINT 3. Define a STOPPING RULE based on the primary endpoint 4. Ensure that written INFORMED CONSENT is given 5. Have a DSMB to review the data periodically October 28, 2008 Page 3 of 4 PubH 7460 - Fall 2008 - Exam 1 Name:___________________________________ ================================================================================= Attached to this exam is a report on a clinical trial of Laetrile, a proposed treatment for cancer. Please answer the following questions: 5. Why was this trial undertaken? Laetrile (Amygdalin) was a WIDELY ACCEPTED treatment for cancer, legalized in 27 states. [9] There had not been a previous randomized trial that proved its EFFICACY OR EFFECTIVENESS. There had not been adequated studies of its TOXICITY. 6. What patients were eligible for this trial? Patients with cancer for which NO OTHER EFFECTIVE TREATMENTS WERE KNOWN Patients with tumors at least 5 cm in diameter [9] Patients in STABLE AMBULATORY condition with no recent previous treatments Patients with NO PREVIOUS EXPOSURE to cytotoxic drugs Patients who gave INFORMED CONSENT to be in the study 7. How many patients were randomized? ZERO. All the patients were assigned to Laetrile therapy. There was NO CONTROL GROUP. [5] 8. What was the primary outcome? Success was defined as REGRESSION OF THE TUMOR by 50% or more, [10] and no other signs of new malignant areas. 9. What were the authors' main conclusions? Do you think they were correct? ONLY ONE PATIENT had a partial positive response. The great majority of patients had PROGRESSION OF THEIR CANCER. About 95% of the patients [11] DIED by 18 months after starting therapy. There were signs of serious CYANIDE TOXICITY. There was essentially no positive aspect of the results of this study. October 28, 2008 Page 4 of 4 PubH 7460 - Fall 2008 - Exam 1 Name:___________________________________ ================================================================================= Laetrile trial, contin. 10. Could this clinical trial be criticized for its design? Explain. 1) There was NO CONTROL GROUP. We cannot tell from this whether patients given Laetrile would do better than patients on placebo. 2) ONLY PATIENTS THAT WERE REGARDED AS ESSENTIALLY INCURABLE by all other [12] means were included. Laetrile might have a beneficial effect in less advanced cases. But: if any other known-to-be-effective treatment was available, it would have been UNETHICAL to randomize patients to Laetrile. 3) Laetrile was given in combination with VITAMIN THERAPY. This makes it impossible to know whether the outcomes were affected by Laetrile or by the vitamins. That is, there was complete CONFOUNDING of Laetrile with vitamin therapy. 11. What do you think the effects of this trial on medical practice or patient behavior might have been? What SHOULD have happened: People should have stopped using Laetrile. If MDs or other practitioners were prescribing Laetrile, they should have stopped. The FDA could have tried to REGULATE Laetrile. It could have been OUTLAWED as a treatment [12] in the states in which it was previously legal. What DID happen: After this trial, in spite of its defects, Laetrile use sharply declined. A manufacturer of Laetrile tried to sue the NCI because sales of the drug dropped to 1/3 of the previous. Reasons for the decrease in use: Dr. Moertel was a famous cancer doc. The study was carried out by the Mayo Clinic, which has great prestige and respect both in the medical community and the general population. The study was published in NEJM, which is the most highly respected medical journal. The results were unambiguously negative for Laetrile. Laetrile can still be obtained through the Internet and in Mexico.