You are in charge of a therapeutic area for the US subsidiary of a European-based company that does not have a global development team or a standard operating procedure that ensures a single, globally agreed final medical report. You have just received the final medical report from Europe of a pivotal trial that was conducted entirely in Europe. All of the statistical analyses appear sound, but you are astounded at the very positive conclusions drawn, and in your opinion, the data were overinterpreted. You do not agree with the interpretation and must submit the medical report to the Food and Drug Administration (FDA). If the conclusion is not moderated, you are certain that the FDA will reject the conclusions and/or interpretations of the trial, but your company does not like people to alter interpretations of a completed final medical report. Your view is that the FDA is more conservative than the European Union, and for strategic or political reasons, you want to modify the conclusions for the FDA. How will you handle this situation? What are your options?

Your company has put you in charge of a new project to develop a recently discovered compound that has just entered the development phase. It is hoped that the drug will be used both orally and intravenously to treat patients with a very serious and life-threatening disease. At present, you have little idea of the anticipated safe or effective dose that will be used in patients because the animal data are not very extrapolatable to humans. The personnel resources available to help you with this project consist of one assistant from the medical group and minimal help from elsewhere in the company. What options will you propose for developing this drug to the research management committee that will review the project’s status?

Your company is designing a Phase 2b, well-controlled protocol for a chronic disease for which it is traditionally very difficult to get patients to enroll. Your drug is a modest advance over existing therapy, but it is not a major breakthrough.

The statisticians tell you that, to achieve adequate power, you need 50% of patients to be on active drug and the remainder on placebo. Your concern is that this split will further discourage patient enrollment in the trial, and you are thinking of proposing an 80%/20% split to encourage patient enrollment. The trial is designed to last four weeks, and patients have to be weaned from existing therapy before they enter your protocol. What options do you have to solve this dilemma?

You have designed a well-controlled parallel trial to compare your drug and placebo. The disease the drug is intended to treat is fairly uncommon. The treatment period is three months. To encourage enrollment, you want to offer patients the opportunity to enter a long-term continuation protocol where patients would theoretically stay on their original therapy until the main trial is completed and the blind is broken. At that time, you intend to offer patients on placebo the opportunity to receive active drug. However, you do not think it is ethical to keep patients on placebo in the continuation protocol for longer than ten weeks. The problem is that it will be two years before the investigators can enroll all patients and complete the main trial. It is important to keep the identity of the patient’s continuation drug blinded until the major trial is completed. The dilemma is how to keep the original trial blinded while it continues and not keep patients on placebo for more than ten weeks in the continuation trial.

Patients are presently randomized in blocks of four, and there are 20 patients per site. Everyone from the major trial must be withdrawn slowly from drug at the end of the major trial for safety
reasons, whether or not they are transferred to the continuation study. When patients are escalated in dose in the continuation trial, they will generally know if they were on placebo in the major trial because their reactions to treatment are likely to differ when given the active drug. This is likely to unblind part of the major trial when the patients discuss their clinical reactions to the drug with the staff at follow-up visits in the continuation protocol. What is the best approach to address this issue?

Two well-respected specialists at a large academic medical school call a news conference to announce that they have found an important and previously unreported electrocardiogram abnormality in four patients with one of your company’s marketed drugs. This makes the evening news. Your boss calls you in the next morning and tells you to investigate. What are the specific research activities you will conduct?

You are running a major pivotal trial at ten academic institutions on an important new product for your company. Unfortunately, none of the sites are enrolling patients at the minimum rate you calculated necessary to complete this trial on schedule. Each investigator knows this number, and all of them give you different reasons about why they are not meeting their commitments. What steps will you take to increase enrollment?

An investigator in one of your trials calls you to discuss a patient who had a serious adverse event. The investigator has no idea if the patient was in the placebo or test drug group. In discussing the patient with you as the monitor, various treatment options and possible clinical trial discontinuation are covered. The investigator notes that you are very calm about the situation. The investigator decides that the patient must be in the placebo group since he would not expect you to be so calm otherwise. At the end of the conversation, the investigator’s medical judgment and course of action are heavily influenced by this impression.

In the actual situation, the investigator mentioned this to the monitor at the very end of the conversation, so that the monitor became aware of this reasoning by the investigator.

On a routine monitoring site visit for a pivotal clinical trial, the monitor finds that the rate of patient enrollment has fallen to a lower than anticipated level. On exploring the situation, the monitor learns that the investigator has also initiated a clinical trial for one of the sponsor’s competitors. The newer trial is clearly taking patients away from the monitor’s trial.

Well-conducted, cost-effectiveness studies show that Drug A will cost your hospital $200 more per patient each month than Drug B. You are a member of the formulary committee for a hospital and must decide whether or not to put Drug A on the formulary. How will you vote, and why? Are there other data that you want to see first?

Ten medical school freshmen were enlisted as volunteers by a professor with his first Investigational New Drug Application to test a new biological agent for the first time in humans. The study was performed in the early afternoon, shortly after the students’ biochemistry final was completed. The professor who taught biochemistry was not the same one who was conducting this trial. The students sat around a small parlor, where all the measurements were to be made, after being given the biological. After half an hour, one student felt hot and flushed in the small overheated room. Soon, she felt cold and clammy.

Over the next 30 minutes, most of the other volunteers had “contact reactions” as they were affected psychologically by the female’s emesis and nausea. Soon, almost everyone was vomiting.

You are the project leader of a newly marketed drug for your company. Shortly after the launch, your boss enters your office excitedly waving a journal and saying in a loud voice, “Did you see this ad? Our competitors are claiming that their drug is cost effective because it enables patients to return to work sooner than with other drugs. But their drug costs four times as much as ours. Design an economic trial to show that our drug is more cost effective than theirs.” How do you respond?

The clinical trial you put your heart and soul in as the overall monitor got off to a great start. All 30 sites were doing a great job, but that was six months ago. Now almost all of the sites seem to be losing interest, and the trial is only about half over in terms of patient enrollment. When you speak with the investigators, they appear to lack their original motivation. The drug being tested is to treat a major disease for which there are several other drugs on the market. What are you going to do to turn the situation around?