Session I. After the Clinical Trial? Then What?

Discussion Leaders: Marian C. Limacher, M.D., Professor of Medicine, University of Florida College of Medicine, Gainesville, Florida, and Deneen Robinson, B.S.W., HIV Treatment Consultant, Dallas, Texas

Different Types of Clinical Trials and Implications for Post-Trial Management

Dr. Marian C. Limacher pointed out that some HIV-positive clinical trial participants have private health insurance, but because of fear of stigma and losing their employment, they do not use their medical insurance when seeking medical care. Instead, they enter clinical trials. Therefore, several issues involving people living with HIV necessitate various answers to the "then what?" question, and those answers are often unique to the individual who is participating in the trial.

Ms. Deneen Robinson added that for HIV patients, the clinical trial may be the major provider of medical care. Treatments for HIV often have not been used in the population; therefore, the purpose of the trial is to ensure not only that the product is safe but that it can actually work in combination with other drugs to treat HIV disease.

Researchers want HIV medications to do four things: (1) prolong quality of life, (2) limit the onset of opportunistic infections or life-altering diseases, (3) provide some reconstitution of the immune system, and (4) result in the least amount of toxicity damage to the person taking the medication.

If a person's main reason for going into an HIV trial is access to medical treatment, then a monetary incentive is unnecessary. Such people are willing to tolerate changes in how they look and feel because they are offered the opportunity to prolong their life. The research team takes on all aspects of medical care and provides medications not otherwise available. The participants are often people of color. Many newly infected men who do not have access to health care enter HIV clinical trials without understanding HIV disease and the impact of treatment on them. They are not adequately informed about other options, and if they opt to drop out of the trial, they know they will lose their access to health care.

In clinical trials involving chronic diseases such as cardiovascular disease, participants generally are of higher socioeconomic status than individuals who enter HIV trials, and their reasons for enrollment are altruistic as well as personal. They are interested in the benefits to future generations or other patients. They tend to have high levels of attendance, adherence, and retention. Staff involvement is less personal and there is a higher participant-to-staff ratio than in HIV trials.

Considerations at Trial Closeout and Study Termination

Clinical trials involve a broad spectrum of activities, and their timelines are highly variable. The phases of a clinical trial include concept development, funding, acquisition, protocol development and refinement, recruitment and followup, and closeout of the trial. However, these phases are not distinct--they overlap. Therefore, the planning for each phase must take place at the very beginning; communication, retention, and closeout and post-trial activity should be part of the early planning for a clinical trial.

Early planning meetings should cover what needs to be accomplished at trial closeout. First and foremost is acknowledgment of the value of the participants' contribution to the trial through a thank-you letter, certificate, or token of appreciation. Second, the participants should be provided with information about the trial results. The actual findings should be provided, if available, at the last visit, or they should be communicated to the participants by letter, phone call, or Web site. Conveying the results to the participants almost always involves some sort of mailing; therefore, post-trial funding is necessary to accomplish this task. Third, transition care to a nonresearch setting should be provided. The researcher should consider options for primary medical care for participants who need it.

Another consideration at closeout is maintaining a positive relationship between the participant and the research staff. It is important to remember that the main reason for good adherence and attendance in a clinical trial is the participants' relationship with staff. Maintaining a positive relationship also can be viewed as a recruitment tool for future research studies; participants can spread the word to others that participating in a clinical trial is a positive experience. One of the roles of a research clinic is securing populations for future studies.

A shift in the continuity of care occurs with the change from a protocol-driven practice to standard care procedures. Quality of care might decrease. Participants lose both their medical care coordinator--that is, the PI, the nurse practitioner, the social worker, or the case manager who makes referrals to other providers for various problems--and their access to care. In addition, the change in provision of medications means that medications will no longer be obtained regularly and easily even if there is some other way to pay for them.

The special issues at trial end include limited financial resources, lack of health care coverage, loss of "family" interaction and support of the clinical research staff, potential loss of medications, the lack of an alternative provider, reduction in quality of care, and concern about changes in clinical status.

Case Example: Lipid-Lowering Trial

The lipid-lowering trial involved patients with known coronary disease who were randomized to a statin or placebo. Followup occurred over a 4-year period. The closeout occurred as planned, and the preliminary findings were available at closeout. All the patients had a personal physician throughout the study. The clinic visits documented outcomes and events, assessed lab work, and included physical exams. At closeout, letters were sent to participants and providers thanking them for their participation. The participants were invited to a group meeting to hear the preliminary study results and to learn what their participation revealed. They were "unblinded" at the time of the closeout, so they actually got to find out what medication they were on. They also were given a 3 month supply of medications because of the positive results of the study. The closeout event was well attended and well received. Participants were very satisfied with the whole experience, and many of them have enrolled in subsequent studies at the same sites.

Case Example: Women's Health Initiative

The Women's Health Initiative (WHI) study is ongoing, but the estrogen plus progestin arm of the hormone study was terminated early. The study began in 1993, and enrollment was completed in 1998 with a population of more than 16,000 postmenopausal women. The estrogen plus progestin arm was part of a large, complex WHI program. In May 2002, the Data and Safety Monitoring Board (DSMB) determined that the risks of breast cancer and cardiovascular disease events outweighed the benefits for active treatment with estrogen plus progestin. The DSMB determined that this arm of the study should close early. The recommendation was forwarded to and approved by the National Heart, Lung, and Blood Institute (NHLBI), and the director of NHLBI concurred with the recommendation.

Simultaneous with these events, the WHI Executive Committee drafted a paper with the findings, planned notification, and closeout, but the investigators were not notified until 1 month before closeout was to occur. The manuscript was published, and participants received notification on July 8, the day before the press release. They were told to stop their study medication and to attend a scheduled appointment. The result was an immense media response. Participants and providers called the clinics, and national organizations weighed in on the early termination of this arm of the study.

Overall, the participants appreciated being notified first and understood the process and the results. They realized that determining risks versus benefits was the reason they participated in the study in the first place. They felt proud to be "part of the answer." The participants were instructed to discuss further hormone treatment decisions with their personal providers, and all of them continued in the study for followup purposes. On the other hand, the health care providers and professional societies did not feel they had enough "warning" even though they had received annual letters describing the study. In addition, they failed to access the online manuscript in time to respond to individual patients' questions and were bombarded by non-WHI patients with questions, demands, and even lawsuits. Overall reactions criticized the study for not asking the right questions and for applying only to a few people. The industry response was to mobilize its forces to counteract the findings.

Lessons learned from the WHI experience include trying to anticipate media reaction, providing better and faster information to providers, engaging providers throughout the study to avoid "surprises," and paying attention to industry's potential response.

Case Example: HIV/AIDS

Ms. Robinson described two different case studies. One study took place in a community clinic setting where patients were recruited into the trial when they came to the clinic to access medical care. The trial site was in the same building as the clinic but on a different floor. The trial staff consistently tried to meet all the needs of the patients, including food and childcare. They also tried to provide support for participants' comorbidities, such as substance use, diabetes, and hepatitis C.

Once the trial was over, patients began to access care "downstairs" in the clinic, where they had to wait at least 4 hours to see a physician and where they did not get the kind of hands-on care offered "upstairs" at the trial site. Clinic patients had to go to a separate building to wait to pick up their medications. Other barriers involved income and transportation, both issues addressed by the trial but not by the clinic. Suggestions for improving the transition from trial site to clinical care include offering advice at the beginning of the trial for continuing health care once the trial is over, introducing patients as the trial is ending to the new clinic setting, and introducing patients to the care team or social worker they will deal with after the trial is over. If these suggestions are followed, then people who are no longer participating in a clinical trial would not have to learn how to navigate a new system on their own.

The second case study involves a white male in his 30s who was newly infected with HIV. He had no health insurance and no access to medications. He joined the trial in a private doctor's office because he wanted to get optimal care. Because of treatment failure, the patient switched to a new regimen. When that regimen failed, the individual was removed from the trial. He could not continue care with the private doctor because he could not afford to pay. He was forced to go to a community clinic, but he dropped out of care for a while because he was overwhelmed by the process of changing from a private physician to a community clinic. Suggestions for improving the lot of people as they transition from a clinical trial to standard care include offering a community educator for assistance, giving patients information about options, and providing patients with information for the health care provider. Following these suggestions will enable patients to make a smooth transition to the community clinic setting if they deplete their funds and can no longer afford care by a private physician.

Discussion

The breakout session raised the following issues and questions:

• Community advisory boards can play an important communication role at the end of a study, as well as during startup. Efforts should be made to keep them involved throughout the life of the trial.

• An attendee reiterated the importance of being prepared for trial closeout, including knowing how to handle timelines and negative findings from the Data Safety and Monitoring Board. Also, participants must be prepared for what happens at the end of a trial, not only for reentry into a clinic setting, but also for ending the trial relationships. In addition, followup through newsletters, phone calls, or e-mails should occur for individuals who fail the screening process for a particular trial but might be participants in future studies.

• Another participant suggested that psychologists be on hand to discuss the closeout process with HIV participants.

• Post-trial planning should entail merging research concerns with concerns about care. This notion should be added to research protocols, or a care plan should be included. Researchers do not think about care of the individual; they think about getting independent, objective data that will answer a specific aim or a specific objective. Researchers want to answer scientific questions, and care is seldom considered when planning a research study. This fact makes closeout, especially in HIV studies, very difficult.

• Another attendee asked a question about the phases of clinical trials: "What is the relationship between closeout and recruitment?" Closeout can mean the end of treatment, but it also can mean dissemination and enrollment in other clinical trials. Dr. Limacher agreed that closeout encompasses much more than just contact with participants; it includes dissemination of the findings and changes in practice. The planning for closeout should be part of the initial strategy. IRBs require that during recruitment, participants be told how they will learn-or if they will learn-the results of the study. Being part of the solution at the end is part of the recruitment process. Participants might be recruited into additional studies depending on whether other studies are available at the clinic and how the mechanism to maintain contact is funded and managed. Continuity can be planned.

• Another participant asked whether former trial participants can help to transition patients from the trial setting to the clinic setting. Speaking from his own positive experience, this participant noted the continuity of care he received as a participant in multiple studies at a clinic that is tied to a study site. Ms. Robinson noted that the examples she gave of HIV/AIDS trials concerned patients who tested positive and immediately entered a trial. In that case, the patients enter the research setting without establishing a relationship with the clinical care people. When the trial is over, they must make the difficult transition to care.