Phase 1 clinical trials begin the process of moving a potential medication from the laboratory to the patient. Unlike the later types of studies, the focus of Phase 1 investigations is to clarify the appropriate dose of the agent, define a preliminary toxicity profile, and describe its pharmacokinetics.
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“Phase 1 studies are the first link between the laboratory and the patient,” says Jill Buyon, MD, professor of medicine at New York University School of Medicine and founder of the systemic lupus erythematosus (SLE) clinic at the Hospital for Joint Diseases in New York City. “It is the ultimate transition of discovery to the patient.”
Initial phase trials can be broken into subgroups. One type uses healthy volunteers, the other stable patients with the specific disease under study. Many of the early trials currently underway in the area of rheumatology focus on SLE.
“Research in SLE is exploding and there are several promising agents moving through the pipeline that will need to be tested,” says Cynthia Aranow, MD, associate investigator at the Feinstein Institute for Medical Research in Manhassett, N.Y. “Making sure these trials are completed and done well is really important.”
Participants Not Always Clear on Efficacy Considerations
In addition to the ethical considerations inherent in any clinical trial (see “Are You Informed About Consent?” p. 1, May 2008), Phase 1 trials add concerns about how well the potential participant understands the reasons for undertaking these kinds of studies—to look at safety rather than efficacy.
“Although Phase 1 studies are mostly designed to look at initial uses and safety issues, a majority of patients think they are in a therapeutic trial and are going to benefit,” says Eric Matteson, MD, professor of medicine and chair of the division of rheumatology at the Mayo Clinic in Rochester, Minn. “Special care needs to be taken by the doctors and others charged with obtaining informed consent to make sure the participants know this difference.”
Although the new agent under investigation in these early trials may have extensive data on toxicity in animal models, it is not always clear how these translate to humans. Thus, it is hard to describe during the informed consent process exactly what the concerns are going to be.
“One of the risks that needs to be stressed to a potential subject is that we just don’t know what all the risks are going to be,” says Dr. Aranow. “Although inherent in all studies, unknown risks are a huge part of the Phase 1 trials. There is more uncertainty [in Phase 1 trials] for the investigator who is asking patients to put themselves at risk.”
Investigator Should Know the Molecule’s History
To help the participant understand what may happen, it is the duty of the investigator to know the history of the molecule up to that point. The experts interviewed here suggest asking many questions of the basic science experts at the pharmaceutical company. One of the first questions to ask is why the company picked this potential medication out of the entire pipeline for the very expensive clinical trials phase. Why was this one so special?
Next would be to understand the proposed mechanism of action. More importantly, does the mechanism make sense from a pharmacokinetic and biological standpoint? “I am also interested in knowing if the sponsor is interested in the mechanistic impacts of the molecule in addition to just safety parameters,” says Dr. Aranow. “We are exposing people to a new agent. To not learn as much as possible while exposing them to risk would be a crime.”
Finally, discuss what the animal studies have shown to be toxicity concerns. Also, ask about what has been discovered about the toxicity profiles of similar molecules. “To me it is a belief in the mechanism and belief that the company will continue to move the molecule forward if the safety looks good,” says Dr. Buyon. “It is a partnership between the investigator, the sponsor, and the participant.”
What happens after the study is over is an ethical concern that should be discussed at length with a participant. Although Phase 1 trials are not specifically focused on efficacy, the potential for efficacy remains, or the molecule would not a viable candidate for study. So, what happens if there is a therapeutic benefit to an individual? It is not always possible from a protocol perspective to include those participating in the Phase 1 trial in later-stage trials. Thus, another part of the informed consent is to make sure that subjects know they may not have access to the drug unless it reaches the market as much as a decade later.
“These are mainly short-term trials lasting six to 12 weeks at the most,” says Christine Barr, RN, CCRC, clinical research coordinator at the Center for Rheumatology in Albany, N.Y. “In reality, many with chronic illnesses get into these studies to find some relief. What comes after is an important consideration that should be addressed early in the process.”
Family and Patient Concerns Sometimes Conflict
Taking into consideration the personal concerns of the patient’s family with the needs of the study is an especially tricky balancing act. What should happen when the potential participant is eager, but a spouse or adult child is hesitant?
“When this occurs, I speak to the family members and ask what their concerns are,” says Dr. Aranow. “Much of the time, it will be that there was something the family member misunderstood and the objections go away with the misunderstanding. Sometimes the family just doesn’t want the study participant to take part in any kind of research, period.”
The other side of the family equation can occur when the family member is eager for participation, but the patient is unsure. This is a tricky moral dilemma for those involved in running the study. The participant who is enrolled in a trial must have decided on their course freely and without coercion from anyone.
“I have had some instances where the spouse is all for it,” says Mellynn Nuite, RN, CCRC, clinical research coordinator in the Center for Arthritis and Rheumatic Diseases at Tufts-New England Medical Center in Boston. “I always try to speak to the potential participant alone to see if this is something they really want to do. In almost all studies there is an exclusion criteria option the investigator may use to not enroll patients which can be used if there is any lingering doubt about voluntary study participation.”
However, in the end, the participants are autonomous adults and their decisions should be honored. “The real bottom line, I tell the participant, is that if nobody volunteers for Phase 1 trials, there will never be a drug approved for use in lupus,” says Dr. Buyon. “There will be no such thing as translational medicine if someone doesn’t step up to be the first.”
Kurt Ullman is a freelance writer based in Indiana.