Throughout his life, Dan Bond has offered his time and body to the cause of science. The Galveston, Texas, engineer with severe hemophilia B took part in clinical trials before he even knew what that phrase meant. As a child, he served as a subject for his father, a research hematologist at the University of Texas Medical Branch in Galveston.
As an adult, Bond, 55, has participated in trials running the gamut from improved factor replacement products to gene therapy, each with varying levels of time commitment and medical risk. For Bond, both the time and the risks are worth it.
[Steps for Living: Clinical Trials]
“All of the advances that I benefit from are the result of people before me doing clinical trials,” Bond says. “I look at it as my obligation to both the past and the future. People did it for me, and I need to do it for the people of the future.”
Clinical trials—whether they’re testing a new drug or treatment, measuring the safety of an experimental therapy or fine-tuning dosages of an existing product—move science and medicine forward. But without participants like Bond, there’s no movement at all.
That’s why Margaret Ragni, MD, MPH, praises clinical trial participants. Ragni, professor of medicine at the University of Pittsburgh and director of the Hemophilia Center of Western Pennsylvania, matches Bond’s enthusiasm for clinical trials. “They are the mechanism by which we move science into clinical care,” she says. “Without clinical studies, we cannot take these wonderful findings in the lab to patients. We want better drugs and treatments. We want our patients to feel better. We want them to benefit from every bit of science that’s out there.”
Early Conversations
For people with bleeding disorders, the clinical trial process starts with an open and honest conversation with their doctors. During this “informed consent” process, they discuss the purpose of a trial, the risks involved, the possible benefits, the time commitment and many other factors. Ragni and fellow researchers recommend that people start by checking with their doctors and hemophilia treatment centers to find out what trials are available. Then, individuals have to meet a trial’s criteria to participate.
Hospitals and research institutions screen participants carefully to ensure effective trials and patient safety. Criteria such as age, gender, type of bleeding disorder, treatment history or current state of health may determine a person’s ability to participate in a particular trial.
Even if a person is qualified, Ragni won’t accept a yes or no answer on the spot. “You have to know that it’s what patients want to do, not just what you want them to do.”
When Ragni discussed a gene therapy trial during a routine checkup, Scott Contreras, a 32-year-old drafting designer from Pittsburgh with severe hemophilia B, quickly expressed interest. Still, Ragni insisted that Contreras sleep on it. He heeded her advice. He weighed the pros and cons. He talked with his parents and fiancée. After all that, his enthusiasm remained. He saw a chance to help the medical community that had long helped him.
“I looked at the possible end results and the possible medical advancements,” Contreras says. “The positives more than outweighed the negatives.”
As seriously as the informed consent process is taken for adults, it may be even more important when children are involved. Trials that include children often will test therapies or specific drug dosages already proven to work safely in adults. Safeguards minimize the risk to children, Ragni says. But even with reduced risk, researchers must work closely with parents of minors to obtain the informed consent. If those minors are old enough to understand the process, researchers also will try to explain to them, in simple terms, the things that will happen in a trial before getting their agreement to participate.
Risks, Reviews and Safety Nets
For researchers, the clinical trial process begins long before any conversations with prospective participants take place. First, they design a study’s protocol and submit it for approval by an Institutional Review Board (IRB), an independent committee that reviews all clinical trials and monitors those in progress. The protocol and the IRB approval process are designed to ensure that the safety of participants is maintained, their privacy is protected, the science is valid and the end results are worth pursuing.
Knowing whether a study is worthwhile comes easier in the bleeding disorders community than in other areas, says Craig Kessler, MD, professor of medicine and pathology and director of the Hemophilia and Thrombophilia Comprehensive Care Center at Georgetown University Hospital in Washington, D.C. He is also chair of the National Hemophilia Foundation’s (NHF’s) Medical and Scientific Advisory Council. Kessler and other researchers have become adept at identifying studies 
that might benefit participants or the community as a whole, versus those that are just marketing tools for drug companies.
“We’re very fortunate in the hemophilia community because it’s so tightly knit,” Kessler says. “The physicians know each other, so if there’s any question at all, they contact each other to make sure the design and aims of the trial are not going to harm the individual, and also that there’s a potential benefit.”
The risks depend on the nature of the trial. For example, frequent blood draws may cause bruising, bleeding or lightheadedness for people with and without bleeding disorders. In drug trials, unknown side effects or allergic reactions may occur in the course of the treatment. For gene therapy research trials, the risks and unknowns are even more complicated. Injecting a viral vector, a virus modified to deliver gene therapy, may adversely affect the immune system. The research team must monitor for all potential risks going into a trial, follow all regulations and have a plan to manage any side effects that arise, Ragni says.
The risk level also varies depending on the “phase” of a trial. Phase I trials typically test the safety of a new drug or procedure. They include a small number of patients in order to expose as few people as possible to risk.
When an acceptable safety level has been shown, phase II trials begin. They include a larger number of participants and test for efficacy. For a new factor replacement product, a phase II trial might involve testing participants’ blood for improved factor levels.
By phase III, researchers know that a drug is safe and somewhat effective. At this stage, they are testing to see if it is clinically effective in a wide range of people, what the side effects are, what dosages work best and whether the product is more effective than existing products. Trials commonly go beyond phase III to phase IV to fine-tune a drug or its dosages.
Kessler says the best trials are double-blind, meaning that participants don’t know whether they’re getting the new treatment or not. They may be in a control group that receives standard therapy instead.
However, safety nets are built into the process. A trial participant can quit at any time, for any reason. Trials have stopping points at which an independent group evaluates the benefits and risks. “If there’s an overwhelming benefit in one group of a study versus the other,” Kessler says, “the study stops, and all patients get the beneficial treatment.” In that case, trial participants end up with early access to novel therapies they might otherwise not receive for years.
The clinical trial process is long for all involved. But researchers and the people who benefit from new drugs and therapies tend to think it is worth the time. “When you do it right, you take the time and are careful. You let the patients know every step of the way what’s going on, asking them how they feel, how things are going, what bothers them,” says Ragni. “That way, you make sure it’s a good experience for them, and you get answers to important scientific questions.”
Motivations and Barriers
Dan Bond knows all about the time and sacrifice involved in clinical trials. As part of a gene therapy trial several years ago, he flew from his home (at the time) in Austin to Houston once a week for about six months, with a small kit full of his blood and other fluids in tow. “I realized very quickly that I should check it rather than try to take it through airport security,” he jokes.
Bond’s participation in early gene therapy research illustrates several barriers that make it difficult to recruit people for trials. He had to overcome geographic distance. He had to undergo a liver biopsy. He had to take time off work. He had to take the inherent medical risks associated with any early-stage trial. And he knew he wasn’t likely to receive any immediate personal benefit.
Bond says he was motivated by a sense of obligation and an adventurous spirit. “Sometimes you just have to put on your big-boy pants and give it a try,” he says. However, he adds that he’d have a hard time personally advising someone to take part in such a trial where the risks may outweigh the benefits.
Bond also has been on the other end of the motivation spectrum. When he was first diagnosed with HIV, he had no health insurance and no access to drugs—until he took part in an early 1990s trial for an AZT “cocktail” that proved effective.
“That trial may very well have saved my life,” he says.
That motivation is familiar to Mark Skinner, president of the World Federation of Hemophilia, who has severe hemophilia A and also participated in an early HIV drug trial (see sidebar “Opening Access to HIV Trials”). He understands that people in that era often acted out of sheer necessity. The trials may have provided their only access to HIV drugs.
Skinner stresses that people today need to draw an important distinction. “Clinical research is fundamentally important to advancing knowledge and science, but patients should not confuse research with treatment,” he says.
Skinner, Ragni and Kessler all point to what is perhaps a more appropriate motivation in the modern era: altruism. All three have seen it in many clinical trial participants. It ultimately motivated Contreras when he volunteered for the gene therapy trial with Ragni.
“I don’t want others, either future generations of my family or other children, to have to go through what I went through growing up,” he says. “I’ve been through a lot of pain through the years, with joint bleeds and other symptoms. To help others avoid that pain makes all the time and effort worth it.”
Still, even in a community prone to selflessness, the biggest barrier to clinical trials may be scarcity. The bleeding disorders community is relatively small and quite dispersed. That’s why many trials in this community, from those early HIV trials to those testing new factor replacement products, are “multi-site” studies. Multi-site studies harness the power of the nationwide network of hemophilia treatment centers to provide enough patients and data to produce worthwhile results.
Further, multi-site studies can make trials more cost-effective, which is crucial in an era in which dollars can be more scarce than trial participants. Federal funding has decreased for gene therapy trials, for example, because of the sheer expense, Kessler says. That expense comes from the number of people involved—physicians, statisticians, data managers, nurses and many more—and from the fact that such trials can take years to produce meaningful results.
In this economic climate, collaboration is key, Skinner says. “Certainly one treatment center, or one researcher, or even one country isn’t going to produce the next advance alone.”
Cautious Steps Forward
The many trials under way right now offer people with bleeding disorders a variety of ways to get involved. Current trials (see sidebar “How to Get Involved”) include those studying recombinant factor products free of animal or human proteins; early-stage safety studies on new replacement therapies; alternative products and methods for people who have developed inhibitors to their treatments; and prophylaxis (preventive treatment regimens).
Other trials are testing replacement therapies for von Willebrand disease (VWD); medications to help patients with hemophilia manage HIV; treatment regimens for patients undergoing elective surgery; ankle braces for people with target joints who are in pain; treatments for rare factor deficiencies; and more. For example, Ragni’s team is conducting three separate studies of a drug delivered subcutaneously (under the skin) to reduce blood loss for women with VWD who have heavy periods, for adults undergoing surgery and for those unresponsive to DDAVP. Researchers expect more trials on such “alternative” drug delivery methods in the future. Developing factor products that are faster acting, with longer half-lives also will be a focus in the future to reduce the frequency with which people need to infuse.
Many of these are quality-of-life improvements, designed to adjust and improve treatments that already work fairly well. But for some researchers, the goal still is to develop a “cure” through gene therapy. Since the 1999 death of Jesse Gelsinger, an 18-year-old participant in an early human gene therapy trial for a rare inherited metabolic disease, a few trials have proceeded cautiously.
“A lot of structure has been built around the clinical trial process to ensure that the patient is protected and informed,” Skinner says. “In many ways that has slowed down the process, but the patient is better off because of it. It’s moving at a slower pace, but the exciting thing is that it’s still moving.”
For more than a decade, NHF has been bringing leading scientists and researchers to its “Novel Technologies and Gene Transfer for Hemophilia” workshop. Researchers are exploring better therapies and possible cures in mice, dogs, primates and hogs. Likewise, a couple of human safety trials are moving forward. The Children’s Hospital of Philadelphia (CHOP) is recruiting adults with hemophilia B for a long-term safety trial for gene therapy.
Researchers are recruiting patients with specific mutations for other clinical trials. At St. Jude Children’s Research Hospital in Memphis, researchers are evaluating the safety of a longer-lasting factor treatment using gene therapy techniques in adults with hemophilia B who have a mutation that has not been associated with an inhibitor. “The first patient received the vector infusion in a peripheral vein in March 2010,” said Arthur W. Nienhuis, MD, principal investigator of the study and hematologist at St. Jude. “We are encouraged by the early results and are continuing to recruit patients.”
A research team at CHOP and St. Vincent Indianapolis Hospital and Puget Sound Blood Center in Seattle has a trial underway to test the effectiveness of an oral drug in overriding the stop signals from a nonsense mutation that prematurely prevents production of factor protein in people with hemophilia A or B. (See genotyping sidebar “The Allure of Ataluren,” HemAware Spring 2010.) Researchers are also pursuing nonviral delivery methods in the lab and the use of oral medications to treat both types of hemophilia.
In the end, though, all research depends on people committing their time and effort to clinical trials—and trusting physicians and researchers enough to work with them every step of the way.
“I look at individuals who participate in clinical trials as being just as courageous as the first astronauts to go up in a spaceship,” Kessler says. “It’s like going up in a rocket built by others on a mission designed by others. They depend on the knowledge, sense of humanity and expertise of the individuals who designed the trial. They trust those individuals implicitly. Participants are to be commended, admired and certainly thanked.”