Sickle cell disease patients’ willingness to participate in clinical trials for investigational treatments hinges on a number of factors, including the severity of their own disease, what’s known about the compound under study and whether the agent is more likely to help them than hurt them, patients and advocates told FDA at a Feb. 7 meeting.

The potential for rare but serious side effects, considerations about how the treatment might improve their health and how the trial might impact an individual’s current treatment plan also are important factors in deciding whether to participate in a clinical study, meeting participants said.

Sickle cell disease affects about 100,000 people in the U.S., including one in every 500 African American births.

In addition to laying out the reasons and conditions under which they would agree to participate in a clinical trial, patients and advocates told FDA there is a disconnect within the treatment community about the availability of clinical trials and that more needs to be done to publicize such studies to providers who treat sickle cell patients.

They also had some thoughts on their ideal treatment – something that targets the underlying disease and organ damage, rather than just providing symptom relief.

Many Symptoms, Limited Treatment Options

The sickle cell meeting marked the fifth of 20 disease area meetings conducted under the patient-focused drug development initiative, a program created through the 2012 reauthorization of the Prescription Drug User Fee Act. The program is aimed at systematically gathering patient input on the burden of disease and current treatment options, with the idea that such information would aid in regulatory decision-making on such matters as clinical trial design, development of patient-reported outcomes instruments and other endpoints, and product approval decisions.

Patient-focused meetings conducted in 2013 covered chronic fatigue syndrome/myalgic encephalomyelitis, HIV/AIDS, lung cancer and narcolepsy. The agency has issued two “Voice of the Patient” reports summarizing the meeting proceedings on CFS/ME and lung cancer Also see "“Patient Voice” Report Puts Chronic Fatigue Symptoms, Treatments In Benefit/Risk Framework" - Pink Sheet, 7 October, 2013..

A meeting on fibromyalgia, originally set for Dec. 10 but postponed due to weather-related closures, has been rescheduled for March 26. Pulmonary arterial hypertension will be the focus of a May 13 session ([A#14140206003]).

Sickle cell disease affects about 100,000 people in the U.S., including one in every 500 African American births, said Nicole Verdun, a medical officer in FDA’s Division of Hematology Products.

It is an inherited red blood cell disorder resulting from a mutation in the beta globin gene. Red blood cells are more prone to an abnormal shape and rigidity, which causes multi-organ damage over time. The disease is characterized by a variety of symptoms, including debilitating pain crises, increased risk of infections, stroke, pulmonary hypertension, acute chest syndrome, priapism, gallstones and kidney dysfunction.

At the meeting, patients and caregivers described a host of other symptoms and impacts caused by the disease. These included splenectomy, compression fractures, chronic bone pain, avascular necrosis, leg ulcers, asthma, vision and hearing loss, limited mobility, difficulties concentrating, fatigue and inability to sleep, depression, difficulty maintaining social relationships, interrupted education, inability to hold a job, and worries about the ability to have and care for a family.

Therapies to prevent the complications of sickle cell disease are limited. Hydroxyurea is approved to reduce the frequency of painful crises and to reduce the need for blood transfusions in adults with sickle cell anemia with recurrent moderate to severe painful crises. However, the drug is a cytotoxic and myelosuppressive agent associated with numerous adverse events and is a potent teratogen when used during pregnancy. It also does not work for all patients.

Bone marrow transplantation is an option for some patients. Other therapies used to manage the disease include red blood cell transfusions, pain medications, antibiotics, oxygen, vitamin supplements and alternative medicine. New approaches to treating the disease or preventing its complications are being explored, FDA said, including new medicines, advances in transplantation and gene therapies.

Would You Enroll In This Study?

FDA used the meeting as opportunity to explore what issues – on an individual patient level – might impact enrollment in studies of sickle cell treatments.

“If you had the opportunity to consider participating in a clinical trial studying experimental treatments for sickle cell disease, what things would you consider when deciding whether or not to participate,” the agency asked in questions presented ahead of the meeting.

The agency has not asked patients to discuss clinical trial participation for most of the other disease area meetings held thus far, although for the HIV meeting FDA did ask a series of questions about participation in HIV cure trials, including motivation to do so and willingness to stop taking other HIV medications during such a study. The agency also sought discussion about what types of information should be conveyed as part of the informed consent process for HIV cure research ([A#00130624014]).

At the sickle cell meeting, FDA described a hypothetical clinical trial and asked patients to comment on their willingness to participate in such a study.

In the scenario, there was early research in animals and humans to suggest that the investigational compound may decrease the number of pain crises or hospitalizations in some people with sickle cell disease. The one-year study would enroll 1,000 patients and require participants make a total of four clinic visits, one every three months.

Patients said they would want to know more about the underlying research, including the populations already studied, and the drug’s mechanism of action before deciding whether to enroll in the type of trial described by FDA.

Common side effects of therapy may include nausea, diarrhea, fatigue, headache and rash. Rare but more serious side effects may include infection, bleeding and life-threatening allergic reactions.

Several meeting participants said they would want to know more about the underlying research, including the populations already studied, and the drug’s mechanism of action before deciding whether to enroll in such a study.

One patient who said she has done biomedical research on treatments for sickle cell focused on the fact that the drug is expected to help “some people.”

“If I were vetting this therapy and trying to decide whether or not I wanted to subject myself to this experimental medication, I would want to know exactly how ‘some people’ were determined,” she said. “I think in the end we need clear guidelines of who are the people who are going to be helped by the therapy. We’ve seen here there’s a lot of diversity in the symptoms that people have and experience with sickle cell disease, so if it’s a drug that helps people who have ulcers, I might not be the best person for that study. So I think very detailed and clear information is necessary.”

Sickle cell patient Lakiea Bailey, a research scientist, said she would want to know more about the compound, including why and how it is expected to help sickle cell patients.

“What’s its method of action? Is this something that I would benefit from? Is it something that I need that outweighs the risks of it,” Bailey asked. “I need to know not just this is going to help sickle cell, but this is going to help treat the persistent acute chest syndrome that you’re dealing with by approaching this particular target area. … When it comes to actually taking a drug into myself, I would need to know more about how that drug’s going to work and why you think that’s something that would work for me.”

Bailey said the severity of her disease has not yet reached a point where she is comfortable entering a clinical trial for an experimental therapy. However, she laid out a list of things she considers in looking at such opportunities, including weighing the known and theorized risks of the drug against its potential benefit. “I also consider the phase the drug trial is in, how long it’s been tested, and the number of previous patients enrolled,” she said.

Others who participated in the meeting in person or through a webcast said they would need more information than they usually receive about clinical trials before deciding whether to participate. In addition, they want more information about the motives of entities sponsoring trials, and they want more transparency on the preclinical and early clinical data.

Although 49% of respondents had participated in a clinical trial for an experimental sickle cell treatment, many learned about study opportunities from sources other than their health care providers.

Patients and advocates also bemoaned treating physicians’ lack of knowledge about clinical trial opportunities, suggesting a disconnect between the treatment and research communities in this disease area.

Although 49% of those responding to a polling question said they had participated in a clinical trial for an experimental sickle cell treatment, most seemed to have learned about clinical trial opportunities not from their health care providers, but rather from advocacy groups, other patients and social media.

FDA also asked meeting participants which of several factors were the most important in their decision about whether to participate in a clinical trial of an experimental drug. The largest percentage of respondents said rare but serious side effects, followed by considerations of how the treatment might improve their health, how the trial might affect their current treatment plan, and common side effects associated with the investigational drug.

Among those in the meeting room who responded to a polling question, 46% said they would generally be willing to participate in the clinical trial described in FDA’s hypothetical scenario but would want more information.

Thoughts On An Ideal Treatment

Patients also had some thoughts on what they would like to see in their ideal treatment for sickle cell, with several saying they would like a therapy that moves beyond treating symptoms to having a direct effect on the disease and preventing tissue damage.

“I understand the pain, I can deal with the pain on a variety of levels, but what I feel is being most affective to my future that I’m most concerned about is the fact that my organs are dying, my tissues are dying every time I’m having a sickle cell episode, whether I’m in the hospital or I’m at home,” said one female patient. “And when you go to the hospital, the only thing that they’re giving you generally is pain medicine, and nothing addresses the tissue damage that’s occurring with every single crisis.”

“For people that die from sickle cell, it’s never on the death certificate that they die from sickle cell pain. It’s always they die from complications of sickle cell,” she continued. “And these complications are coming because of the tissue damage that’s occurring, and really that’s what I want treatments to address.”

Bailey noted that her current treatment focuses entirely on pain and iron overload, which results from blood transfusions. She said she would like a treatment that addresses the underlying anemia that leads to excessive fatigue.

“Mostly my treatments, they’re looking at downstream, they’re looking at afterwards. But I’d like to address upstream. Can we look at it before it gets to be that bad,” she said. “My ideal treatment would decrease duration of sickling events and increase my hemoglobin.”

“A drug that prevented red blood cells from sickling and causing organ damage would be seen as a cure,” said Nancy Rene, whose 10-year-old grandson has sickle cell and suffered a stroke at nine months of age that left him partially paralyzed.

However, Rene also saw a need for drugs that better address the pain crises sickle cell patients endure.

“If there were a drug to stop the pain crisis in its tracks, children wouldn’t miss so much time from school, young adults could spend more time in college and beginning those first jobs,” she said. “A safer drug for pain control would be key to effective treatment and keep many out of the ER.”

Sickle Cell Patients Weigh Clinical Trial Participation At FDA Meeting

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