How to design studies, who to include, how to get drug approval and prescription coverage
In part two of Beyond Celiac Research Summit coverage, researchers, physicians, patient advocacy groups, the Food and Drug Administration and a representative from a health insurance company give their perspectives issues related to the study of celiac disease. Patients had their say in part one.
By Amy Ratner, Medical and Science News Analyst
Joseph Murray, MD, a celiac disease expert at the Mayo Clinic, raised a provocative question as the Beyond Celiac 2019 Research Summit moved from patients’ perspective to the viewpoints of physicians, researchers, the Food and Drug Administration and health insurance companies.
“Why should a patient with celiac disease be denied the opportunity to live a normal life or at least a healthy one in a gluten-rich environment,” asked Murray, a member of the Beyond Celiac scientific advisory council and a gastroenterologist in Rochester, Minnesota. “Is it inherently any different from a [person allergic to ragweed] living in the Midwest?”
The recent Beyond Celiac summit was intensive workshop where all groups that play a role in advancing new treatments, and eventually a cure for celiac disease, brainstormed about how to overcome existing barriers and accelerate clinical trials. It resulted in more than a dozen recommendations for ways to accomplish those goals.
Murray likened the state of celiac disease to a horse race in which various treatments still have many fences to jump over. He pointed to at least 192 clinical trials that have been done, enrolling more than 2,000 patients. Several drugs have been studied in multiple trials.
Related: The celiac disease drug pipeline
The drugs are designed with the potential to treat celiac in various ways at various points in the disease process.
While some trials have had encouraging results and one, Larazotide, is moving to the furthest phase any celiac disease drug has ever reached, some have had disappointing outcomes, in particular, Nexvax2, in which study has been discontinued.
Related: How celiac disease affects the gut
Overall celiac disease research has developed a track record with the FDA and proven that clinical trials are feasible with and without a gluten challenge. However, when a trial is designed to prevent the effects of gluten it can’t work unless it can be assured that study participants are consuming gluten.
A panel of drug company representatives identified lack of early phase markers of celiac disease as a challenging barrier when clinical trials are done. “The trials end up being very complex and cumbersome,” said Michael Boyne, PhD, vice president of product development and analytics at Cour Pharmaceuticals. “I think celiac disease in particular struggles with [needing] things we can point to and say, ‘Yes, this drug is working in the way we intended, and it has the appropriate safety levels.’”
Dan Leffler, MD, medical director for Takeda Pharmaceuticals and a member of the Beyond Celiac scientific advisory council, noted that one of the struggles researchers face is figuring out where celiac disease fits in with other gastrointestinal diseases that have drugs for treatment and where it does not. Designs of clinical trials have to take differences between celiac disease and other gastrointestinal conditions into consideration.
“The more different you make your trial designs, the less precedent there is and the less understanding of clinically [predicting] how the trial is going to turn out,” said Leffler, who is also director of research at the Celiac Center at Beth Israel Deaconess Medical Center. Additionally, it’s less clear how patients, health insurance companies and the FDA are going to accept the drug.
Bob Anderson, PhD, a celiac disease researcher who worked on the now discontinued Nexvax2 celiac disease vaccine, said some of the takeaways from his experience included the fact that the scientific community has not yet articulated what causes celiac disease and which symptoms are truly caused by gluten as opposed to some other component of food, such as FODMAPs.
Related: What happened to Nexvax2?
“I am grateful to the people who swallowed the revolting mixture,” he said in reference to patients’ complaints about the nature of the gluten challenge during earlier patient panels. “But it did show that nausea and vomiting were the key symptoms caused by gluten.” He noted that diarrhea was not a clear symptom and abdominal pain occurred but was not prominent. “Until we really know what the symptoms are that we are trying to treat, it’s really hard to make a drug and get a successful primary endpoint,” Anderson said.
Figuring out what went wrong in a clinical trial of a drug that ImmunogenX subsequently purchased is the biggest barrier facing the company, said Jennifer Sealey-Voyksner, PhD, ImmunogenX chief scientific officer and a celiac disease patient. She noted the question at hand is: “How do we move forward with the next trial and make sure we don’t go down the same highway and make sure we are more diligent about patient involvement?” Valuable data came out of the trial in relationship to symptom relief and the company is now figuring out how to make sure to emphasize symptom relief in the next trial.
Related: Results of CeliaAction study
Researchers also need to connect the dots between biomarkers, including T-cell response, biopsy results and symptoms, according to Leffler, who said that there needs to be proof that improvement in one will lead to improvement in the others. “We do interventions, but we really don’t connect them well with how patients do in the long run,” he noted.
Doug Jacobstein, vice president of clinical development for Provention Bio, who moderated the panel, said that patients currently have a stronger interest in a treatment that would prevent the cross-contact that is nearly unavoidable on the gluten-free diet than in a cure. He pointed to a 2016 study that found 87 percent of patients surveyed were interested in a drug they could take in addition to a diet, compared to 65 percent interested in one that would replace the diet.
“As we take baby steps towards developing therapies, maybe an adjunct to the gluten-free free diet may be the way to go until there are definitive therapies that can eliminate the need for the diet,” he said. The panelists agreed that lack of funding is a major barrier to advancing celiac disease research.
Pediatric celiac disease experts who formed a panel to discuss including children in clinical trials made a case for paying more attention to this often neglected area of celiac disease research. Including adolescents in adult clinical trials could be a first step toward filling the pediatric gap, the panelists concluded.
“We in pediatrics should not be an afterthought to the adult celiac disease community,” said Ritu Verma, MD, medical director of the University of Chicago Celiac Center and panel moderator. “It is critical that children be involved in all clinical trials. Children are our future.”
“Children have the most to gain,” said Jocelyn Silvester, MD, director of research at the Celiac Disease Program at Boston Children’s Hospital. “The first group that should be treated is not the adults but the children.”
Silvester noted that adolescents are a group that stands to benefit from clinical trials and can agree to participate, called giving assent, and comprehend what is going on in the trial.
Laura Gordon, CEO of I-ACT for Children and a celiac disease patient, said her organization recently held a workshop with the FDA about including adolescents in adult clinical trials and concluded they should be part of a study if a disease is the same for both adolescent and adult patients, the endpoints of the clinical trial are similar and the safety of the treatment is known or assumed to be similar. I-ACT and the FDA are currently working on a position paper on pediatric participation in clinical trial and recommendation for its implementation.
“The hope is that this would be a great way to accelerate getting drugs tested in at least that part of the pediatric population,” Gordon said. “It is beautifully applicable [in celiac disease].
Daniel Mallon, MD, a pediatric gastroenterologist at Cincinnati Children’s Hospital, said there are also advantages and opportunities for younger children to participate in clinical trials. He acknowledged there is particular worry about subjecting young children to a clinical trial or even an endoscopy, but parents also have anxiety about whether what they are doing to manage celiac disease daily for their children is working.
A safety net provided by a drug or therapy would be “very, very attractive” to parents, Mallon said. “Simultaneous thirst for an alternative [to the gluten-free diet] and anxiety [about their children’s’ health] would drive participation,”
While young children are likely to have better adherence to the gluten-free diet compared to adolescents, adolescents can report their own study reactions compared to young children, whose reactions have to come through an observer, usually a parent. Both dietary adherence and self-reporting are components of many celiac disease trials.
The type study being done can also influence which pediatric population would make better trial participants, Silvester pointed out, for example whether a trial was designed to test a drug that would be used in addition to the gluten-free diet or if it would replace it.
An immunological-based therapy would have to take into consideration that fact that the immune system of young children is different from the system of adolescents and adults.
“When trying a therapy where we are hoping it suppresses those T-cells, what if it doesn’t work? Silvester asked. “What if it activates those cells and makes children hypersensitive to gluten for the rest of their lives?”
One of the barriers to getting children into trails is what Silvester called “the mutual abandonment of patients and physicians.” After diagnosis many patients don’t return for follow-up care, making it difficult for clinicians to really know what ongoing celiac disease involves. “We don’t know our patient population,” Silvester explained, noting it’s not even clear how many symptoms someone should to be considered a symptomatic patient.
And Verma said pediatric celiac disease clinics across the country are forming a consortium that is working collaboratively on many issues, including pediatric quality of life, diagnosis and follow up. “The pediatric groups are getting together,” Verma said.
Benefits in how patients feel, function and survive are key ways in which the FDA assesses response in clinical trials, said Irena Lavine, MD, medical officer for the FDA Center for Drug Evaluation Research. Additionally, benefits have to be meaningful, measurable and interpretable.
A big challenge in celiac disease is how to define target populations in clinical trials since symptoms vary and overlap with other diseases. “We know one of the main reasons trials fail is they do not have the right patient populations,” she noted. To address this dilemma, researchers need to be sure that study participants have active celiac disease identified through biopsy and sufficient symptoms.
Other challenges include selecting what can be measured objectively to determine whether the treatment being studied is beneficial and choosing the how to measure the methods of observation and the criteria used to assess response.
Researchers need tools to measure relevant signs and symptoms that show the needed clinical benefit and determine how much improvement is needed to provide convincing evidence patients have benefited from treatment.
The FDA also looks for patient perspectives, including which symptoms most impact daily life for patients and caregivers and the type of treatments patients are most interested in, for example a drug in addition to the gluten-free diet or one that replaces it.
Lavine suggested that patients, advocacy groups, researchers and pharmaceutical companies, could collaborate to develop clinical outcome assessments. These assessments could then be used to establish how much change, for example in symptoms, are considered clinically meaningful to patients.
“Early planning in the drug development process is critical to meet the challenges associated with defining the target population and outcome measurement,” Lavine said.
“We are learning that drug development is picking up in celiac disease, and there are some very unique aspects of celiac disease that are different from what we knew before,” said Juli Tomaino, MD, lead medical officer at the center for drug evaluation of the FDA. She noted that there are aspects of other drug development programs that would apply but adaptations might be needed.
When it comes to drug approval, patient experience is increasingly being incorporated. “One thing we need to see in the data and hear from patients is, is this something you would want?” Tomaino said. “Your histology [biopsy] is getting better, but you feel miserable, so it this really a treatment for you?”
Lavine also addressed the so-called Hawthorne effect, in which patients who know they are being observed become more restrictive on their gluten-free diet while participating in a study. She said this phenomenon can make showing a difference between treatment and placebo groups in a study difficult. “I think being creative in trial designs and trying to come up with ways that more closely emulated what patients typically encounter in a day is a good possibility,” she noted.
But incorporating gluten exposure from cross-contact is hard to quantify and build it into a trial that mimics real life, Tomaino added. “How does one design a trial and the get the reassurance from the trial that patients are truly protected,” she asked. “We need to continue to think about how we might structure that,” she said.
Health insurance companies do not fully understand the unmet need in celiac disease, according to Ionnis Petrakis, PhD, global head of GI payer value and patient access at Takeda. He said Takeda has found this to be the case globally when the company meets with payer representatives. “
He described a potential scenario in which a drug makes it through the FDA approval process but “patient access never comes because a payer decides that the value is not there.” He encouraged collaboration between all groups with a stake in celiac disease drug development to change the status quo with health insurance companies.
Deneen Bowlin, MD, a medical director for CareFirst Blue Cross Blue Shield Maryland, the only payer representative to participate in the summit, said the science that demonstrates that a medication is effective is necessary to get payers, as well as the medical community, on board.
Some considerations include: is the drug the only one to treat the disease; if not, how does it compare to other drugs or treatments in being effective and in cost; and how prevalent is the disease the drug is designed to treat and how that will determine use of the mediation or treatment?
Bowlin agreed that getting payers to be aware of and understand the unmet need of celiac disease is important. “I don’t think some of us realize all the ripple effects that it has on the family and traveling,” she said. “I think the [summit] really brought that to light to me.”
But she also noted that payers will be looking at how any new drug compares to the standard of care that already exists, in the case of celiac disease that is the gluten-free diet, which often considered effective. Side effects from any drug will have to be weighed against the severity of symptoms, too. A new celiac disease treatment would be compared to the standard of care to whether it’s used in addition to or as a replacement for the gluten-free diet.
“Upfront drug costs may avoid downstream healthcare costs,” Bowlin said. In relationship to celiac disease, that would mean looking at the cost of long-term complications of the disease in quality of life and use of healthcare resources. In addition, lost days at work and school could be considered. “Those all may take up healthcare resources that may have been prevented if there is a drug therapy that is effective.”
The cost of the gluten-free diet is now borne by patients, and approval of a drug to treat celiac disease would shift the cost to health insurance companies. But Bowlin said Care First would look at a variety of factors. “Since we are a non-profit, our members are paying to have care given to them…It’s something I think we would need to look at,” she said, adding that the company would want to hear from patients and clinicians and would look at issues like the complications of celiac disease.
Alice Bast, Beyond Celiac CEO, who moderated a patient advocacy group panel, noted that the organization has focused its mission on advancing research and finding a cure for celiac disease. “We are engaging the community in research,” she said. “We want patients to know that even though we focused for a number of years on early diagnosis and making sure they can manage the disease and gluten-free diet, we now want to get across the message that the gluten-free diet is not enough.”
Beyond Celiac spends most of its time on connecting patients to the research community and engaging them in a way that will advance research. In the past two years, Beyond Celiac has created a science department with a chief scientific officer, a science department and a science plan, and has awarded more than $600,00 in grant to early- and mid-career researchers.
In written remarks submitted to the panel, Hilary Croft, CEO of Coeliac UK, said the group has committed nearly 3 million pounds, equal to about $3.8 million, to celiac disease research in the past 15 years. “We proactively disseminate research and encourage international collaborations,” wrote Croft.
Melissa Secord, executive director of the Canadian Celiac Association (CCA), said one of the organization’s major contributions to advancing research is seeding of young investigators with an initial grant to get their research started and to encourage interest in studying celiac disease.
In addition to funding, CCA works to explain research to patients to enable them to make decisions about participating in clinical trials, turning to the association’s professional advisory council for clear explanations of studies and perspective on what they mean.
“It’s important we give some context to the research that’s going on and what shiny objects you should focus on and what research is still percolating and is not there yet,” Secord said.
“Part of the process is about rebranding celiac disease as the serious autoimmune condition that it is,” Bast said. “I know we like to look at our glass as half full, but we know that the burden of celiac disease is high.”