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For immediate release
In the latest in a series of live webcasts by The Forum at Harvard T.H. Chan School of Public Health, a panel of experts explored the complexities of drug trials and the ways they affect disease treatment and prevention, especially for conditions with few or no therapeutic options. Using Alzheimer's Disease as a case study of urgent medical need, some panelists suggested that clinical trials are in crisis; they are increasingly complex, with slower startup and enrollment times and higher costs. To improve the next generation of drugs, trials must become more efficient, more numerous, more quality-driven and more diverse in representing test participants. Panelists also said the regulatory process is not blocking treatments or cures, and that patients -- especially women -- should be equal partners in trial design and post-market drug evaluation in order to increase public support for clinical trials.
Below are highlights of the conversation for media use.
This Forum was presented in partnership with HHMI Tangled Bank Studios, in collaboration with STAT and in association with NOVA.
EXPERT PARTICIPANTS
Reisa Sperling, Professor of Neurology, Harvard Medical School, and Director of the Center for Alzheimer's Research and Treatment and of the Clinical Research, Memory Disorders Unit, Brigham and Women's Hospital
Aaron Kesselheim, Associate Professor of Medicine, Harvard Medical School/Brigham and Women’s Hospital, and Director of the Program On Regulation, Therapeutics, And Law
Pamela Tenaerts, Executive Director of the Clinical Trials Transformation Initiative
Jill Goldstein, Professor of Psychiatry and Medicine at Harvard Medical School and Director of Research at the Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital
MODERATOR
Sharon Begley, Senior Science Writer, STAT
HIGHLIGHTS OF THE DISCUSSION
Clinical trials began as a way to eliminate outside factors in proving a drug safe and effective. The Food and Drug Administration now allows flexibility in the classic three-phase trial, so that new drugs meeting unmet or life-threatening needs can follow an expedited approval process. A single phase-3 trial, in addition to confirmatory evidence, is sufficient to meet the efficacy standard. These drugs may be compared to a placebo only and not to active therapy; may be shown to affect a biomarker or other surrogate endpoint, not actual patients; or may undergo only a very short test period.
Sperling described her A-4 Study, which is testing the effectiveness of anti-amyloid treatment against Alzheimer's disease among people who show no symptoms of dementia, although amyloid is accumulating in their brains. The thinking was that going in earlier in the disease, we'd have a better chance, she said.
Clinical trials are basically “in crisis," Tenaerts said, with higher costs, slower results and enrollment, so that investigators and the public alike are pulling out of them. Others added that the Alzheimer's threat heightens the need for such trials. The FDA wants more ethnic and gender diversity in participants as well as more efficiency.
Sex differences pervade chronic disease medicine from onset through treatment responses and prognoses. Women and men metabolize drugs differently, Goldstein said. Hormones also can make a difference. For example, estradiol regulates expression of the main Alzheimer's risk gene, but why are some post-menopausal women at higher risk for Alzheimer's than others?
Only 5 percent of cancer patients are involved in clinical trials, and few clinical physicians talk to their patients about taking part in any trial. We need new ways to recruit trial participants, especially minorities, who are at elevated risk for Alzheimer's but almost absent from studies so far.
The idea that FDA regulations are blocking treatments or cures is a "terrible misconception," Kesselheim said, as is the perception that trials cost too much -- successful drugs earn back many times their development costs. He said pending legislation to allow drug marketing without controlled clinical trials is "misguided" but Tenaerts said it would speed approvals and is overall "a positive thing."
Drugs targeting the biomarker cholesterol may not reduce heart disease, and those targeting brain plaque may not reduce dementia; we don't know enough yet to say. We do, however, see sex differences in the expression of biomarkers, and that could lead to "sex-dependent therapeutics," Goldstein said.
Gender and minority diversity needs to be incorporated into study design and post-market analysis as well as participant recruitment. Public education and outreach can let patients become equal partners invested in the clinical trial process.
To watch the full one-hour Forum, visit ForumHSPH.org.
Contact: Christina Roache, croache@hsph.harvard.edu tel. 617-432-7094
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Click the links below to watch clips from the event.
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The A4 study to fight Alzheimer's
Sperling: "I am honored to lead a study called the A4 study...in an asymptomatic, or a pre-clinical population...people don't yet have symptoms...we can now detect evidence of Alzheimer's pathology...before symptoms, hopefully intervene, and prevent the progression...I suspect our results will really be in the end of 2019 or more likely 2020."
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Clinical trials are in crisis
Tenaerts: "Over the past 10 to 15 years, though, is that clinical trials have been increasingly become complex...basically they're in crisis...startup times are getting slower...enrollment is slowing...costs are increasing...the public really is not aware of clinical trials in the way that maybe they ought to be...there really also needs to be more diversity...[we should] figure out what it is we need to do to make them more efficient."
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Sex differences are pervasive in medicine
Goldstein: "Well, sex differences in the frequency of chronic disease are absolutely pervasive...it is incumbent upon us to use this knowledge...estradiol can reduce the accumulation of amyloid in the brain...so what happens to women with a loss of ovarian function?...we can use our knowledge of sex differences in the brain to help identify who might be at early risk for Alzheimer's 10, 15 years later."
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Getting the public more involved in clinical trials
Sperling: "In Alzheimer's disease there's particular reasons to be involved in trials...this is something they can do."
Tenaerts: "If you think about it, every time you go to a doctor and that doctor prescribes you something, that was because somebody participated in a clinical trial...[yet] only 15% to 17% of physicians talk to their patients about clinical trials...forums and movies, such as these, definitely help a lot as well."
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Regulatory needs and the Cures Act proposal
Kesselheim: "I appreciate your bringing up this terrible misconception that is out there, that the FDA or that regulation in this area is somehow blocking cures or treatments from getting to patients...stimulating, actually, this very misguided legislation [the Cures Act] that is in front of Congress right now...imagine what life in the therapeutic space would be like without a need to do clinical trials...look at the nutritional [supplement] market...a lot of them end up killing people...the FDA is the fastest drug regulatory agency in the world...when those drugs are shown to work."
Sperling: "When I came into Alzheimer's disease I definitely heard that the FDA and the regulators were the problem...they've been very flexible in evolving...they're doing a good job."
Tenaerts: "So some of the things in the legislations...are very good...they've done a lot of homework...in my personal opinion it's a positive thing rather than a negative thing that they're proposing."
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Use of biomarkers
Begley: "Something long thought to be a biomarker for cardiovascular disease is lipid levels...it's not so clear they do good things [against] cardiovascular disease...[some] brains have these plaques, but...seem to be functioning OK."
Sperling: "We need to understand this...we don't yet know enough...something that I hope A4 will do...we need lots of biomarkers, lots of trials."
Goldstein: "These things also show sex differences in their biomarkers, in their expression...understanding the sex differential [will enhance] clinical trial design and eventually hopefully the generation of what we're calling sex dependent therapeutics."
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Recruiting minorities and women
Sperling: "Most clinical trials in Alzheimer's disease actually have more women than men...[but] less than 5% of African-Americans and Latinos...we really need outreach...to say this is really important to your community as well."
Tenaerts: "We think patients are an equal voice to the researchers, to industry...they need to be part of the planning...to have an equal voice in the whole drug and development process."
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Expert recommendations
Each expert offered a single policy recommendation at the end of the show.
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Through in-person events paired with state-of-the-art interactive webcasting, The Forum at Harvard T.H. Chan School of Public Health convenes the best-informed and most influential scientists, policymakers, and practitioners to address worldwide health problems that require immediate decisions and practical solutions.
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Harvard T.H. Chan School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives-not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at the Harvard Chan School teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America's oldest professional training program in public health.
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