Speak out for increased Alzheimer's research funding: Your voice is more important than ever
We need you to join advocates from across the nation on Capitol Hill during the Alzheimer's Association Advocacy Forum, March 7–9. Alzheimer's disease (AD) must be a top issue as legislators discuss research funding and funding for the care required by people with AD. The best way to get our message to lawmakers is with your support.
The Association remains concerned that the current level of federal research funding for AD and other dementias is inadequate and does not sufficiently reflect: 1) the impact of AD and other dementias on individuals, families, and the nation's healthcare system and economy and 2) the needed level of investment to stop and even reverse the growing epidemic of AD.
For seven consecutive years, federal funding for AD and other dementia research has not kept pace with inflation. Even with dedicated stimulus funding, the budget battle continues in Washington. As scientists, clinicians, and healthcare providers, you offer critical perspectives on the funding issues and other hurdles faced in an era of diminishing budgets. It is more important than ever that the scientific community join with AD advocates to make all of our voices heard on Capitol Hill.
Please make time to join your colleagues, caregivers, and people with AD to advocate for increased AD research funding by attending the Advocacy Forum. On March 9, attendees will visit Congressional offices to ask lawmakers to support increased funding, among other important issues. For more information on the Advocacy Forum, visit http://www.alz.org/summit/.
Not able to attend the Forum? The voices of scientists who can speak firsthand about the challenges of advancing innovative AD research in the current funding environment are critically needed. Speak up at www.alz.kintera.org/fundresearch.
A disease that will impact us all, AD will also require us all to confront it effectively. We need your voice.
Research Roundtable highlights challenges and benefits of international clinical trials
More than 100 researchers from the pharmaceutical industry, academia, National Institutes of Health, and regulatory agencies gathered November 9–10 in Washington, D.C., to attend the Alzheimer's Association Research Roundtable. Researchers heard from 20 speakers and panelists as they described the challenges, benefits, and ethical issues involved in conducting international AD clinical trials.
Several factors drive the need to conduct international clinical trials. Some sponsors of clinical trials, and the clinical research organizations (CROs) with which they partner to conduct clinical trials, have found the United States to be saturated with clinical trials. As a result, they have difficulty finding the number and types of clinical trial participants required to conduct the study. For example, the trial may require that participants are “treatment-naïve,” that is, have never taken a drug to treat AD. These types of participants are typically easier found outside the United States.
Another motivator is that trials conducted today tend to be longer and require more participants than the clinical trials that led to the development of the five drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of AD. The increased length of studies is due in part to the incorporation of biomarker studies that were not in use when currently approved drugs were in clinical trials. These studies include magnetic resonance imaging to measure brain volume, positron emission tomography to measure glucose use and the amount of the AD hallmark protein beta-amyloid in the brain, and cerebrospinal fluid tests measuring beta-amyloid and another AD hallmark protein, phosphorylated tau.
Cost is yet another factor in conducting international clinical trials abroad. A clinical trial conducted in China, for example, can cost 20 percent of conducting that same trial in the United States. In addition, participant recruitment numbers are often reached more quickly outside of the United States and participant retention and compliance may be significantly increased in clinical trials conducted abroad.
However, with these benefits come implementation challenges and cultural complexities not present in United States clinical trials. A challenge that frequently surfaced during the Roundtable was the extended time required to get a trial up and running. While 48 days might be typical in the United States, start-up times can approach six months in Poland and Italy, four to eight months in Latin America, and even longer in some Asian countries. Speaker Michele Bronson, PhD, of Medivation, Inc. (San Francisco, CA), noted that Latin America, Chile, Argentina, and Brazil have the shortest start-up times, in that order, while in the European Union (EU), the fastest start-up times were in the United Kingdom, Belgium, and The Netherlands. In the EU, she remarked, each country has different requirements for the material that needs to be submitted for the study; the clinical trial sponsor may receive questions about the basic study design, something unlikely to be encountered in the United States; and all countries are very sensitive to the rights of populations with diminished mental capacity. Speaker Michael Murphy, MD, PhD, of the CRO Worldwide Clinical Trials added that each country has its own approach to regulation. For example, one country may allow a biomarker sample, such as cerebrospinal fluid, to be obtained, but not allow videotaping of a participant to help assess the effect of a treatment.
To address the complexity of clinical trials held across the globe, pharmaceutical companies are increasingly relying on CROs and other partner organizations to provide expertise in areas such as biomarker studies, training of on-site clinical trial staff members, and clinical trial advocacy. In describing a study involving biofluid and neuroimaging biomarkers of AD, Eric Siemers, MD, of Eli Lilly & Company (Indianapolis, IN), noted that for each of the biomarkers studied, specific assistance from CROs was needed. To effectively conduct the clinical trial, communication with and among CROs was crucial.
Implementation of clinical trials abroad can also be hampered by insufficient numbers of well-trained individuals to conduct and rate results of AD cognitive tests such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE). David Miller, MD, of Bethesda, MD-based United Biosource Corporation (UBC), which helps pharmaceutical companies gather and analyze data, discussed an experience in China in which 38 percent of those considered to be the country's best raters had administered the ADAS-cog fewer than five times. To address concerns about raters' abilities, UBC created a training program to better prepare raters and a ratings surveillance program of real-time rater monitoring. Miller described one experience in which 332 of 658 raters required more than one remediation to correct a misunderstanding in test administration. He shared with Roundtable attendees simple but key findings pertaining to test raters: experience is not a guarantee of success and those who have no experience as raters but receive training do about as well as experienced raters.
In addition to the relative ease of recruiting sufficient numbers of clinical trial participants, potential costs savings, and potential gains in participant compliance and retention, conducting international trials enables study sponsors to provide evidence whether their experimental drugs are effective in a wide range of populations. Providing this evidence boosts the market potential of a new drug.
In conducting clinical trials from Africa to Asia and across the globe, sponsors may encounter unanticipated cultural issues and provocative ethical issues that add to the complexity of conducting those trials. Rachelle Doody, MD, PhD, of Baylor College of Medicine, noted that for some clinical trial participants, the study site may be the only place for them to receive medical care. In that situation, participants may not report an adverse event for fear of being pulled from the trial and the medical care they cannot otherwise obtain. Doody also noted that discontinuation rates differ among countries. For example, in Japan, if one patient has an adverse event, the entire study may be stopped. If a principal investigator in Japan is displeased with an element of a clinical trial, a representative of the sponsoring company may need to meet with him personally, noted Roza Hayduk, MD, of the CRO Quintiles. A call or e-mail may not suffice.
Joan Shen, MD, PhD, of Wyeth shared five strategies for overcoming the challenges of conducting clinical trials in Asia:
•Training: Provide protocol, procedure, and rater training—treating all raters as new regardless of experience—and conduct workshops on good clinical practice for both the site principal investigator and staff members.
•Make a research alliance with the site: Obtain site feedback before finalizing a study protocol so that concerns such as low literacy can be discussed. This is also an opportunity to learn about cultural differences in defining AD; for example, mild AD may be defined by a different range of MMSE scores in Asia than elsewhere.
•Identify the key opinion leader in the country or region where the clinical trial is being held: This individual can act as an advocate on behalf of the trial and facilitate the study. Likewise, select a principal investigator with high status in that country or region.
•Site qualifications: Does the site have adequate resources? Also, review the investigators' credentials. The person who signs the contract is often not the person conducting the study; make sure to communicate with both. The second-level person should have all the details; the first person might be a university administrator.
•Site monitoring: Ensure human subject protection; identify problems early; and conduct scheduled and unscheduled site monitoring to ensure quality.
Russell Katz, MD, of the FDA, echoed Shen's theme of the importance of site monitoring and urged those in the audience who are involved in international clinical trials to monitor study sites carefully to avoid audits. “With problematic international sites, the FDA will ask the sponsor to throw out the data from those sites, but that might not be enough,” said Katz. “We may ask a sponsor to do a complete audit of sites. This causes a huge delay. We don't want to do this.”
While global clinical trials may be destined to become increasingly common, the published literature includes cautions that should not be taken lightly, said Jason Karlawish, MD, of the University of Pennsylvania. These include concerns about the variable qualifications of investigators and the fact that no global system is in place to identify investigators who uphold the highest standards for clinical trials.
Economic exploitation is another area of concern. In some countries, clinical trials are viewed as an example of “new colonialism.” Conducting a clinical trial in a low- or middle-income country may be good for the trial sponsor, but not good for the country in which it's being held. For example, physicians who are paid large sums of money by local standards to conduct a clinical trial have less time to devote to their own practices, which results in decreased access to care for many individuals. Another significant concern is to what degree clinical trial sponsors feel compelled to help clinical trial participants or the country in which the trial is held if the experimental drug is marketed.
“Clinical trials should not be restricted to the rich,” remarked speaker Martin Prince, MD, of the Institute of Psychiatry in London, England. “Those who put themselves at risk to be in clinical trials should share in the benefits if the drug becomes available. How do we make it available to them when the cost would be high and they might not be able to afford it?”
Obtaining true informed consent is yet another area of concern. Informed consent should be regarded as an international human right, said Karlawish, yet potential clinical trial participants may lack the literacy skills needed to understand the consent document. Charles Weijer, MD, PhD, of the University of Western Ontario, Canada, added that in some societies, the individual cannot give informed consent. For example, in the Middle East, a husband must give consent for his wife to be in a clinical trial; in other regions, a group leader may tell the members of his group to participate in a clinical trial and they do so because they have been instructed do. “That's not true informed consent,” remarked Weijer.
Karlawish asked attendees to consider the value of AD studies in sites being considered for clinical trials before proceeding with site selection. For example, AD studies may hold little value in low-income countries, where the leading cause of death is lower respiratory disease, shorter life spans mean that many people may not live long enough to develop AD, and extended families with multiple caregivers lessen the burden of AD care. In this case, said Karlawish, it falls upon the clinical trial sponsor to explain why individuals should participate in a study of a disease that currently holds little value to them.
The next Research Roundtable will be held April 29–30 in Washington, D.C., and will focus on neuropsychiatric symptoms of AD. For more information on the Research Roundtable, visit www.alz.org. To become a sponsor, contact Jay Thompson: jay.thompson@alz.org, or 312-335-5192.
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