eBriefing

Fast-tracking Alzheimer's Research: Global Alzheimer's Platform Design Workshop

Fast-tracking Alzheimer's Research
Reported by
Alla Katsnelson

Posted April 18, 2014

Presented By

Overview

The enormous socioeconomic cost of Alzheimer's disease (AD) is a burden on the global economy that will grow increasingly unsustainable as the disease becomes more prevalent. Despite the urgent need to develop therapies to prevent and treat AD, drug development efforts are highly inefficient and have yielded multiple costly phase III failures. There is currently no cure, validated prevention strategy, or disease-modifying treatment for AD.

Through a series of meetings and workshops held over the past year, stakeholders in AD drug development have begun to outline strategies to surmount these challenges. The Global Alzheimer's Platform (GAP), conceived through this process, aims to establish a framework for testing prospective AD therapies that promotes cooperation and data sharing among existing and future drug development initiatives. At the Global Alzheimer's Platform Design Workshop on February 19–20, 2014, the Academy's Alzheimer's Disease and Dementia Initiative and the Global CEO Initiative on Alzheimer's Disease convened design teams to plan how to move GAP from concept to active development. The workshop highlighted the platform's four components—registries to cohort, trial site activation, trial innovation, and funding—and aimed to define, in each area, the current needs, a vision for change, and how to measure impact.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Paul Aisen, MD (University of California, San Diego)
Russell L. Barton, MSc (Eli Lilly and Company)
Randall J. Bateman, MD (Washington University)
Howard Feldman, MD (University of British Columbia, Canada)
Richard J. Hodes, MD (National Institute on Aging, NIH)
Michael T. Ropacki, PhD (Janssen Research & Development)
Andrew Satlin, MD (Eisai Inc.)
Eric R. Siemers, MD (Eli Lilly and Company)
Reisa A. Sperling, MD, MMSc (Harvard Medical School)
Luc Truyen, MD, PhD (Johnson & Johnson)
Janet Woodcock, MD (U.S. Food and Drug Administration)


Presented by

  • The New York Academy of Sciences
  • Global CEO Initiative on Alzheimer's Disease

Opening Remarks


Janet Woodcock (U.S. Food and Drug Administration)

Keynote Presentation


Richard J. Hodes (National Institute on Aging, NIH)

Reports Out


  • 00:01
    1. Registries to cohort
  • 30:40
    2. Trial site activation
  • 49:20
    3. Trial innovation
  • 64:30
    4. Funding
  • 78:49
    5. Concluding remark

Session I: Registries to Cohort


Co-leads: Randall J. Bateman (Washington University) and Michael T. Ropacki (Janssen R&D)
  • 00:01
    1. Introduction to Registries to Cohort
  • 01:58
    2. The current state; Problem statements
  • 10:10
    3. Benefits and opportunities; Examples
  • 20:21
    4. The charge
  • 25:27
    5. General discussio

Session II: Trial Site Activation


Co-leads: Paul Aisen (UC San Diego) and Russell L. Barton (Eli Lilly and Co.)
  • 00:01
    1. Introduction to Trial Site Activation; Problem statement
  • 06:36
    2. The charge; Goals; Scope; Key milestones
  • 16:54
    3. Going forward
  • 23:17
    4. General discussio

Session III: Trial Innovation


Co-leads: Howard Feldman (University of British Columbia), Andrew Satlin (Eisai Inc.), Eric Siemers (Eli Lilly and Co.), and Reisa A. Sperling (Harvard University)
  • 00:01
    1. Introduction to Trial Innovation; Problem statement; The charge
  • 05:24
    2. Challenges/risks to implementation; Scope issues; Opportunities for innovation
  • 12:36
    3. Business case
  • 14:12
    4. General discussio

Session IV: Funding


Co-lead: Luc Truyen (Johnson & Johnson)
  • 00:01
    1. Introduction to Funding; Core and extended groups; Problem statement
  • 05:22
    2. Sustainable funding of research and development; Objective of GAP
  • 10:54
    3. The problem of funding GAP; Vision for success; Cost drivers; Defining the workplan
  • 18:22
    4. General discussio

Resources

Keynote address

Lauer MS, D'Agostino RB. The randomized registry trial — the next disruptive technology in clinical research? N Engl J Med. 2013;369:1579-81.

NIH Collaboratory. Health Care Systems Research Collaboratory.
Supported by the Common Fund at the National Institutes of Health, the Health Care Systems Research Collaboratory is intended to improve the way clinical trials are conducted by creating a new infrastructure for collaborative research.

Patient-Centered Outcomes Research Institute
The Patient-Centered Outcomes Research Institute (PCORI) is authorized by the U.S. Congress to conduct research to provide information about the best available evidence to help patients and their health care providers make more informed decisions.

UK Biobank
UK Biobank recruited 500 000 people aged 40 to 69 in 2006 to 2010. It aims to improve the prevention, diagnosis, and treatment of a wide range of serious and life-threatening illnesses, including cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, depression, and forms of dementia.

Janet Woodcock: Insights from the U.S. Food and Drug Administration

I-SPY 2 TRIAL
I-SPY 2 Trial for breast cancer rapidly tests emerging and promising new agents with the goal of significantly reducing the cost, time, and number of patients required to efficiently bring new drug therapies for breast cancer to market.

Friends of Cancer Research. Lung Cancer Master Protocol.
The Lung Cancer Master Protocol is an innovate clinical trial design protocol that was officially announced at the 2013 Conference on Clinical Cancer Research, hosted by Friends of Cancer Research and the Engelberg Center for Health Care Reform at the Brookings Institution.

Mini-Sentinel
Mini-Sentinel is a pilot project sponsored by the U.S. Food and Drug Administration to create an active surveillance system—the Sentinel System—to monitor the safety of FDA-regulated medical products.

TransCelerate Biopharma
TransCelerate BioPharma Inc. is a nonprofit organization focused on advancing innovation in research and development with the goal of delivering more high-quality medicines to patients.

Related initiatives

Accelerate Cure/Treatments for Alzheimer's Disease
ACT-AD is a coalition of national organizations seeking to accelerate the development of potential cures and treatments to slow, halt, or reverse the progression of Alzheimer's disease through research.

Alzheimer's Association Research Roundtable
Research Roundtable members seek to facilitate the development and implementation of new treatments for Alzheimer's disease by collectively addressing obstacles to research and development, clinical care, and public health education.

Alzheimer's Disease Cooperative Study
ADCS was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. It is part of the NIA Division of Neuroscience effort to facilitate the discovery, development, and testing of new drugs for the treatment of AD. It is also part of the Alzheimer's Disease Prevention Initiative.

Banner Alzheimer's Institute. Alzheimer's Prevention Initiative.
Led by Banner Alzheimer's Institute, the Alzheimer's Prevention Initiative is an international collaborative formed to launch a new era of Alzheimer's prevention research by evaluating the most promising therapies in cognitively normal people who, based on their age and genetic background, are at the highest imminent risk of developing Alzheimer's disease symptoms.

DIAN-TU Trial
The DIAN-TU trial is a global adaptive trial which enrolls dominantly inherited Alzheimer's disease families in a multi-drug seamless phase II/III trial design. It is supported by the NIH, pharmaceutical partners, and the Alzheimer's Association and receives nominations from the DIAN Pharma Consortium.

DIAN Expanded Registry
The DIAN Expanded Registry is a registry for participants who have dominantly inherited Alzheimer's disease, their families, and associated researchers and physicians. It provides regular updates, webinars, and referrals to research studies, genetic counseling, and testing.

Dominantly Inherited Alzheimer's Network (DIAN)
DIAN is an international research partnership of leading scientists determined to understand a rare form of Alzheimer's disease that is caused by a gene mutation.

Innovative Medicines Initiative: Alzheimer's Disease
The Innovative Medicines Initiative (IMI) is Europe's largest public–private partnership aiming to improve the drug development process by supporting more efficient discovery and development of better and safer medicines for patients.

Medical Research Council. UK Dementias Research Platform
The MRC UK Dementias Research Platform aims to bring together many of the UK's best-characterized cohorts to create a unique single research platform for the investigation of dementia.

National Institutes of Health. Accelerating Medicines Partnership: Alzheimer's.
A partnership between the NIH, 10 biopharmaceutical companies, and several nonprofit organizations to identify and validate the most promising biological targets of disease for new diagnostic and drug development efforts in Alzheimer's and other diseases.

At the Academy

Alzheimer's Disease Summit: The Path to 2025

Prevention of Alzheimer's Disease — What Will It Take?

Organizers

Paul Aisen, MD

University of California, San Diego
website | publications

Russell L. Barton, MSc

Eli Lilly and Company

Randall J. Bateman, MD

Washington University
website | publications

Howard Feldman, MD

University of British Columbia, Canada
website | publications

Phyllis Barkman Ferrell, MBA

Eli Lilly and Company

Debra R. Lappin, JD

FaegreBD Consulting
The Global CEO Initiative on Alzheimer's Disease
website

Erin O'Malley

FaegreBD Consulting
The Global CEO Initiative on Alzheimer's Disease
website

Michael T. Ropacki, PhD

Janssen Research & Development
publications

Andrew Satlin, MD

Eisai Inc.
publications

Eric R. Siemers, MD

Eli Lilly and Company
publications

Michael Simmons, DBA

Eli Lilly and Company

Reisa A. Sperling, MD, MMSc

Harvard Medical School
website | publications

Luc Truyen, MD, PhD

Johnson & Johnson
publications

Roy Twyman, MD

Janssen Research & Development

George Vradenburg

The Global CEO Initiative on Alzheimer's Disease
website | publications

Cynthia Duggan, PhD

The New York Academy of Sciences

Diana L. van de Hoef, PhD

The New York Academy of Sciences

Ellis Rubinstein

The New York Academy of Sciences


Keynote Speaker

Richard J. Hodes, MD

National Institute on Aging, NIH
website | publications

Opening Remarks

Janet Woodcock, MD

U.S. Food and Drug Administration
website | publications


Panelists

Monique M. B. Breteler, MD, PhD

German Center for Neurodegenerative Diseases (DZNE)
website | publications

Maria Freire, PhD

Foundation for the National Institutes of Health
website

Elisabetta Vaudano, DVM, PhD

Innovative Medicines Initiative
website | publications


Alla Katsnelson

Alla Katsnelson is a freelance science writer and editor, specializing in health, biomedical research, and policy. She has a doctorate in developmental neuroscience from Oxford University and a certificate in science communication from the University of California, Santa Cruz, and writes regularly for scientists and non-scientists alike.

Sponsorship

Presented by

  • The New York Academy of Sciences
  • Global CEO Initiative on Alzheimer's Disease

Sponsors

  • AC Immune
  • Alzheimer's Drug Discovery Foundation
  • AstraZeneca
  • Bank of America
  • Banner Health
  • GE Healthcare Life Sciences
  • Janssen Pharmaceuticals
  • Eli Lilly and Company
  • Merck
  • Nestle Health Science
  • Pfizer
  • Sanofi
  • Takeda

The enormous socioeconomic cost of Alzheimer's disease (AD) places a strain on the global economy that will soon burgeon to an unprecedented and unsustainable burden on health care systems and national budgets as the global population ages. In the United States alone, the over $200 billion annual cost of AD is expected to reach $1.2 trillion by 2050. The economic and human costs imposed by this illness are directly experienced by patients and their families. There is currently no cure, validated prevention strategy, or disease-modifying treatment for AD. The most recent symptomatic treatment was approved 10 years ago and several drug candidates have since failed in phase III trials.

There is an urgent need to develop therapeutics and interventions for AD; yet pharmaceutical companies have traditionally worked in silos, often chasing the same targets and running trials that compete for the same patients, with wasteful redundancies of effort and costly phase III failures that have set back the field. In a transformation within the pharmaceutical industry, companies are beginning to share clinical trial data and safety information precompetitively in an effort to improve our understanding of study design, clinical efficacy, safety, biomarkers, and clinical endpoints.

The Global Alzheimer's Platform (GAP), conceived in a series of workshops held over the past year, aims to establish a drug discovery process that promotes cooperation and data sharing among existing and future AD drug development efforts. The overarching goal is to develop a network of trial sites across the world that are certified and standing ready to conduct AD trials. The initiative aims to accelerate trial recruitment; to significantly reduce trial redundancy, expense, and time; to deliver consistent, high-quality trial performance; to apply innovative trial designs; and to incorporate mechanisms for information and data sharing designed to advance science and translation, including the discovery and validation of a biomarker to measure neuronal loss in AD.

At the GAP Design Workshop on February 19–20, 2014, stakeholders fleshed out the details of the initiative and discussed the infrastructure needed for it to succeed, as well as the challenges it faces. The group came up with the following immediate next steps:

  • Establish an office of project management, and identify executive leadership and a governance structure that can drive the execution of GAP.
  • Define a business plan for GAP, including goals, strategies, milestones, and a budget.
  • Develop innovative trial design approaches that will effectively and efficiently test AD therapies and accelerate the identification and validation of novel theragnostic and surrogate biomarkers.
  • Identify sources of sustainable funding to build the project.
  • Align and coordinate GAP with ongoing global efforts, such as the Innovative Medicines Initiative and TransCelerate.
  • Maintain alignment with and the cooperation of global regulatory and funding authorities as the GAP business plan framework develops.

Keynote Speaker:
Richard J. Hodes, National Institute on Aging, NIH
 
Speakers:
George Vradenburg, Global CEO Initiative on Alzheimer's Disease
Maria Freire, Foundation for the National Institutes of Health
Janet Woodcock, U.S. Food and Drug Administration

Highlights

  • Clear goals, deliverables, and milestones will be needed to successfully launch GAP.
  • Stakeholders should look to existing clinical trial innovations to identify elements that could be incorporated into GAP.
  • Three key components for success will be scientific preeminence, policy framework, and administrative architecture.
  • GAP will set up a network of patient registries that can be used as the basis for trial-ready cohorts. It should allow researchers to perform proof-of-concept studies and may build in a capacity for larger confirmatory trials.

Setting the stage

The Global Alzheimer's Platform emerged as the first priority for action at the Alzheimer's Disease Summit: The Path to 2025, convened in November 2013 to outline a research agenda to advance the goals of the U.S. National Alzheimer's Plan and aim toward effective prevention and treatment of Alzheimer's disease by 2025. The second priority established at the Summit is to build novel funding models to support a higher level of financing for AD research, and the third priority is to develop technology-driven tools and platforms to manage big data. George Vradenburg of CEOi noted that action plans are in development for all three goals. This workshop aimed to create a roadmap for GAP.

Vradenburg stressed that the goals of GAP—to improve AD clinical trials and bring AD drugs to market more quickly and efficiently—can be achieved by combining science policy with a strong execution team and by establishing clear milestones and deliverables. The purpose of GAP, he said, is not to debate or drive science but to advance discovery by serving science, supporting research without taking up scientific questions. The GAP team includes a diverse group of stakeholders from government, industry, academia, patient advocacy groups, and the finance sector, who must come together to tackle the global challenge of AD.

Keynote address

In his keynotes address, Richard J. Hodes of the National Institute on Aging, NIH, explained that GAP has the potential to fill a need for improved clinical trial infrastructure in AD. Recent initiatives point to the types of infrastructure and mechanisms that are needed, and thus can inform GAP strategy.

There is a need across all disease areas to run trials that are inexpensive, efficient, and relevant. The randomized registry trial is a recently proposed disruptive model for clinical research that could be incorporated into AD research. The GAP plan to create registries from which to draw trial-ready cohorts has a precedent in the TASTE trial, described in a recent editorial in the New England Journal of Medicine. By using disease-specific observational registries in Scandinavia, the 6000-patient cardiovascular disease study was able to report significant findings while costing just $300 000 above the cost of clinical care. It is important to examine the possibilities and challenges inherent in embracing such an approach for AD, Hodes argued.

Innovations in U.S.-based clinical trial infrastructure include an NIH-supported project called the Health Care Systems Research Collaboratory, in which HMOs and other health care providers form partnerships and harmonize patient databases to study clinical topics including suicide prevention and lumbar imaging. The more recent Patient-Centered Outcomes Research Institute (PCORI) is working to establish procedures for sharing health records among provider networks. Another model, which aligns well with the goals of GAP, is the UK Biobank. It has recruited 500 000 volunteers to donate blood and undergo cognitive testing for an observational study, while a subset of participants are monitored through MR imaging. Individuals in the registry can be recruited to interventional trials, and follow-up is managed cost-efficiently through the established system.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) and other efforts demonstrate that cognitive performance deficits occur well before dementia strikes. One recent trial funded through a collaboration between the Banner Institute at the University of Arizona, the NIH, and industry also hints at the potential benefits of tracking brain changes over time, beginning before symptoms appear. It examined members of the largest known family with a Mendelian inherited form of AD; individuals carrying a single point mutation in the gene presenilin develop the disease, and dementia appears by about age 49. The researchers found that carriers of the mutation showed a marked abnormality in amyloid PET imaging by ages 35 to 39—a decade or more before the onset of symptoms. Thus it is crucial to track individuals for years and even decades before symptoms become evident, and trial cohorts must span the spectrum of disease to monitor changes at the earliest possible stage. Until recently, most trials have focused on later stages of AD, when a cohort could be assembled through diagnosis and monitored using clinical or biomarker endpoints. But this recruitment approach can also work for participants at the earlier stage of mild clinical impairment.

Recruiting participants for preventative trials is challenging, but high-risk populations could be defined with genetics and then tracked to measure the impact of an intervention. The statistical power in preventative trials will depend on the magnitude of participants' AD risk as well as the trajectory of change in biomarker endpoints. Hodes pointed out that early preclinical signs of changes in amyloid cannot be detected by imaging on a timescale shorter than 18–24 months, which is fairly slow. Moreover, to achieve long-term success, tests must be cost-effective and applicable to large, diverse populations. More than half of dementia cases today occur in low- and middle-income countries; by 2030, the proportion will be 63%, and by 2080 it will climb to 71%. Thus, high-cost scans may be of limited use on a global scale. Despite challenges in patient recruitment, trial time, and cost, it is nonetheless important to pursue prevention trials to combat AD.

Observations on the requirements for success

In her opening remarks, Maria Freire, president of the Foundation for the National Institutes of Health, called the GAP initiative a "big hairy audacious goal." If successful, it will not only provide a tremendous impetus for AD research but also establish a roadmap for other disease areas, demonstrating how to shorten the time between the first discovery of a potential drug and the arrival of a new therapeutic on the market.

There are three essential components for success in such an ambitious initiative. The first is scientific preeminence, without which the program cannot stand. The second is policy influence, including the political will to galvanize stakeholders into action to build a framework around the scientific enterprise. The third—not sexy but nonetheless crucial—is an administrative architecture to mobilize resources, oversee goal setting, and mark milestones. All three components are in place for GAP, Freire asserted, and the FNIH looks forward to working with GAP to support its success.

Insights from the U.S. Food and Drug Administration

Successful treatment and prevention of AD is an inspiring goal, but achieving it will take monumental effort. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, explained that what's largely missing today is translational apparatus to screen biomarkers and interventions, and then efficiently perform confirmatory tests for promising candidates. Without this capacity, the field faces decades of uncoordinated one-off efforts.

GAP can provide this missing framework, most importantly through its concept of a standing network of patient registries. This network should include participants with a range of disease severity, including non-symptomatic at-risk individuals, and support exploratory work while being scalable to large confirmatory trials.

The first step in creating the network is to link existing investigators and registries by creating standardized data collection systems such that common data elements such as age, race, and cognitive status could be examined as trials proceed. The FDA's Mini-Sentinel effort is exploring similar strategies. The second step is to prepare for expanded trial capacity by establishing agreed-upon procedures, such as the use of central institutional review boards (IRBs) and standardized consent forms. TransCelerate Biopharma is investigating elements of trial standardization. The third step is to implement small-scale biomarker trials and natural history studies to begin to deeply characterize participants. The final step is to expand capacity to enable large-scale, multi-site, multinational confirmatory trials, in which even a few data elements—if standardized—could be highly informative. The transition between small-scale and confirmatory trials should be seamless and will require the existence of a standing cohort of subjects that can be quickly enrolled.

Woodcock noted that there are precedents for such networks, such as the Lung Cancer Master Protocol and the I-SPY 2 Trial in breast cancer. Still, the concept is unusual and does not conform to the traditional model for how academic researchers, pharmaceutical and diagnostic companies, and even patients operate, and thus funding and building the platform could be challenging. However, Woodcock encouraged researchers to focus on the project's goal to help the millions of people affected by AD.

Team Leaders:
Randall J. Bateman, Washington University
Michael T. Ropacki, Janssen Research & Development
Paul Aisen, University of California, San Diego
Russell L. Barton, Eli Lilly and Company

Highlights

  • GAP will create a system of standardized and linked registries from which clinical trial participants can be recruited through a common data management system into well-characterized, trial-ready cohorts.
  • The registry network aims to shorten clinical trial time by at least one year.
  • GAP will establish a global network of clinical trial sites with standardized protocols, procedures, and datasets. The sites will be certified and ready to conduct both proof-of-concept and confirmatory AD trials.
  • The network should reduce trial site activation time by one year, and member sites should be able to recruit two patients per month.

Registries to cohort

Despite the enormous unmet clinical need for AD therapies, clinical trials are slow, expensive, and difficult, explained team leaders Randall J. Bateman of Washington University and Michael T. Ropacki of Janssen Research & Development. One hallmark of and major contributor to the high cost and low efficiency of clinical trials is the one-year or longer delay between the decision to conduct a trial and the enrollment of its first patient. A global infrastructure of registries, with a standing group of perhaps 50 000 or more potential participants who could be recruited quickly into a clinical trial, would go a long way toward mitigating that delay and increasing the efficiency of clinical trial recruitment.

The Registries to Cohort design team is charged with developing criteria for and establishing standardized and linked registries, as well as a common data management system through which to recruit participants into well-characterized, trial-ready cohorts. The goal is to shorten clinical trial time by at least one year. The network will seek to recruit participants through channels including major health system service providers, primary physician networks, Internet-based enterprises, new direct-to-consumer campaigns, public databases, and social media networks. Individuals will consent to be contacted for future studies, and basic patient data useful for screening candidates for specific trials will be aggregated to group participants from registries into trial-ready cohorts. A registry network of 50 000+ could also be used to mount a prospective longitudinal cohort study of perhaps 10 000+ individuals at various pre-symptomatic or symptomatic stages of AD, who could later be enrolled in interventional trials.

The first step in launching a registry network is to inventory the many existing registries and cohorts, including those in large-scale integrated national and private health care systems, to clarify which elements of the plan will be leveraged from existing projects or created from scratch. The team also needs to identify key data the registry network should collect and establish a global informed consent procedure and common data management system. Much thought will need to be given to overcoming practical, bureaucratic, and intellectual property barriers to sharing patient information. The team will also need to devise a public outreach plan to engage and enlist large numbers of participants.

The team plans to create a business plan and appoint members to manage the registries. The costs of establishing a network of registries will be determined in the business plan, which will be based in part on a comparison to existing projects such as the UK Biobank cohort. The aim is to enroll at least 50 000 participants in a global registry by the end of 2015.

Trial site activation

Time at the start of any AD clinical trial is lost to the inefficient process of identifying and activating individual clinical trial sites. Variability in performance, outcomes, and participant retention across different sites can decrease the quality of the data generated in a trial, explained team leaders Paul Aisen of the University of California, San Diego, and Russell L. Barton of Eli Lilly and Company. Delays in trial site activation result in unacceptably slow drug development, highly inefficient trials, unacceptable or unreliable trial results, and a high drug failure rate. The hope is that these barriers could be overcome by building a global network of clinical trial sites certified to meet a core set of minimum criteria that would be widely accepted by industry clinical trial sponsors and reflect trial site quality and efficiency.

The Trial Activation design team is charged with developing criteria for and establishing a global network of clinical trial sites with standardized protocols, procedures, and datasets, certified and standing ready to conduct both proof-of-concept and confirmatory AD trials. Ideally, this network should reduce trial site activation time by one year, and member sites should be able to recruit two patients per month.

The first step to creating a global network of high-performance AD trial sites will be to map academic, industry, and private clinical trial sites worldwide to identify those that could participate. Next, the team will need to define key elements of clinical trial site certification—such as biospecimen collection, personnel training, and site quality measures—as well as common systems of institutional review board (IRB) approval and participant consent. It may be possible to leverage existing efforts, such as the industry partnership TransCelerate Biopharma, to tackle some of these issues. This design team aims to establish a functioning trial network with at least the first 100 nodes in place by the end of 2015.

Building and maintaining a standing network of clinical trial sites and a common data management system will require upfront and ongoing funding, the source of which is still an open question. Because such a network is expected to reduce the time and cost for conducting AD clinical trials, industry may be willing to provide financial support. Alternatively, because participation in the network will carry benefits, the sites themselves may be required to cover some or all of the costs of meeting certification standards. A third option is a combined model, in one variant of which sites might pay for the expense of qualifying to join the network while companies pay for access to the data management needed to engage with the sites.

Team Leaders:
Howard Feldman, University of British Columbia, Canada
Andrew Satlin, Eisai Inc.
Eric R. Siemers, Eli Lilly and Company
Reisa A. Sperling, Harvard University
Luc Truyen, Johnson & Johnson

Highlights

  • GAP will develop a platform for flexible and innovative adaptive and combination clinical trial designs that will enable speedier and more robust proof-of-concept trials.
  • Establishing and maintaining GAP will require a sustainable multi-stakeholder funding framework.

Trial innovation

This is a hopeful and exciting time in Alzheimer's drug development, according to the leaders of the Trial Innovation design team. Researchers are getting closer to identifying reliable biomarkers for target engagement and have a reasonable understanding of appropriate biological targets, as well as an emerging understanding of the genetic underpinnings of AD. Researchers are optimistic that at least one of the compounds in phase II and phase III trials will achieve approval. However, successful treatment of AD, particularly in low- and middle-income countries, will almost certainly require multiple interventions as well as therapies that are more cost-efficient and easier to administer than the first or even second- and third-generation treatments are likely to be. Therefore, developing AD drugs suitable for the global at-risk population will require innovative approaches to trial design, in which single or multiple drugs and interventions can be tested simultaneously using well-defined endpoints. A clinical trial platform that enables adaptive trials and has the flexibility to incorporate multiple studies on different populations will thus greatly improve the efficiency of AD drug development.

The Trial Innovation design team is charged with developing flexible and innovative adaptive and combination clinical trial designs that will enable speedier and more robust proof-of-concept trials and incorporate mechanisms for sharing information and data. One possibility is to launch a single, standing adaptive clinical trial that employs interim analyses to evaluate the success or failure of prospective therapies, allows researchers to randomize subject subgroups to therapies and doses based on emerging data, and enables the sharing of placebo groups. Such a continuously run trial would contain common outcome measures and assays. A standing trial platform in combination with the GAP network of clinical trial sites could be used to conduct large validation studies and develop more sensitive clinical measures.

Large, integrated trials will require agreement among industry participants on procedures for data sharing and intellectual property. The scope of trials has yet to be determined, but such trials would also need to be aligned and integrated with related efforts in the U.S. and abroad. The first step to building a clinical trial platform is to acquire seed funding to cover the costs of both designing a business case for successful implementation and identifying funding sources. The cost of running the trials can be estimated from other innovative trial efforts, such as the Dominantly Inherited Alzheimer Network (DIAN).

Funding

As governmental and international bodies become more aware of the growing socioeconomic burden of AD, momentum is gathering to commit funds to support research. However, the recent string of clinical trial failures has shown that funding AD clinical research is a risky proposition. Luc Truyen of Johnson & Johnson, who led the Funding design team, explained that creating a sustainable multi-stakeholder funding framework for GAP will require demonstrable paths to success, transparency and accountability, and mechanisms to allow stakeholders to share in projects' risks while also guaranteeing a fair financial or social return on investment.

The Funding design team is charged with exploring innovative funding mechanisms to support the establishment and maintenance of GAP. In addition to government or philanthropic funding models, several market-based frameworks are being considered to build sustainable incremental funding for the initiative. In the gym model, members of industry who would like to use the resources that GAP provides, including registries, a clinical trial site network, and adaptive clinical trial capability, would pay an initial membership fee and then continue to use the resources on a pay-as-you-go basis. In another approach, parties would invest in the platform, with early investors paying less and late investors paying a premium. In a third model, parties that commit funding would receive benefits, such as IP extension or a waiver adding six months of market exclusivity to AD-related products.

To build funding infrastructure for GAP, the team will need a business plan, which is slated for completion in the next several months. Many of the cost drivers will not be apparent until the other three teams have clearly defined goals, milestones, timelines, and funding needs.

Moderator:
George Vradenburg, Global CEO Initiative on Alzheimer's Disease
 
Panelists:
Monique M. B. Breteler, German Center for Neurodegenerative Diseases (DZNE)
Maria Freire, Foundation for the National Institutes of Health
Elisabetta Vaudano, Innovative Medicines Initiative

Highlights

  • GAP should maintain close consultation with the IMI consortium, which is set to launch by the end of 2014.
  • Translational research should be in dialogue with basic science and population research.
  • GAP's success will require investment in a secretariat to align the components of the project and put metrics in place to track progress.

Panel discussion

The success of GAP hinges on its ability to coordinate with global efforts in AD translational research. Moderator George Vradenburg began the panel session by asking Elisabetta Vaudano of the Innovative Medicines Initiative (IMI), a European public–private partnership, to explain how GAP can best align its goals with the IMI timeframe and aims. Vaudano explained that IMI hopes to select and launch its AD consortium by the end of the year, and welcomes discussion on alignment with GAP as soon as the winning consortium is selected. Although the IMI effort will incorporate specific mechanisms for cooperating with AD efforts around the world, the initiative can fund only European-based research. Vaudano proposed ensuring strategic alignment between the two initiatives by including GAP members in the IMI scientific advisory board. She also stressed the need for GAP to engage in close discussion with regulators from the beginning, as the IMI consortium will be required to do in Europe.

Vradenburg next asked Monique M. B. Breteler of the German Center for Neurodegenerative Diseases for her thoughts on the strength of translational research in Germany. Breteler replied that translational research involves more than the trajectory from bench to bedside, and instead requires integration of clinical, basic, and population research. Her institute has embraced this dynamic approach. Basic research can be conducted in an animal model, and responses to prospective therapies that are seen in human studies can later inform how to improve the animal model. Similarly, population-based research should be mined for hypotheses that should be explored in the other arenas. One example from AD research is the observation that AD and dementia incidence have declined significantly in developed countries while increasing in the developing world. Breteler suggested that an integrated approach be more directly incorporated into GAP.

Finally, Vradenburg asked Freire to offer advice for bringing a project as geographically vast and sectorally diverse as GAP to fruition. Freire described her experience in the early 2000s as CEO of the Global Alliance for TB Drug Development, which faced many similar challenges—a need for funding, major scientific questions, a lack of drug candidates to bring forward, and a need to build a clinical trial structure. She stressed that coordinating the disparate pieces of a project such as GAP is itself a major task, and that doing so successfully will require investment in a secretariat to ensure project alignment and to track metrics and progress.

Closing remarks

The GAP Design Workshop brought together key stakeholders on short notice to begin to define goals and metrics for success, Vradenburg told participants at the close of the meeting. The next stage of the project will involve developing a comprehensive business plan and funding strategy for the design phase of GAP and establishing a multi-stakeholder funding infrastructure to sustain GAP in the long term. Meanwhile, the Registries to Cohort, Trial Site Activation, and Trial Innovation design teams will continue to define their operational components based on established timelines and milestones.

Which existing registries offer models for GAP?

Which data would be most useful to collect for the GAP registries network?

How can registries effectively conduct public outreach and recruit participants?

What are the key elements for clinical trial site certification, and how should sites be standardized?

How should the performance of the clinical trial network be assessed?

What is the scope of the kinds of trials GAP should be prepared to conduct?

How can GAP develop more sensitive clinical trial measures and reduce data variability?