Introduction

On Monday, 27 October 2008, a live Webinar was held by Alzheimer’s research leaders on a national action plan to accelerate discoveries of treatments to prevent dementia. The plan will be presented to the 111th U.S. Congress in March 2009. Presentations were given by Marilyn Albert, Jeffrey Cummings, Rachelle Doody, Robert Egge, Serge Gauthier, Mike Grundman, June Kinoshita, Ron Petersen, Lon Schneider, Dale Schenk, Peter Snyder, and Zaven Khachaturian (moderator).

The panel was followed by a Q&A session open to audience members. Alzforum members may also submit questions via e-mail after the live Web event. The Alzforum hosted this discussion in collaboration with the 2008 Leon Thal Symposium on Prevention of Dementia (LTS’08) and the Alzheimer’s Study Group (ASG) to solicit suggestions from the scientific community on this important topic. (See our Virtual Town Hall: Early Detection of Alzheimer Disease for our previous live forum to solicit input from the research community for the National Strategic Plan.)

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Background

Background Text
By Leon Thal Symposium organizers

Presently the field of Alzheimer’s research is at a crossroads: transitioning from symptomatic treatments of people with the disease to the prevention of the precursor in asymptomatic people.

The primary focus of this Webinar is to stimulate discussion and identify

1. The most critical barriers and challenges the field faces

2. Strategies to overcome these barriers to progress

3. Factors that would accelerate the development of therapies for the prevention of AD

4. Additional resources or infrastructure needs of ongoing programs or initiatives

5. Issues related to clinical trials, e.g., study design, cost, and study duration

6. Regulatory issues

7. New models to financing the cost of prevention trials

8. Incentives to promote prevention e.g., increased funding of discovery research, extending exclusivity, etc.

The panel members will start the discussions by briefly reviewing and commenting on some of the recommendations proposed by other groups, listed below. These are intended to be illustrative; panelists as well as Webinar participants are encouraged to suggest other ideas or comment/expand on those that are proposed.

Some of the recommendations for public policy initiatives include

1. Mandate National Institutes of Health (NIH) through reauthorization and specific appropriations to

  • Redirect current intramural and extramural programs or establish new focused programs to focus specifically on translational medicine, thus addressing the gaps in research and funding of technology transfer from early drug discovery to early commercialization of putative therapeutic agents.
  • Substantially increase the pipeline of therapies targeting the pathogenic mechanism.
  • Demonstrate the efficacy of compounds designed to modify, slow or stop the pathogenesis of the disease.
  • Emphasize discovery, validation, characterization of early biomarkers in prodromal stages of the disease in asymptomatic people, including biochemical markers, proteomics, gene expression, MRI imaging, PET/SPECT/amyloid imaging, neuropsychological, behavioral, non-invasive markers of daily function.
  • Modify current merit review process and grant mechanisms to support a) long-term multisite collaborative studies, e.g., Alzheimer’s Disease Neuroimaging Initiatives (ADNI) and b) high-risk, high-payoff projects.
  • Increase the efficiency and capacity of integrated clinical trial networks e.g., Alzheimer’s Disease Clinical Studies Program.
  • Revamp and expand the Alzheimer’s Center’s program to encourage more integrative and translational research on asymptomatic stages of the disease, early detection, prevention, and therapy development.

2. Mandate Center for Disease Control (CDC) and/or NIH through reauthorization and specific appropriations to

  • Plan, develop, and administer (fund) a national infrastructure for a broad spectrum of population-based studies; a national omnibus database (or a registry of people at risk) as shared or public research resource for epidemiological studies on incidence, prevalence, discovery of risks, clinical trials, validation of early risk factors or biomarkers, and topics related to health services research, e.g., resource utilization or health economics.

3. Mandate Food and Drug Administration (FDA) through reauthorization and specific appropriations to

  • Require that clinical trials and future studies examine specific sets of biomarkers determined by an expert panel, with data results shared to help rapidly identify successful disease-modifying drugs seeking approval from the FDA.
  • Explore viable incentives to encourage investments in large-scale prevention programs.
  • Identify attractive inducements to entice drug developers to engage in serious planning and regulatory filings that are initiated in a timely fashion.
  • Determine how to extend laws that provide for the marketing of generic drugs.
  • Press for laws that protect the continuity of research that make drugs better. Prevention trials could then be expediently initiated, perhaps even before Phase 3 trials are completed.
  • Address the increase in the number of applications for neurological therapies by increasing FDA and creating an office for neurological therapies at the FDA, as well as a process for: Priority Review, Accelerated Approval, or Fast Track review of drugs for Alzheimer disease.
  • Promote collaboration and information sharing between the NIH and the FDA to accelerate research therapies for people with Alzheimer disease by opening pipelines.

4. Mandate the Center for Medicare and Medicaid Services (CMS) through reauthorization and specific appropriations to

  • Create economic incentives to stimulate therapy development.
  • Clarify strategies to secure a commitment from the Center for Medicare and Medicaid Services (CMS) to make subjects recruited for longitudinal and other dementia research studies eligible for reimbursement.
  • Offset encumbrances of reimbursement.
  • Study reimbursement experiences outside of North America.
  • Evaluate the consequences of poor or non-existent Medicare and other third-party reimbursements on prevention trials and/or clinical care for dementia patients.
  • Assess potential economic incentives (such as a commitment from the Center of Medicare and Medicaid Services to make subjects in longitudinal prevention studies eligible for reimbursement) to stimulate therapy development for prevention.

5. Mandate the Department of Commerce through reauthorization and specific appropriations to

  • Amend current patent protection laws, as an incentive for investment and promotion of therapies for prevention.
  • Provide incentives for investors, pharmaceutical and biotechnology companies to invest in Alzheimer disease therapies. Incentives could include economic incentives such as tax credits, patent extensions, and partnerships with federal and state agencies to develop and deliver products for treatment and prevention.

Alzforum members may also submit questions via e-mail before and after the live Web event.

Audience Q&A

Q: Will the national action plan to accelerate discoveries of treatments to prevent dementia also take into consideration, as a group, adults with Down syndrome?

Q: Laypeople are frequently bombarded with advice and advertisements on how to prevent AD. Examples would be advice on keeping your brain active, playing crosswords, Nintendo Wii, taking certain types of vitamins, having an advanced degree, etc. Do you consider these to be a barrier to getting at successful prevention of AD?

Q: Following up on Lon's point, what's wrong with incidence of dementia or AD as a relatively hard endpoint?

Q: Should the application of this policy be restricted to peer-reviewed NIH, VA, Alzheimer's Association, etc., research?

Q: What about the NCI CTEP program as a model? CTEP (Cancer Therapeutic Evaluation Program) is a congressionally mandated program that supports clinical trials in oncology. It is the framework for the cancer co-operative group trials, provides precompetitive space where compounds can be studied in combination without compromising companies’ IP, and has a mechanism for doing screening toxicology and pilot clinical trials for compounds originating in academic laboratories.

Q: Zaven, ask Lew Kuller to comment on the GEM trial.

Q: Could private practice physicians who maintain geriatric practices be tapped in a model to enhance registries or recruitment for prevention trials? This method has been used in the U.K., but will require changes in health care delivery and perhaps HIPAA.

Q: Please discuss potential non-pharmacologic treatments, such as physical exercise, and ways that we might do internally and externally valid studies of such treatments in the U.S.

Q: I think there should be a task force that would look into the epidemiologic methodology involved in participation issues in prevention trials, because participation in asymptomatic people will likely be abysmal.

Q: Discussing prevention is good, but how can we ensure we are doing valid research in an environment where individuals in the general population (asymptomatic) don't want to participate in research? I think we need to address the epidemiologic methodology inherent in this problem.

Q: What about the Welcome to Medicare Kit? Could that be an initial point of screening for AD?

Q: Which neuropsychological test do you recommend for 1) screening of dementia in the epidemiological studies, and 2) for cognitive assessment in the patients with AD, who are illiterate?

Q: While great attention is being placed on a suitable pharmaceutical attack on dementia (as well it should), will equal attention be given to helping caregivers in their struggles, especially if a drug solution is not available in the near future?

Comments

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Comments on this content

  1. Efforts should be made to work together with other nonprofits, e.g., the Alzheimer's Association, Institute for Aging Research, etc. Also, companies should be encouraged to create an alliance for the development of anti-Alzheimer's drugs. This can be achieved through the Pharmaceutical Manufacturers Association.

  2. Regarding research funding designed to discover the (real) causes of the pathogenesis of neurodegenerative disease: in my view there is an unmet (and generally unrecognized) need for funding that is focused on proving the validation of specific mechanisms of pathogenesis, prior to considering them for translational research.

    Many of these efforts are likely to show that correcting the proposed dysfunction in the specific mechanism has little or no corrective effect on the pathogenesis of the disease, or even makes the disease symptoms worse. The discoverer of a new mechanism, who often thereby morphs into a champion of it, cannot be expected, in the absence of significant inducements, to take on such a research effort.

    Such efforts/results are required to bridge the research designed to discover potential mechanism of pathogenesis in some model of the disease and the proposals to initiate the process of target selection and identification, and drug discovery, development, and testing. They should be a required component of any translational research proposal.

    I anticipate that most of the research projects imagined here would involve the manipulation of specific gene expression in in-vivo mammalian models of the disease.

  3. Although preventative and disease-modifying neurological treatments for AD are unquestionably a high-priority goal, considerably more attention also needs to be directed urgently toward developing more effective treatments for the behavioral symptoms associated with dementia. These are often the most crippling for dementia patients and contribute the greatest burden to caregivers.

    Difficulties in managing behavioral symptoms are often the reason for nursing home placement and, even after patient placement, they remain a significant management challenge. The current and projected economic burden they add to the care of demented patients is enormous. The need to develop behavioral treatments for dementia has become even more acute since the efficacy and safety of existing pharmacological treatments, such as neuroleptic agents, is being seriously questioned. Intensified research in this understudied area is recommended.

  4. If we have a chance to come back to methodologic dilemmas confronting Primary Prevention trials, it may be worth noting that it's possible to measure endpoints from trial populations that are very widely dispersed geographically. Think of ADAMS with its cluster sampling method, or the old Richard Peto notion of big and crude, relying on randomization and masking to prevent systematic error.

  5. Two endpoints should not be a problem, if one of the endpoints is reduced incidence of dementia. Dementia by definition implies functional impairment, which fills the need for a second endpoint.

  6. CMS stands to benefit hugely from any successful development of efficacious interventions for prevention. They should be highly motivated to facilitate prevention research. We could start by clarifying that CMS will pay for clinical evaluation when the need for evaluation arises specifically from a trial's discovery of disease (including research evaluation).

  7. We see people who are very interested in participating in clinical trials, but they want to get into the most promising active treatment trials, not something like a prevention via exercise study. They are asking for the most promising trials. Do we dare give some studies triple A ratings in that respect?

  8. The primary impediment to small firms entering the Alzheimer disease drug development market is lack of private funds. Called the "Valley of Death," the space between basic research and clinical trials lacks private funds because of the extraordinary high risk. But the Valley must be crossed. The Maryland Venture Fund is a state-funded seed and early-stage equity fund, which invested over $45 million in 175 companies since inception. The Fund has been very successful with a return of over $57 million to Maryland and having attracted $1 billion in private equity. Adapting the Maryland Fund at the federal level to AD could similarly attract the capital needed by small firms to conduct AD drug discovery. The return on investment for the government would primarily be the enormous cost savings to the health care system that would result from the development of an efficacious drug.

  9. Extend the exclusive use provision of the FDA Orphan Drug Act (ODA) to AD drugs. When a new mechanism of drug action is hypothesized as potentially effective, old compounds, which affect that mechanism and are safe to use, are often the best candidates for clinical testing because their toxicology is known. For small firms, old and safe compounds are attractive because they can get to the clinic sooner at lower cost to test the hypothesis. But the lack of compound protection makes raising private capital difficult. Although method of use patents are possible, they too can be problematic. The problem was recognized in the development of drugs for rare diseases. The FDA ODA provides seven-year exclusivity for the use of an old compound for treatment of a rare disease. This has been successful as more than 200 drugs have been brought to market for such diseases since 1983. Extending the exclusive use license of the ODA to AD will provide exclusivity for AD drug development.

  10. As a patent attorney, I would require the "prior art" to be enabled. Now, a throwaway statement in prior art for using a compound without teaching how to do that is presumed "enabled" in patent law. But if the prior art had to actually teach how to use the compound in order to be applicable prior art, then such throwaway statements would not block the eventual development of a compound for that use. But messing with patent law is a titanic task as other industries, such as IT, have an entirely different outlook toward patents than does the biomedical community.

  11. Practical innovation usually arises through small, entrepreneurial firms willing to take the risk of developing a new approach. As a result of the investment made in NIH, the U.S. is the world's leader in basic biomedical research. The Small Business Innovative Research grant program is one of the few NIH programs focused on translating that research into applied products. Increased funding for the NIH SBIR program would attract more small firms into the market and thereby allow more varied "shots on goal" for scoring an effective Alzheimer disease treatment.

  12. Use the potential power of social networking. Check out the ALS trial at patientslikeme.com.

  13. My refrain for this meeting is that we need to look into history. The drug development programs have existed and do exist in the various NIH institutes, including technical drug development, chemistry, toxicology. These can be utilized now.

  14. The ability to effectively form population-based registries depends on the determination of some "study base" which will give rise to the cases and ensure that all cases from that base are included in the registry. Further, if those persons with the disease had not contracted disease, they would have been part of the population base. The usual problem with doing this is that we may be starting to identify persons too late in the disease process. Reliable and valid identification of the disease both at the asymptomatic stage and at the symptomatic stage is a continuing problem. Large studies tend to apply cursory screens to identify cases rather than to apply detailed examination or mobilize to identify and apply biomarkers of the pathologic disease process to the asymptomatic population. We must, it seems, focus on measures of disease modification as outcomes rather than accept that symptoms represent disease.

    Much of the issue involved with prevention trials could, it seems, be addressed by a
    fundamental shift in the definition of disease. For example, the definition of disease based on only deposition of amyloid NFTs, neuronal death, etc., and outcome measures (yet to be developed) which would detect the occurrence of that pathology and measure its change over time in various treatment conditions may be the direction things need to go in that the redefinition of disease would allow FDA or other regulators to determine efficacy, etc., in the usual way.

  15. One of the challenges in drug discovery and development is the time and money it takes to satisfy the FDA insofar as transitioning a drug from preclinical development to first-in-human use. Perhaps many researchers and clinicians are not cognizant of the fact that the FDA's jurisdiction is predicated on there being a nexus with interstate commerce. Simply stated, if, for example, a hospital synthesizes an Alzheimer's investigational new drug, and that drug does not enter interstate commerce, the FDA is without jurisdiction to regulate its use by requiring the filing of an IND application. (Depending on which state the hospital is located, the use of an investigational new drug intrastate may be regulated by state law.)

  16. Suggestions: as part of a prevention trial, take an exhaustive look at those aged 85+ who do not have AD or MCI. When you can only find a small number of participants, make an effort to extrapolate every piece of potentially important information you can from them.

  17. We need to discuss the role of Dimebon in protecting neurons in AD patients. We also need to focus on molecules that decrease calcium levels, and molecules that inhibit mitochondrial permeability transition pore opening.

References

Book page Citations

  1. Contact Us

Webinar Citations

  1. Early Detection of Alzheimer Disease—A Virtual Town Hall Meeting

Other Citations

  1. Marilyn Albert

External Citations

  1. Alzheimer’s Study Group (ASG)

Further Reading

Papers

  1. . In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol. 2000 Mar;18(3):321-5. PubMed.