In light of recent failures in high-profile Alzheimer’s disease clinical trials, scientists have turned their attention with increasing urgency toward testing therapies in early-stage patients who have underlying brain pathology but little to no functional impairment. Now, the U.S. Food and Drug Administration is formally recognizing this shift. The agency yesterday held a Webinar on a draft guidance it had issued last month to companies developing AD drugs. In it, the agency acknowledged that testing drugs in the dementia stage of the illness may be too late to have a clinically meaningful effect. “The goals of the guidance are to provide a framework for how drugs might be studied in patients with early-stage AD, and to provide a forum for further discussion,” Nicholas Kozauer told Webinar attendees. Kozauer and Russell Katz, both of the FDA’s Division of Neurology Products, led the Webinar and coauthored an editorial in the March 28 New England Journal of Medicine that describes the guidance and its rationale.

On 7 February 2013, the FDA released the guidance to industry in draft form and welcomes public input until 9 April (electronic comments can be submitted here). The guidance states that traditional criteria—which require drugs to improve performance in both cognitive and functional domains—will not work for early-stage patients who show mild cognitive impairment (MCI) yet still carry on with life normally. The document acknowledges the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other natural history studies that suggest biological changes can reflect AD in advance of clinical symptoms. The draft guidance recognizes “prodromal AD” (i.e., MCI-like deficits anchored by AD biomarkers) and “preclinical AD” (cognitively normal with AD risk factors or biomarker changes) as part of the disease spectrum. The guidance proposes using continuous outcome measures in clinical trials rather than trying to measure time to dementia. It encourages drug developers to consider taking disease-modifying compounds into late MCI using composite measures that assess cognition and function on the same scale, for example, Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Other scales are under development, for example, cognitive composites as recently discussed in an ARF Webinar and an ARF conference story. Katz said the FDA would consider these as well. For early MCI or preclinical populations, the agency suggests it may be possible to approve a drug based on an isolated cognitive measure through the agency’s accelerated approval pathway. This mechanism speeds approval of drugs for unmet medical needs, and would require post-approval studies to verify the clinical benefit.

“This really launches a new age, and it’s very much built on the ADNI collaborative effort. I just wanted to recognize that,” Paul Aisen of the University of California, San Diego, said at the ADNI steering committee meeting on 18 March during the American Academy of Neurology annual conference in San Diego.

That same day, the New York Times ran an editorial warning ominously that the FDA’s proposal “lowers the bar” for AD drug development. The newspaper editors argue that it could be risky to allow companies to test compounds in people without obvious dementia using biological markers and subtle changes in cognitive performance, instead of improved function, to gauge therapeutic efficacy. “A small decline in scores on cognitive tests may have no bearing on whether patients will progress to serious disease,” the editors wrote. “The test scores might also mistakenly identify people who are not in the early stages of Alzheimer’s and who, if treated, would suffer adverse side effects without receiving any clinical benefit.”

Aisen—along with Ron Petersen of the Mayo Clinic, Rochester, Minnesota; Michael Weiner of UC San Francisco; and Reisa Sperling of Brigham and Women’s Hospital, Boston, Massachusetts—submitted a letter to the New York Times editors declaring the FDA’s proposal “the only feasible drug development plan” and arguing that the “cautious approach suggested by the [New York Times editors] would take an incalculable toll on our health.” The scientists' letter is posted below.

AD researchers praise the FDA’s efforts as a sensible adaptation to new AD drug development challenges. “We herald this as a real shot in the arm with massive implications for the field,” said Marwan Sabbagh of Sun Health Research Institute in Sun City, Arizona. Adam Fleisher of Banner Alzheimer’s Institute in Phoenix, Arizona, says the FDA has been “forward thinking but cautious” in rising to the challenge of finding treatments for AD in its earliest stages while “encouraging cautious scientific diligence.”

They and other scientists disagree with the New York Times editors’ claim that the proposal loosens the rules for drug approval. “The bar is not lower with these new guidelines,” wrote Sterling Johnson of the University of Wisconsin, Madison, in an e-mail to Alzforum (see full comment below).

At the Webinar, Katz said, “It only makes sense to use outcome measures appropriate for the condition being treated. We do that every day with every drug we deal with. We are attempting to tailor the outcome measure to the early-stage AD population. Using a single outcome measure instead of two is just the appropriate thing to do in this population. We absolutely do not believe we are loosening guidelines.”

William Jagust of the University of California, Berkeley, points out that the FDA is “suitably skeptical of using only a biomarker as an endpoint in a clinical trial.” Kozauer and Katz expressed a similar sentiment. “Despite our growing understanding of the relationship between various disease-based biomarkers and the clinical course of Alzheimer’s disease,” they wrote in the NEJM editorial, “it remains unclear whether the effect of a drug on one or more such biomarkers can actually predict a meaningful clinical benefit.” This was borne out in recent clinical trials showing discordant biomarker changes and cognitive endpoints (see ARF conference story).

Even for early MCI trials using a single cognitive measure in lieu of the traditional two-pronged requirement for both cognitive and functional gains, Kozauer told the Webinar audience that the agency “would have to be convinced that patients being identified for treatment are very likely to go on to develop AD dementia. We recognize that number is not going to be 100 percent, but we would have to have a good understanding of the risk before we contemplate using the [accelerated approval] pathway,” he said. Still, even if some amyloid-positive seniors do not develop dementia within their lifetime, “early treatment could have a substantial impact on AD at a population level,” Sperling noted. “Delaying dementia by just five years is estimated to reduce Medicare costs of AD by more than 50 percent.”—Esther Landhuis

Submitted to The New York Times on 18 March 2013

To the Editors,

Nearly half of the population over the age of 70 will be affected by Alzheimer’s disease with accumulation of abnormal amyloid protein in brain associated with cognitive decline and eventual dementia and death. Drugs now in development can reduce amyloid accumulation, but such treatments at late stages of AD dementia do not provide substantial clinical benefit. A simple analogy might be trying to treat heart disease by lowering cholesterol at the stage of heart failure in the intensive care unit.

The new anti-amyloid drugs must be tested at the earliest, asymptomatic stage before there is widespread, irreversible loss of nerve cells in the brain. The only feasible drug development plan, as noted in the well-considered draft guidance document by the FDA, must rely on demonstration of slowing subtle cognitive decline, along with evidence of amelioration of the underlying disease pathology. The cautious approach suggested by the Editors [Editorial, 18 March 2013] would take an incalculable toll on our health.

Paul S. Aisen, MD
Director, Alzheimer’s Disease Cooperative Study
Professor of Neurosciences, University of California, San Diego
9500 Gilman Drive M/C 0949
La Jolla, CA 92093
 858-246-1365

Ronald C. Petersen, MD, PhD
Director, Mayo Clinic Alzheimer’s Disease Research Center
Professor of Neurology, Mayo Clinic

Reisa A. Sperling, MD
Director, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital
Professor of Neurology, Harvard Medical School

Michael W. Weiner, MD
Director, Alzheimer’s Disease Neuroimaging Initiative
Professor of Medicine, Radiology, Psychiatry, and Neurology
University of California, San Francisco

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  1. The editors list valid concerns; however, I doubt there is the risk that a prevention would be approved that causes side effects without clinical benefit. The concerns listed are well known and have been thought through by the FDA and others.

    For example, the FDA is highly conservative in approving drugs in general, and takes an appropriate evidence-based approach. The FDA decisions are not made in a vacuum, but with the consensus of independent stakeholders including patient advocacy groups, academic researchers, and physicians. The recent FDA guidance about prevention efforts reflects the accepted consensus of the Alzheimer’s disease field and is not a new approach. In fact, many of medicine’s most successful treatments are secondary prevention: lowering cholesterol to prevent heart attacks and strokes, decreasing weight, lowering blood pressure, etc. We should support all effective efforts to combat the modern scourge of aging—Alzheimer’s disease. To quote a medical adage—"An ounce of prevention is worth a pound of cure"….

  2. This editorial by the New York Times raises important points and is understandably skeptical of this change in approach to clinical trials in AD. But a change in approach is what is needed. The numbers of baby boomers who may be on their way to dementia will severely strain the healthcare system, as recently explained in detail by the <a href="http://www.alz.org/alzheimers_disease_facts_and_figures.asp" target="_new">Alzheimer's Association's Facts and Figures</a>. Current approaches entail testing agents at the dementia stage, and this has clearly not worked. By this phase of the disease, the extent of degeneration may be too great to overcome. The field is now clearly shifting toward testing agents at the predementia stage. The relevant measurements and outcomes are different at this phase of the disease because cognition is still largely intact and functional decline is not evident in the predementia and presymptomatic phases.

    <p>The FDA's new guidance on outcome measures is not lowering the bar—it’s simply adapting to the relevant measurement requirements at the early phases of the disease.

    </p><p>As the New York Times editorial indicates, this shift in focus to early-stage AD also shifts the risk-benefit calculation for any candidate drug administered to asymptomatic people in a Phase 3 trial. The risks of a drug should be as well characterized as possible, and careful monitoring will be needed to avoid doing harm.

    </p><p>It is also critical that asymptomatic or prodromal individuals selected for trials are indeed those who will reliably progress to AD. We can do this type of prediction at the late MCI stage, but are not yet capable
    of making an accurate prediction in presymptomatic persons or in the earliest phases of prodromal disease. Several studies are underway that are helping in this regard, including the groundbreaking ADNI study that
    was cited in the New England Journal of Medicine article that is now studying early MCI. Another is the Wisconsin Registry for Alzheimer's Prevention that has enrolled 1,500 people (mean age 54 at entry) into an observational longitudinal study. Seventy percent of the cohort have a parent with AD. The biomarkers derived from studies such as these for early phases of disease will require greater validation with clinical endpoints. All of this will take more intensive study and funding.

    </p><p>In sum, the bar is not lower with these new guidelines. If anything, the bar is higher now, given the work we will need to do to increase prediction precision in asymptomatic people required for trial enrichment, and the greater responsibilities required when administering drugs to ostensibly healthy patients. I am convinced this is the best way forward, and gratified by the FDA's adaptation to the field's shift in
    focus to early intervention.
    </p>

  3. I think that both the FDA guidance and the New York Times editorial are thoughtful responses to a difficult problem. We have to change the way we test drugs for AD if we want to move to trials in preclinical individuals, and the FDA guidance provides a reasonable approach. It simply isn't possible to measure functional improvement, at least with instruments we now have, in asymptomatic people, so looking at cognitive change is the only possible clinically meaningful endpoint. However, I do agree with the New York Times perspective that even showing a drug effect on cognitive change does not guarantee that we will stop the progression to AD. It is worth pointing out that the FDA is suitably skeptical of using only a biomarker as an endpoint in a clinical trial. This is something that might be useful with the appropriate evidence, but so far that evidence is lacking (i.e., that changing the biomarker affects clinical outcomes).

    How to solve this problem? There are only two ways that have been proposed: very long and complex clinical trials in asymptomatic people (i.e., long enough to show effect on actual disease incidence or progression to functional impairment), or continued post-approval follow-up studies to show the benefit to clinically meaningful endpoints. A requirement for the first approach will squelch innovation and development of pharmaceuticals for AD. The latter approach makes sense, but it is often not implemented, required, or well regulated in the current environment. To me, the solution is the requirement and regulation of post-approval studies, with some period of drug approval and marketing permitted, but a "sunset" on this approval, absent further evidence of clinically meaningful outcomes. But this would require a major overhaul of drug approval processes, and I somehow doubt it's going to happen. The only other question is to what extent evidence from naturalistic studies will contribute to our thinking. There is increasing evidence, for example, that brain Aβ is associated with cognitive decline in aging. If solid evidence of the risk of Aβ for cognitive decline—and the relationship between this decline and AD—can be gathered, treating cognitive decline alone will be on stronger ground.

  4. As a professional working to provide meaningful answers to patients, I can but rejoice at the approach of the FDA. The New York Times editorial raises the concern that "the agency would end up approving drugs that provide little or no clinical benefit, yet cause harmful side effects."

    The concern about potentially harmful side effects is not a sensible argument. The FDA's facilitated approval does not imply more relaxed criteria for safety, but for efficacy. Too bad the New York Times has missed this.

    As to efficacy, what the FDA is proposing (approving drugs based on an intermediate clinical endpoint, i.e., cognitive deterioration) is not a disruptively innovative approach. After all, cognitive deterioration is the clinical core of dementia, as disability follows cognitive deficits, not vice versa. One might argue whether the magnitude of cognitive deterioration that will be used as an outcome is or is not clinically significant, but this is an unresolved discussion even for the currently approved symptomatics.

    The disruptively innovative approach would be the use of a biomarker as a surrogate outcome, i.e., regarding the effect of a drug on CSF, blood, or imaging markers as a proxy of clinical efficacy for registration purposes. This would dramatically boost drug development for the smaller group size and shorter duration of such trials. Unfortunately, none of the current biomarkers is indisputably a valid surrogate outcome. As a consequence, as stated by Drs. Kozauer and Katz, this approach "could someday be accepted, but further research will clearly be needed." Thus, I believe that the FDA's approach makes great sense from a clinical and scientific point of view.

  5. The FDA has been incredibly forward thinking but cautious in the field of Alzheimer’s disease drug development. They realize that if we wait until the endstages of disease, where irreversible brain damage has already occurred, as in overt dementia, we will simply never address the overwhelming health burden that this country and the world are facing with an expanding demented population to care for. Great accomplishments come with risk.

    While encouraging cautious scientific diligence, the FDA is advocating that the scientific and drug development community continue efforts to find treatments for Alzheimer’s disease in its earliest stages. These are individuals with a pathological disease, and often already have subtle clinical manifestations. To claim that we must wait for a patient to have overt dementia before we target treatment development is analogous to limiting cancer therapy development to only patients that have clinical symptoms. This is, of course, absurd and would condemn the field to focusing only on stages of disease that offer little hope in reversing damage done by a longstanding pathological process. Alzheimer’s disease is a disease of the brain, one which is silent for the majority of its course as it slowly destroys brain tissue. Biomarker development has advanced to allow us to begin to identify Alzheimer’s pathology independently of clinical manifestations.

    More work needs to be done to understand how biomarkers of disease predict clinical outcomes. We are well on our way to answers with longitudinal studies of aging and upcoming early-stage treatment trials. But we must encourage early-stage drug discovery in parallel to our biomarker development efforts. This is what the FDA’s recent accelerated-approval mechanism based on surrogate endpoints or intermediate clinical endpoints is proposing, in order to address this critical unmet need. It is imperative to focus on addressing the pathology, and not wait for overt dementia. This is not lowering the bar by any means; it is rising to the challenge—a challenge that must be faced in a disease that threatens to cripple our aging population and public healthcare systems. Our regulatory framework must remain flexible and open to innovative approaches, encouraging the scientific community to push forward with what will likely be one of the most important healthcare challenges of this century.

  6. The FDA draft guidance represents a positive step forward in the development of new treatments for early stages of Alzheimer’s disease (AD). The FDA guidance and editorial recognize that older individuals with evidence of amyloid pathology are at high risk for developing progressive cognitive decline and dementia. Since the symptoms in these individuals are very mild, the FDA accepts that the initial primary outcomes will likely be subtle changes on sensitive cognitive measures and one or more biomarkers showing a slowing in markers of neurodegeneration. Continuation trials will be needed to demonstrate long-term safety and convincing benefits in cognition and daily function. The New York Times editorial was out of touch with the urgent need to treat AD early, before brain injury is well established. The FDA is not “lowering the bar," but rather adjusting the outcome criteria to fit the clinical characteristics of people at high risk for AD. As a society, we must increase our risk tolerance to explore promising opportunities to prevent or delay the crippling stages of Alzheimer’s disease that endanger the vitality of our aging population and pose a crippling threat to our already overburdened healthcare system.

  7. We have seen in our AIBL study that 25 percent of cognitively unimpaired individuals with high Aβ burden in the brain have a significantly higher likelihood (odds ratio of 5) to show cognitive decline and progression to mild cognitive impairment and even Alzheimer’s dementia within three years. So if these new trials show a significant decrease in the incidence of cognitive impairment in these individuals, they will support the early intervention approach with disease-modifying drugs.

    Furthermore, if this lower incidence of cognitive decline is accompanied by a low incidence of serious side effects, it will provide a strong argument for the approval of these drugs by the FDA, through one of the many mechanisms available to them.

  8. It is critical to test anti-amyloid treatments at much earlier stages of AD to determine if we can slow disease progression before there is widespread, irreversible neurodegeneration. It is not currently feasible to conduct 10-year trials in >10,000 subjects, with detailed clinical and biomarker assessments, to demonstrate long-term effects on clinical function. The draft FDA guidance is excellent, providing a reasonable path to detect therapeutic effects on sensitive cognitive measures in very early AD. I don't actually think of this guidance as "lowering the bar," as it is known that loss of clinical function is a relatively late manifestation of AD, and that early change in cognition is strongly linked to subsequent functional decline and dementia progression.

    In terms of the concerns raised in the New York Times editorial about treating apparently healthy individuals, it is, of course, important to consider safety issues and balance risk/benefit in all clinical trials. However, many older individuals fear Alzheimer's disease more than cancer, and we must not be afraid to try biologically active drugs at the stage of disease when they may be most beneficial. It is true that we do not yet fully understand the individual risk of progression to dementia in asymptomatic individuals with biomarker evidence of early AD pathology. The proposed AD secondary prevention trials will provide crucial information on the best predictors of cognitive decline and the potential benefits of lowering amyloid in slowing the rate of decline.

    Even if some proportion of amyloid-positive older individuals will not develop dementia within their lifetime, early treatment could have a substantial impact on AD at a population level. The vast majority of individuals treated for high cholesterol will never develop a heart attack or stroke, but lowering cholesterol at a population level is estimated to have reduced cardiac morbidity and mortality by 28 percent over the past two decades. Delaying dementia by just five years is estimated to reduce Medicare costs of AD by over 50 percent. We must move forward in testing potential interventions at a stage of AD when we may be able to delay and ultimately prevent clinical disability. The FDA should be lauded for its forward thinking and its willingness to work with academia and industry to facilitate feasible efficient trial designs in earlier stages of disease.

  9. Treating a disease at early stages certainly increases the chances of a successful outcome. However, based on the following reasons, I think there are drawbacks associated with the approach (testing the anti-amyloid therapies in asymptomatic individuals), which could outweigh the potential benefits.

    1. The impetus for testing anti-amyloid therapy in asymptomatic/prodromal individuals arose as a result of multiple failures of this approach in MCI patients, with the rationale being that the therapeutic interventions were started too late to be effective. However, a possibility exists that the trials failed because amyloid is simply not an effective target (even if a correct target) in the majority of late-onset AD cases. This notion is supported by the emerging evidence from preclinical (new genetic risk factors, basic cell biology) and clinical investigations (neuroimaging and discordance between biomarkers, and clinical outcomes of trials). Therefore, the current thrust for testing anti-amyloid therapies in asymptomatic/prodromal populations could turn out to be risky, the risk being that after several years down the road, we may still not have an effective treatment because the efforts were aimed at an ineffective target.

    2. As Bateman quotes, an ounce of prevention is worth a pound of cure. But it is true only if the prevention is effective! So, a better approach might be to test the treatments that have the best evidence for being effective in preventing AD/cognitive decline in humans. The available evidence shows that most effective treatments to date are: anti-inflammatory treatment when initiated at a prodromal stage (several epidemiological NSAIDs studies), and lifestyle changes involving exercise (increased physical activity) and a diet rich in plant-based foods. Preliminary IVIg data suggest that anti-inflammatory therapies may also be effective at later stages of the disease. Thus, there are multiple underexplored alternative therapeutic avenues available today, and it will be prudent to dedicate the resources towards testing these approaches in asymptomatic/prodromal populations.

    3. Finally, to be most cost effective at the population level, the treatment should be effective at a stage when the memory deficits start to appear. Even if the proposed approach (anti-amyloid therapy in asymptomatic individuals) shows positive results, a large number of asymptomatic individuals who are destined to get AD may not start the treatment for a number of reasons (not being sure if they will get the disease, financial constraints, fear of side effects, etc.). On the other hand, a fraction of the population (false positive, individuals not going to get AD) may end up receiving unnecessary treatment. Thus, there is a high degree of inefficiency associated with treating the asymptomatic population, and this inefficiency will only add to the escalating healthcare costs in the U.S. I maintain that, through more basic research on the mechanism of AD pathogenesis, treatments that are effective in MCI individuals (or even mild AD patients) can be achieved. Just see what we have been able to achieve for HIV/AIDS and cancer patients.

References

Webinar Citations

  1. New Frontier: Developing Outcome Measures for Pre-dementia Trials

News Citations

  1. CTAD: Adaptive Antibody Trial to Try Bayesian Statistics
  2. CTAD: New Data on Sola, Bapi, Spark Theragnostics Debate

Other Citations

  1. scientists' letter

External Citations

  1. Webinar
  2. draft guidance
  3. editorial
  4. here
  5. Alzheimer’s Disease Neuroimaging Initiative
  6. editorial

Further Reading

Papers

  1. . Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013 Mar 28;368(13):1169-71. PubMed.