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

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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"….

    View all comments by Randall Bateman
  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 Alzheimer's Association's Facts and Figures. 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.

    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.

    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.

    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.

    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.

    View all comments by Sterling Johnson
  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.

    View all comments by William Jagust
  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.

    View all comments by Giovanni Frisoni
  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.

    View all comments by Adam Fleisher
  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.

    View all comments by Stephen Salloway
  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.

    View all comments by Victor L. Villemagne
  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.

    View all comments by Reisa Sperling
  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.

    View all comments by Sanjay Pimplikar

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