Late stage clinical trials

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Thank you! This FOA encourages the submission of applications for the clinical testing of novel candidate therapeutics small molecule and biologics , as well as for repurposed drugs. Investigators are strongly encouraged to incorporate pharmacodynamic biomarkers in the design. Investigators are also expected to collect and store blood and other biosamples for future genomic and other 'omic' analyses aimed at interrogating treatment responsiveness and examining predictors of decline and progression.

Additional guidance for this section is provided below, based on the clinical trial phase. Applications for therapeutic agents against known target s are expected to include information on the mechanism of action for the therapeutic agent, information regarding the target's role in disease pathogenesis and clinical relevance of the target, and information on the predicted optimal disease stage e.

Applicants proposing a multi-target therapeutic should summarize the available information on the pathogenic pathways that the agent engages and provide a strong clinically-relevant rationale for this approach. If the molecular target of the therapeutic agent is not known, applications should summarize what is known about the agent's mechanism of action and whether the agent engages a disease-relevant pathophysiological process.

Finally, applications should contain a plan for future clinical development of the therapeutic agent, including details about the clinical indication disease stage, target population , plan for use of biomarkers in the course of further clinical development i. Applicants should also provide evidence of safety from earlier phase clinical trials and should include further evaluation of safety in the trial design. Finally, applications should contain a plan for future clinical development, i.

This FOA encourages the submission of applications for the testing of novel non-pharmacological interventions,. Applications for clinical trials should include information on proof of mechanism for the intervention s being tested. Applications for clinical trials should also contain a plan for future clinical development, i. Investigators are encouraged to collect and store blood and other biosamples for future genomic and other 'omic' analyses aimed at interrogating treatment responsiveness and examining predictors of decline and progression.

Applications for late stage pharmacological clinical trials that are appropriate for this FOA will have established proof of mechanism or target engagement at earlier stages of clinical development for the intervention s being tested. The intervention s being tested in late stage clinical trials should also have adequate safety data for the populations under study.

All applications for late stage non-pharmacological clinical trials that are appropriate for this FOA will have an established demonstration of efficacy. Note: Delayed onset does NOT apply to a study that can be described but will not start immediately i. Foreign non-U. See Part 1. Section III. Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day. Organizations must submit applications to Grants. NIH and Grants. Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

This initiative is not subject to intergovernmental review. Paper applications will not be accepted. Applicants must complete all required registrations before the application due date. Eligibility Information contains information about registration. For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply — Application Guide.

If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance.

See more tips for avoiding common errors. Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed. Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy. Only the review criteria described below will be considered in the review process.

In addition, for applications involving clinical trials: A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field s involved, in consideration of the following review criteria and additional review criteria as applicable for the project proposed.

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact.

For example, a project that by its nature is not innovative may be essential to advance a field. Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Will the intervention presented help overcome the critical barriers to progress in Alzheimer's clinical trials? In addition, for applications involving clinical trials. For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy?

For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training?

If established, have they demonstrated an ongoing record of accomplishments that have advanced their field s? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense?

Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Is the intervention novel for a clinical trial in Alzheimer's disease and related dementias; age-related cognitive decline? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project?

Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented?

If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Are the mechanisms of action for the intervention included and well presented in regard to the target and the target's role in disease pathogenesis and clinical relevance of the target?

If there is a multi-target therapeutic approach, is it well justified and clinically-relevant in rationale? Is the future clinical development of the therapeutic agent discussed and is there potential?

Is there evidence of safety? Are the pharmacodynamic biomarkers well-reasoned and appropriate to evaluate the success of the intervention? Will the investigator collect biosamples?

How adequate are the applicants' Data Sharing Plans? Does the application adequately address the following, if applicable. Is the trial appropriately designed to conduct the research efficiently? Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate?

Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate?

Is there a plan to obtain required study agent s? Does the application propose to use existing available resources, as applicable? Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions?

Are the procedures for data management and quality control of data adequate at clinical site s or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award? Will the scientific environment in which the work will be done contribute to the probability of success?

Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? I s the proposed trial population readily available and are there adequate resources for recruitment and retention?

Will the project have the resources to collect and store blood and other biosamples? Does the application adequately address the capability and ability to conduct the trial at the proposed site s or centers?

Are the plans to add or drop enrollment centers, as needed, appropriate? As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Specific to applications involving clinical trials. Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources e.

Are potential challenges and corresponding solutions discussed e. For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1 risk to subjects, 2 adequacy of protection against risks, 3 potential benefits to the subjects and others, 4 importance of the knowledge to be gained, and 5 data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1 the justification for the exemption, 2 human subjects involvement and characteristics, and 3 sources of materials.

For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: 1 description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; 2 justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; 3 interventions to minimize discomfort, distress, pain and injury; and 4 justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals.

Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section. For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

For Renewals, the committee will consider the progress made in the last funding period. For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.

Prevention trials have tended to select participants with risk factors such as family history, cardiovascular disease, relatively greater age or existing MCI in an effort to increase the numbers of individuals who progress to dementia over a typical 5-year follow-up.

Dementia prevention trials have generally used available, marketed or safe drugs and food supplements, and often as an add-on or nested within a larger trial for another condition, such as the preventive effects of anti-hypertension medications, conjugated oestrogens, an HMG-CoA reductase inhibitor or vitamin E and selenium [ ].

These as well as prevention trials of antihypertensive agents [ ] did not show protective effects on cognitive function or dementia onset and, indeed, in some cases may have shown the opposite [ 98 ].

Additionally, there are a number of planned trials involving structured physical activity interventions that are discussed elsewhere in this issue [ ]. The A4 trial is testing the concept of treating participants who are amyloid PET positive, without notable cognitive symptoms i. The amyloid cascade hypothesis [ 19 ] has dominated drug development for the past two decades. Other BACE-1 inhibitors are in development, although there have been failures due to toxicity.

Interest in tau-based approaches has led to putative inhibitors of enzymes involved in tau phosphorylation e. Agents in development include small molecules, monoclonal antibodies and vaccines.

Most advanced is a formulation of methylene blue, methylthioninium chloride, TRx TauRx , that may act as a tau aggregation inhibitor. Anti-tau approaches in clinical development are listed in Table 3. Putative disease-modifying drugs. Despite the interest in amyloid-targeted drugs for longer-term, disease-modification trials, there has been continued interest in small molecules that would have relatively quick and symptomatic effects targeting a range of receptor complexes that result in cholinergic enhancement, or modulate monoamine and other neurotransmitter systems.

Thus the pursuit of the cholinergic hypothesis has continued and cholinergic pathways remain viable drug targets. Monoamine oxidase MAO -B inhibitors are being revisited since the early trials of selegiline [ 38 ] and derivatives in the s. For the latter class, preclinical evidence suggests an effect similar to that of acetylcholinesterase inhibitors, and clinical data are now being collected in phase 2a trials. The McKhann et al. The evolution of inclusion criteria in clinical trials reflects the change in clinical diagnosis towards aetiologically directed diagnostic approaches as compared with more clinically and phenotypically based inclusion criteria.

All MCI criteria as used in clinical trials further required relative preservation of other aspects of cognitive function and ADL. In retrospect, the Mayo clinic criteria for amnestic MCI have been recognized as being relatively stringent in their requirements for memory impairment and led to identification of subjects with relatively rapid rates of progression to dementia.

It is noteworthy that memory impairment thought to be related to ageing, categorized by terms such as age-associated memory impairment [ ], age-related cognitive decline and subjective memory impairment or cognitive decline in the elderly, has not been the focus of drug development.

This may reflect a lack of economic incentive, as from a regulatory point of view such conditions are not considered to be illnesses, which is a prerequisite for approval of a drug. However, in the USA, food or dietary supplements have been promoted for such conditions.

The primary outcomes of the trials can be described within cognitive, functional, global change and severity domains Table 5. The two ADL scales are often used interchangeably. The Progressive Deterioration Scale [ ], however, is noteworthy for its use as an ADL rating in important regulatory trials for tacrine, galantamine and rivastigmine. It includes tests of memory, praxis, orientation, language, reasoning and word-finding as well as, in extended versions, executive function and attention.

It is an individualized selection of neuropsychological tests mainly from the Wechsler Memory Scale, the Rey Auditory Verbal Learning Test and verbal fluency tests that are combined into three batteries assessing immediate and delayed memory and executive function [ ].

The ADAS-cog, however, can be expanded to include tests of executive function and episodic memory [ ]. The CDR is the most commonly used severity rating in trials of 12 months and longer. The former is used to assess clinically meaningful change from baseline, and the latter to assess current severity of dementia, either on a staging scale of 0—3 0, 0.

Since the first 6-month trials, co-primary outcomes assessing cognition and either function or clinical global change have been used in phase 2 and 3 trials that are intended as pivotal studies. However, a disease-modifying claim will be granted by the EMA only providing that there is a clinically relevant treatment effect supported by additional CDR sub-items exploratory analyses and results from key secondary endpoints as well as compelling evidence from the biomarker programme showing delay in neurodegeneration.

The EMA requires a comprehensive assessment of efficacy to support the primary outcome that itself must be interpretable as clinically meaningful in addition to being statistically significant.

Any variations have been in the use of a cognitive outcome in addition to the ADAS-cog or the choice of ADL rating, global change or severity scales. Therefore, according to this reasoning, the drugs did not have enough opportunity to work as the brain contained too much amyloid substrate, the neurodegeneration was too advanced or the patients did not have the illness in the first place. Most current longer-term trials use a biomarker in a subset of participants, usually for exploratory and sometimes for disease-modification purposes.

Biomarkers that are affected by the drug might be used for enrichment and prediction, but are limited for use as a surrogate clinical outcome. However, for the most part biomarkers still require validation for the particular purpose for which they are used and need more than just correlation with clinical change. The biomarkers used in clinical trials were developed with the intention of reflecting disease and have been used extensively in observational studies.

They were introduced into clinical trials as potential prognostic and predictive markers. These changes, however, occurred in the absence of detectable clinical change. One explanation for counter-intuitive outcomes is that analyses of biomarker subsets from individual trials lack statistical power to detect significant changes related to treatment effects.

On the other hand, the trials including biomarkers are not designed to make a constructive comparison between biomarker-positive and biomarker-negative patients. Such trials could potentially validate biomarkers for diagnostic and labelling purposes, and possibly as supportive evidence of clinical outcomes, but would require either validation in a biomarker-negative population or neuropathological evidence.

Another consideration is that biomarker determinations and cut-off points are set arbitrarily and vary across studies. A method for validating a biomarker for a particular drug development programme is to document the change in biomarker in phase 1, validate by correlating with the clinical outcome in phase 2, and then use it in confirmatory phase 3 trials.

There is considerable hope that biomarkers can first accurately measure biological change that indicates disease progression and, secondly, be validated as surrogate markers of clinical effect and therefore, by virtue of being more precise than the clinical measures, increase the statistical power of clinical trials, thus requiring fewer participants for faster and more efficient trials.

In such a scenario the standard clinical outcomes considered to be insensitive to change especially in early illness can be wholly replaced [ 92 ].

The outcomes of the recent bapineuzumab and solanezumab trials raised further questions regarding the usefulness of current biomarkers as outcomes for trials.

Consideration regarding the use of biomarkers should be given to several factors including the type of therapeutic intervention, the clinical stage of illness and the time dependence of biomarker changes during illness. Although a risk factor and not a biomarker per se , APOE genotype has been commonly treated as a diagnostic or prognostic biomarker. Among many other responsibilities, the FDA, EMA and other agencies worldwide regulate and assure the safety, effectiveness, quality, labelling and manufacturing standards of prescription and non-prescription drugs.

Specifically they judge whether an investigational drug intended for marketing is safe and effective for its proposed use, the benefits of the drug outweigh the risks, the proposed labelling i. Regulators have generally facilitated drug development by providing standards for later phase development. The EMA issued detailed guidelines for disease modification [ ], and qualified novel methodologies, including the use of biomarkers for enrichment. However, guidelines may constrain some development programmes by limiting how drugs with vastly different actions used in a pleomorphic disorder can be developed.

Effectively, the guidelines encourage very similar programmes regardless of the different characteristics of the drugs or diagnostic subtlety. Pharmaceutical companies and academics, therefore, may restrict themselves to planning standard protocols that might not be the most appropriate for the drug under development.

For these reasons, regulatory agencies may be involved very early in drug development programmes encouraging companies to seek scientific advice meetings. The EMA, for instance, has established the Scientific Advice Working Party SAWP which consists of experts in areas including non-clinical quality and biostatistics, and connects with a network of external clinical experts and patient representatives from the EU. According to the EMA, cholinesterase inhibitors are considered standard care despite their controversial health effectiveness status such that a drug being developed needs to be assessed also in a phase 3 add-on design wherein the new drug is used in a placebo-controlled trial in patients already maintained on cholinesterase inhibitors.

By comparison, patients and physicians would welcome a drug that worked over a long period whether or not it is called a disease modifier. In the late s, the FDA informally suggested two methods to demonstrate disease modification that would be sufficient for a health claim: a randomized-start and a randomized-withdrawal design [ ].

Until recently only the EMA offered guidelines that suggested a method for disease modification. According to the EMA, biomarkers should correlate with the presumed mechanism of action of the drug and ultimately, it is hoped, with the clinical efficacy of the drug [ 89 ]. So far, however, no such relationship has been observed other than in small subsets of larger trials that showed null results in terms of the primary outcomes for the drug in question.

There was a potential trend, depending on the statistical analysis, for tramiprosate to be associated with increased hippocampal volume in a subgroup [ ].

All these observations, however, were unrelated to clinical improvement which did not occur with the experimental drugs, and do not provide evidence to support the biomarkers in question.

The FDA prefers the latter option and first proposed this clinical trial design two decades earlier [ ]. Indeed, in the late s a month trial of propentofylline built in both a randomized-start and randomized-withdrawal design by re-randomizing at 12 months and in a double-blind manner extending the trial by 6 months [ 54 ]. However, the drug was withdrawn from development. Illustration of a randomized-start design for a regulatory clinical trial to demonstrate disease modification.

Reproduced with permission from Leber [ ]. In evaluating the development plans of mainly anti-amyloid drugs, the EMA has issued further scientific advice as to how to contextualize a disease-modification claim in light of the quest to treat patients with very early stage disease and to develop diagnostic companion biomarkers. The first trial should recruit patients with early stage disease with virtually no functional impairment at baseline and efficacy should be demonstrated on a composite endpoint, such as the CDR-SB, or possibly a single primary endpoint providing that it is validated in this population.

The second trial should recruit patients with mild or mild to moderate disease, with efficacy demonstrated on two co-primary endpoints addressing both cognition and function. The evidence from both trials should be robust and supported by secondary endpoints including responder analyses and biomarkers that show delay in brain neurodegeneration. One challenge for disease-modifying drugs will be their costs especially if the majority of older people use them. Cost-effectiveness estimates in this area are controversial, although the findings of a Swedish simulation study suggested that the main costs were the price of the drug and the cost of an expected 1-year decrease in mortality.

However, long-term data are needed to understand the progression of change beyond the trial period, and particularly with drugs intended to interfere with the amyloid cascade to assess for any worsening or rebound that may occur with prolonged therapy.

Nearly drugs were advanced to at least the level of phase 2 development. Moreover, the approved drugs show limited clinical effect and there is controversy regarding whether they are therapeutically useful Fig. The most probable explanation for this failure, of course, is that the tested drugs simply were not effective for their intended indication.

There are many potential drug targets and so far no validated targets except perhaps for the cholinergic system. A comparison of the same effects of donepezil with standard deviation bars showing the distribution of drug and placebo outcomes and standard error bars indicating the precision of the outcomes measures. Reproduced with permission from Lindner et al. Although very few of the many negative trials give clear information about why results were null or inconclusive, the methods used to develop the drugs should be viewed with caution and critically appraised.

Important issues include whether development programmes and trial methods have gone wrong, and are there better approaches to late-stage trials that might enhance the likelihood of success? Explaining after the fact why trials failed despite our best efforts is speculative and any rationalizations are likely to be incorrect. However, although rational and based on observations that amyloid biomarkers in some cohorts precede symptoms, there is no supporting evidence that this approach will be effective.

The cholinesterase inhibitors, including those that were not marketed, showed consistent, albeit small, statistical efficacy over 6 and sometimes 12 months. Even so the drugs do not achieve the minimum clinically important drug—placebo difference of 4 points on the ADAS-cog that was sought by experts in the s; in addition, they are not effective in MCI, i. A model of clinical trials that was recently qualified by the FDA and EMA [ ] demonstrated that cholinesterase inhibitors do not change illness course and have negligible long-term effects on the ADAS-cog.

Muscarinic M 1 agonists showed slight but overall consistent effects. Moreover, the phase 2 and 3 trials showed efficacy with from to patients, far fewer than the sizes of phase 2 and 3 trials for the anti-amyloid drugs that did not show significant effects.

In retrospect this level of consistency demonstrates a robust proof of concept for the cholinergic hypothesis despite the small magnitude of the clinical effects. It is notable that there have been no formal a priori attempts to maximize the effects of cholinesterase inhibitors, for example to identify and target clinical subgroups that might be better responders.

By comparison, the results of trials of drugs for other targets have been disappointing. Phase 3 trials should be hypothesis confirming and such surprises should not be common.

A milestone for drug development is the progression from phase 2, a safety and proof of concept phase, to pivotal trials in phase 2b or 3. The regular failures in phase 3 suggest that decisions may not be based on the evidence from phase 2, that phase 2 is not informative, or that we may be acting on signals that are not signals; in particular, over-valuing or misinterpreting post hoc subset analyses.

Under these circumstances, the negative outcomes of the subsequent phase 3 trials should not have been surprising. No anti-amyloid therapy phase 3 trial has been preceded by a positive phase 2 proof of concept trial.

Moreover, the fact that the protocols of some pivotal trials had to be changed during the study because of toxicity means that characteristics of the drugs, dosages and targets were not known before entering confirmatory trials.

Thus the large phase 3 trials, instead of being confirmatory, are often exploratory. The decision to advance a drug may be more dependent on how pharmaceutical companies make decisions than on an evidence-based likelihood of efficacy. Therefore, the sponsor may be willing to spend relatively large amounts on late-stage trials while recognizing the high probability of failure in pursuit of extremely large returns over the life of the drug.

As the phase 2 trials are negative, the phase 3 trials are conducted without adequate prior information for planning, often with data gleaned from post hoc subgroup analyses, and methods duplicated from previous, unsuccessful trials. The new trial represents, in effect, a large call option for the pharmaceutical company. Although many drugs should not have been brought into phase 2 or 3, for many more development was in fact stopped early and appropriately in phase 1 and 2a and these trials were not included is this review focused on late-stage development.

Some drugs in phase 3 programmes do have significant efficacy results from phase 2 trials to support their advancement. There are few adaptations in trial design for the unique characteristics of different drugs, durations of use, mechanisms by which they exert their effects, or for any expected different outcomes. The minimal changes in trial methods may be a consequence of having no successes to build on and the perceived risk aversion of companies and academics to making changes.

Thus small changes occur: MMSE criteria ranges are expanded or contracted, trial durations are lengthened, similar outcomes are exchanged, sample sizes are increased, amyloid biomarkers are used to increase diagnostic confidence and smaller clinical effects are sought.

Notably, trials now require drug—placebo differences of only 1 to 2 points on the ADAS-cog over 18 to 24 months, i. More refined diagnostic and prognostic markers have advantages and disadvantages. The use of biomarkers may lead to sample enrichment of patients who might benefit from a particular drug, future identification of valid subtypes and drug-responsive genotypes and phenotypes.

On the other hand, the current markers being advanced may be pseudo-specific to the illness and its progression, or may indicate more advanced illness. In this non-systematic review, important drugs may have missed and others may have been over-emphasized. Yet it is apparent that phase 2 and 3 drug development has been over-represented by anti-amyloid approaches.

It is beyond the scope of this review to comment on the validity of the amyloid cascade hypothesis. It is not possible to extrapolate from trial failures to refute the hypothesis; to do so it must be known or demonstrated that the drug entered the brain, had a clear effect on the target, and then resulted in no effect.

Without such information it can only be concluded that these approaches have been tested inadequately. Many trials are including earlier-stage diagnoses or at-risk states, requiring greater numbers of participants, and longer follow-up periods now extending beyond 18 months. Specifically, phase 2 and 3 development programmes have grown from trials with to participants and two 6-month trials, to to participants in trials extending to 24 months.

There is a need to better appreciate the pleomorphism of the illness, its competing risk factors and precipitants such as age, genetics, environmental factors and cerebrovascular and cardiovascular disease.

The wide range of targets make it unlikely that affecting one alone will lead to a more than minimally effective therapeutic agent. The goal of enrichment with biomarkers is targeted research.

However, targeted clinical trials also need to be focused, based on the drug, patient characteristics and ideally a companion biomarker.