Certification of raters will depend on demonstration of skill in administration of all tests relevant to the population appropriate for the GAP-NET trials. Pre-certification and site qualification will reduce redundancy and decrease the burden on sites.
Use of agreed-upon versions of instruments will reduce variability, decrease site demands, and allow greater comparability across trials. Training and certification of new raters will facilitate growth of site teams and expansion of the site network. Improved site and personnel quality along with greater use of biomarkers will result in improved diagnostic accuracy and more uniform subject characteristics.
Use of central IRBs can also reduce trial start-up times by decreasing redundancy of reviews at each institution and establishing templates to which trials and reviewers can adhere. Identification and construction of trial-ready cohorts of patients through registries discussed below and other outreach mechanisms will abbreviate recruitment times. More aggressive use of traditional and social media can help identify appropriate trial candidates and accelerate trial recruitment.
Enhanced site performance and recruitment will mean that fewer sites will be needed for trials. Smaller sample sizes will be required and variability in data collection and trial conduct will be reduced. Requiring fewer sites and shortened recruitment periods will decrease the cost of trials and allow more drugs to be tested.
These advantages represent a value proposition for sponsors, attracting them to work with the network to conduct trials and advance therapeutics. The value for those with or at risk of the disease is acceleration of innovative medicines. GAP-NET will be available for both early stage proof-of-concept trials and for pivotal trials and will conduct trials across the spectrum of cognitive normal elderly to prodromal AD and AD dementia. Inclusion of patients in higher quality trials that are better run, better supervised, and lead to better quality data is more ethical and reflects the precious resource that patient participation in clinical trials represents.
Recruitment of patients to trials that have little chance of leading to new therapies is at best disrespectful and must be discouraged. Pre-competitive cooperation by pharmaceutical companies working with academic and other commercial entities is imperative for GAP-NET to succeed. Use of the network will require that the sponsor agree to use the specific form of each instrument that has been selected.
Similarly, sponsors must agree that the certification and qualification of the sites is acceptable and need not be repeated for their trial. Innovative thinking within the biopharmaceutical industry is resulting in significantly increased transparency of clinical research and safety information and willingness to consider collaboration on study design, measures of clinical efficacy, and biomarkers Test procedures, instrument choice, use of run-in data, and data collection and standards require regulatory discussion to assure the acceptability of data collected by GAP-NET for regulatory purposes.
Sites will be included in GAP-NET with the aim of having enough sites within the network to conduct all clinical trials presented by sponsors. Both academic sites affiliated with major medical centers and independent non-academic sites will be included in the network. Eleven pilot sites have been identified by GAP in its pilot phase. Novel mechanisms are required to speed patient recruitment to trials. Recruitment constitutes the greatest bottleneck for clinical trial conduct in AD and in many other disorders For the GAP registry, interested individuals will enroll on the web-based BHR or collaborating registry, provide demographic information, complete questionnaires, take online cognitive assessments and contribute genetic or other clinical information available through remote collection methods.
Based on these data, adaptive reiterative algorithms will be developed to select participants most likely to meet trial entry criteria Figure 1. The algorithm-based approach is hypothesized to increase the number of patients referred to trials, improve the appropriateness of the referred subjects, reduce the screen failure rate, and decrease of cost of screening. The creation of trial-ready-cohorts is proposed as a means of speeding recruitment and shortening trial cycle times.
Other registries endalznow. Tracking the trajectory of registry and cohort patients after registration and before randomization will provide additional information on drug-induced change in trajectory after trial entry and could help select patients for trials. On-line assessments may reduce the burden on care partners and clinical trial sites to collect participant data. Figure 1. Figure 2. The European IMI inaugurated the EPAD project to create a network of trial sites and conduct clinical trials using adaptive designs to test multiple agents GAP-NET cannot lead to new treatments without a concomitant improvement in AD drug discovery and delivery of a pipeline of high-quality pharmaceutical agents capable of impacting AD pathology.
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GAP-NET can test drugs more quickly and can provide better data that will allow sponsors to more rapidly decide whether or not to advance a compound for further testing. Discovery of better treatments depends on deepening our understanding of the basic biology of AD, comprehending the cellular mechanisms of neurodegeneration, and distinguishing normal and abnormal aging. GAP-NET is an engine that needs to be fueled by optimized compounds and combinations of agents developed in academic, pharmaceutical and biotechnology laboratories that meaningfully impact the biology of AD.
GAP-NET represents a disruptive transformation that will have effects throughout the AD drug development ecosystem; lessons learned from GAP-NET may influence organization of trials in other neurodegenerative disorders and other disease states The GAP-NET will be expanded from the 11 sites in the pilot phase to the number of sites needed to enter patients and conduct trials in a timely way. Sites meeting quality criteria will be GAP-NET partners regardless of their academic or private nature; poor performing sites will be excused from the network. An evolving clinical trial database will allow the investigation and publication of trial site best practices.
Structured introduction of new instruments such as patient- and caregiver-reported outcomes can be facilitated and systematically planned in the network and included in trials after regulatory review by FDA and EMA.
GAP-NET will develop capacity for site qualification clinical, biomarker, imaging , rater certification, site monitoring, and growth of the number of available sites. Russell Barton is an employee of Eli Lilly. Jeffrey Cummings has received in kind research support from Avid Radiopharmaceuticals and Teva Pharmaceuticals. Cummings owns the copyright of the Neuropsychiatric Inventory.
Lastly, Dr. Johanna Egan is an employee of Eli Lilly. Ultimately, the goal is to ensure that any assessment tool employed provides clinically meaningful information. In studies of populations with early AD symptoms, it might be appropriate to consider cognition alone as a primary endpoint, and this may require a better understanding of the clinical meaningfulness of cognitive changes and their ability to predict functional decline.
A composite composed of appropriate cognitive and functional components would also be of use. More sensitive tools, whether cognitive or functional, could help speed clinical development by shortening recruitment time and reducing the required sample size. Biomarkers have become instrumental in efficient clinical development of drug entities for many diseases, assisting with appropriate patient selection, testing target engagement by a drug, and monitoring disease progression.
In the AD field, biomarkers will be essential to speed clinical development. Diagnostic AD markers are considered those reflective of AD pathology. Use of diagnostic markers is essential to ensure enrollment of individuals who have AD pathology; clinical diagnosis alone of AD dementia is not always accurate.
Diagnostic biomarkers, however, need to be inexpensive and simpler to use if they are to be widely integrated. Topographical biomarkers are used to identify downstream brain changes indicative of AD pathology brain regional structural and metabolic changes [ 12 ]. They include magnetic resonance imaging MRI -related biomarkers, for example structural MRI to assess hippocampal atrophy, ventricular volume, whole brain volume, and cortical thickness. While useful as disease progression markers in trials, they lack the specificity of diagnostic markers and may not be helpful in early stages of disease.
In light of the challenges with clinical endpoints and the protracted and unpredictable clinical course of AD, it is crucial to have access to surrogate biomarkers that could provide an early indication that a drug is having an effect that will ultimately lead to cognitive and functional improvements; no qualified surrogates for AD trials are currently available. The use of surrogate markers would make clinical trials of potential DMTs more efficient.
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Their use would enable better decisions about which compounds from a number of closely related candidates to advance and at what dosage, thus reducing the overall risk of failure. The more clinical trials that incorporate potential surrogates, the sooner the discovery and qualification of a surrogate marker can be expected.
Once it is known that a surrogate endpoint predicts clinical benefit, the surrogate endpoint may be used to support additional approvals. Establishment of surrogate status for biomarkers takes years; as a result, they are unlikely to be available to assist reaching the goal. A target engagement biomarker helps determine whether the study drug has engaged its target in the disease process and thus has the opportunity to produce a clinical benefit. They are most useful for eliminating compounds that have inadequate engagement to effect a clinical change, thus freeing resources to invest in more promising agents.
Their use in Phase 2 would help eliminate ineffective drugs so that failures in Phase 3 are reduced. Repurposed agents are drugs that have been approved for another indication but may have pharmacological effects relevant to the treatment of AD [ 41 ].
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Repurposed agents with possible effects in AD include, but are not limited to, statins, anti-hypertensives, cancer treatment agents, and anticonvulsants [ 42 — 44 ]. Repurposed agents have the potential of accelerating the AD drug development timeline. They have already been through preclinical toxicology assessments; Phase 1 human safety, tolerability and pharmacokinetic assessments; Phase 2 safety and efficacy studies for the original indication; Phase 3 studies for the original indication, and regulatory review for the original indication.
Development of a repurposed agent for use in the AD field could begin with a Phase 2 proof-of-concept and dosing study for AD, thus avoiding the time and expense of preclinical development and Phase 1. Challenges do exist, however. While safety and tolerability of these drugs are well known, they will not have been used in AD populations where vulnerabilities may differ. In addition, many of these agents have no or limited patent protection and intellectual property challenges may decrease the interest of pharma in investing in their development [ 45 ].
With a shift in the focus of AD drug development to earlier stages of disease, both the FDA and the European Medicines Agency EMA are putting increasing emphasis on opportunities in this realm and have issued draft guidances addressing drug development for AD [ 34 , 46 ]. We provide both AD-specific and more general examples of where regulatory changes have, or could help, speed AD drug development.
Accelerating the review process could shorten the overall development cycle by several months. The FDA has introduced expedited programs for treatments that address unmet medical needs in serious diseases [ 48 ]:. While fast track does not guarantee a shorter review process, fast track submissions show more promise for receiving priority review, pending study findings. Of the DMTs currently in development, a few less than 10 have received fast track designation;.
Breakthrough Therapy Designation whereby the FDA provides intensive guidance on an efficient drug development program, beginning as early as Phase 1. To date, more than drug development programs, predominantly in oncology, have been granted breakthrough therapy designation. In cancer drug development, breakthrough therapy designation was associated with a 2.
Going forward, this path could be applicable to AD drug programs. In July , the EMA revised their guidelines [ 50 ] on the implementation of accelerated assessment and conditional marketing authorization to accelerate access to medicines that address unmet medical needs. The revisions include more detailed guidance on how to justify fulfilment of major public health interest, allows for a faster assessment of eligible medicines by EMA scientific committees, and emphasizes the importance of early dialogue with the EMA so that accelerated assessment can be planned well ahead of the submission.
The guidelines also specify information on conditional marketing authorization which allows for the early approval of a medicine on the basis of less complete clinical data than normally required if the medicine addresses an unmet medical need and targets a serious disease. As noted above, efficient AD clinical development requires that study endpoints are most appropriate for the mechanism of action of the drug being tested e. In the regulatory setting, it may be appropriate to consider drug approval based on a cognitive outcome only rather than cognition and function in these earlier stages of disease.
The difficulty in showing a drug effect on functional endpoints in those with earlier disease is recognized by the FDA [ 34 ] and EMA [ 46 ]. It may be feasible to use a cognitive primary endpoint as an intermediate or surrogate endpoint for an accelerated approval, followed by a continuation of the study or a separate study demonstrating persistence of benefit to support a later approval with standard endpoints.
Eventually, AD drug development time could be shortened through acceptance of more sensitive clinical endpoints and biomarkers, particularly surrogate markers for efficacy, as data become available to support their predictive utility for clinical benefit. Approval pathways that allow two pivotal studies to use two different populations in the AD continuum e.