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Committee on High‐quality Alzheimer's Disease Studies (CHADS) consensus report

Abstract Background Consensus guidance for the development and identification of high‐quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. Methods An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. Results Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk‐benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. Conclusions This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

Conclusions: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

K E Y W O R D S
Alzheimer's disease, clinical trial, consensus, Delphi, dementia

INTRODUCTION
Over the last decade, there has been a steady increase in the number of high-quality clinical trials focused on cognitive decline and dementia. 1 These trials have targeted the prevention, treatment, and/or disease modification of neurodegenerative, medical, and psychosocial conditions that are associated with and presumed to be causes of cognitive decline and dementia in the aging population. 1,2 Although these studies hold much promise, few therapies have been approved for these indications internationally, despite the wealth of resources invested and the breadth of possible therapeutic targets identified through basic laboratory and clinical research discoveries. 2 The relative lack of new, scientifically justified, and approved therapies for Alzheimer's disease and related disorders (ADRD), combined with the devastating progression of the disease, has created an urgency for many persons and their caregivers to find new ways to treat ADRD. Although such social pressure has spurred engagement in high-quality clinical trials, there has also been an increasing number of lesser quality studies over the last decade. These trials often do not meet best practices for clinical trial conduct, regulatory approval, trial registration, and participant engagement. 3 Clinical trial conduct is regulated through international directives, national laws, institutional review boards (IRBs), research ethics committees (RECs), and trial registration services (such as ClinicalTrials.gov in the United States and the EU Trial registration platform in Europe, https://www.clinicaltrialsregister.eu). Trial conduct is further monitored through national agencies and international consensus groups, such as Consolidated Standards of Reporting Trials (CONSORT), that provide guidance for publication of clinical trial results and which have been widely adopted by leading scientific and medical journals and enforced by the editorial staff. [4][5][6] Such efforts have been successful in enhancing clinical trial participant protections, trial registration, reporting of results, and incentivizing researchers to ensure quality in their research protocols and procedures. [4][5][6] Due to the lack of approved therapies for ADRD, there is widespread off-label use of medicines and interventions that remain untested and unproven. 3,5 The use of such approaches in lieu of evidencebased treatment may fall under the auspices of the "Right to Try" Act, but may also be offered to desperate patients solely for the purpose of financial gain. 5,7 Such "fee-for-treatment" schemes are sometimes presented as clinical trials to legitimize the use of the

Overview
There are few objective reports or studies that have addressed the question of criteria for high-quality clinical trials in ADRD. As such, consensus was sought based on the opinions of experts. Many consensus strategies are available and in the simplest case, a formal majority vote using Robert's Rules of Order can establish consensus. 8 More nuanced approaches such as the Delphi or modified Delphi approach (PubMed search for Delphi consensus retrieved 5041 citations) are also available. 8,9 We used a modified Delphi method to reach consensus.

Modified Delphi method
A modified Delphi approach including anonymous reiterative questionnaires followed by re-survey was repeated until consensus was achieved. It was designed to limit "group think." 8 Using this approach, our expert panel exchanged views, and each independently and anonymously provided feedback through a ques-

RESEARCH IN CONTEXT
tionnaire that included open-ended responses. The facilitator/chair reviewed the data and provided a summary report for each round of discussion. The panel then reviewed and discussed the summary report, and consensus was reevaluated through a refined questionnaire. This process continued until all participants reached a consensus.
The experts at each round had a full record of the anonymous issues raised by other experts. Anonymity allowed the experts to express their opinions freely, encouraging openness and revising earlier consensus agreement/disagreement.

Committee representation
The committee was assembled through directed invitation guided

Areas/topics addressed
The Modified Delphi process was initiated with a series of general questions developed by the facilitator/chair (Table 1).

Delphi round #1
The initial round of the modified Delphi process revealed many areas of consensus among panel members, including (1)  Risk-benefit information need not be included in advertising, but is necessary in the consent and consent processes 100/0 Public-facing materials should specify whether the use of a medicine is off-label or part of a clinical trial 100/0 Using experimental medicines to support the "Right to Try" Act is appropriate, outside of clinical trial engagement 100/0 prespecifying the intervention and outcomes of the study; (2) (5) that the use of unproven treatments to support the "Right to Try" legislation is appropriate, outside of clinical trial engagement (Table 2). There was also complete agreement on the need for appropriate regulatory oversight of clinical trials including IRB/REC review, trial registration, and adherence to CON-SORT reporting recommendations, but determined to be outside the scope of CHADS as these are otherwise clearly accepted practices.
Areas in which consensus was not initially achieved included the type of information that should be provided to potential participants or should be withheld to maintain scientific rigor, whether placebo should be required for clinical trials, the role of off-label use versus openlabel studies, the importance of having preliminary data for efficacy and safety prior to initiating "Right to Try" treatments, and the use of open-label extensions as incentives in clinical trials (Table 3). Questions were revised as part of the modified Delphi approach to provide additional clarification that focused on topics of concern for further discussion in the next round of the process.

Delphi round #2
The second round clarified and highlighted additional areas of consensus among panel members, including: (1) sharing of the justification for the trial with participants; (2) disclosure of funding source and conflict of interest for the investigators to participants; (3) a need for definition of the study population, intervention, and duration of the trial; (4) avoiding coercion through payments for trial participation; and (5) an absolute need for study results to be shared and preferentially published (Table 4). Questions were revised to provide additional clarification that again focused on topics of concern for further discussion.

Delphi round #3
The final round of the Delphi process led to consensus agreement and the development of the final CHADS recommendations (Table 5).

DISCUSSION
The modified Delphi process resulted in a series of recommendations that may help identify high-quality clinical trials. 8,9 This efficient process allowed consensus opinion to be formed by a diverse group of subject experts over the span of a few months. Although many of the issues fall under the purview of existing regulatory guidelines, the committee felt that they required clarification in the context of defining a "highquality" clinical trial. 6 The proposed recommendations are intended to serve as a metric for guiding health-care providers and consumers in the selection of appropriate options for those with and/or at risk for ADRD. Areas of specific concern and focus identified included: (1) recognition of whether the unapproved use of an intervention or treatment represented a clinical trial or off-label use under the "Right to Try" Act, 5,7 (2) trial design, (3) trial conduct including costs and financial considerations/conflicts, (4) adherence to regulatory principles and standards, 6 and (5) public education materials.

Recognition of whether the unapproved use of an intervention or treatment represented a clinical trial or off-label use under the "Right to Try" Act
The distinction between off-label use under the"Right to Try" Act and a clinical trial is a major area of concern. 5,7 This is a critically important issue in the area of dementia trials, given that, to date, no effective disease-modifying therapies have proven efficacious, marking dementia as a high-priority/high-need area for drug development and expedited approval pathways. The CHADS panel clearly appreciated this fact and the potential importance of off-label use and further respected the purpose of the "Right to Try" Act given the lack of disease-modifying or curative agents for the myriad causes of ADRD. 5,7 The committee members also understood from their personal experiences with patients and caregivers that the distinction between such uses and legitimate clinical trial research needs to be made quite clear. Clinical trials embed rigorous safety oversight and protections. 6 Studies focusing on off-label use of existing and/or experimental medications that lack such protections should be suspect. 3,5,7,10  Clear explanation of this distinction is necessary to allow health-care providers and consumers to understand their options when faced with a diagnosis of an incurable condition with few approved treatments, including ADRD.

Trial design considerations
"High-quality" clinical trials in ADRD research should focus on estab- to avoid a type 1 error. Data to be included into the interim analyses (e.g., impute missing data) needs to be discussed. Trials that change or adapt inclusion/exclusion criteria, intervention dose or duration, or outcome measures should be viewed as potentially less than "highquality" and the alterations in the protocol should be reported to facilitate thorough evaluation of both efficacy and safety. Although such changes may occur in any clinical trial based on all available information with regulatory approval, the failure to disclose such changes and or the impetus to make such changes, or to gain regulatory approval for such changes, would likely indicate a less than "high-quality" study.

Trial conduct considerations
One feature distinguishing a "low-quality" versus a "high-quality" clinical trial in ADRD research may be the requirement for payment to participate. 3 This refers to payment specifically for the opportunity to participate rather than costs that participants may incur, for example by travelling to a testing site. This most often indicates that the primary motivation for inviting participants involves financial gain for the provider and/or the institution. "High-quality" clinical trials should be adequately supported, precluding such requests from participants and their health-care surrogates. Requests for payment often suggest a lack of funding, which may mean that peers, sponsors, or granting agencies do not find the approach worthy of pursuit. Although it is possible that early-stage discovery may lack funding, a request for payment for research engagement should be construed as a sign that the "study" may not even be a trial or may be of low quality.
Conversely, clinical trials that pay excessively for participation may also be "predatory" as they seek to engage participants who may be in need of financial gain themselves. Although most regulatory agencies including IRBs evaluate such payments, there is a wide range of financial incentives across clinical trials, legitimate or otherwise. 6 The appearance of excessive payments may signal that the trial is of lower quality although such payments may be included in a "high-quality" clinical trial that is pressured to recruit quickly or require certain study population characteristics that may be more motivated by such incentives.

Adherence to regulatory principles and standards
Irrespective of the "quality" of a clinical trial, all should adhere to common GCP/HSP regulations that require an overseeing regulatory body, which at minimum requires an appropriate IRB/REC and approved consent process. 6 The consent document should include contact information for that regulatory body as well as a contact if participants have questions, concerns, or complaints. In addition, "highquality" studies that intend to appropriately share and or publish their results, should be registered as such with appropriate agencies such as through ClinicalTrials.gov. 4 Unregistered trials involving the proposed use of unapproved or experimental medicines or interventions should

Recommendation Rationale
1. High-quality clinical trials should be designed and conducted to be adherent to the reporting principles specified in the published CONSORT statements and basic HSP standards mandated by regulatory authorities.
Regulatory oversight and reporting of results guidances are well established and should be adhered to in all instances.
2. Adequate justification for the trial should be made available to participants including full disclosure of all positive and negative findings, as well as the lack of any relevant data that may influence their decision to participate.
Incomplete justification, presentation of only selected data, and/or the failure to present prior negative data precludes adequate disclosure of study rationale.
3. Outcomes should be prespecified, but specifics may not necessarily be made available to participants to avoid bias in outcome measures.
To avoid statistical bias, changes in outcome measures should only be made prior to data analysis. To prevent "self-study" by participants, discrete information on specific outcome measures may be withheld, but general descriptions should be provided.
4. Participants may subsume costs for time committed to the trial, travel costs, and standard of care for the medical condition under study and other medical conditions the subject may have, but should never be responsible for research-related costs or the experimental medication under the guise of a trial.
Charging patients for study procedures is a clear sign that the study may not be funded, undergone previous peer review, or may be "predatory" for financial gain by the investigators. Charging for the use of experimental or off-label medicines should be considered "for-profit" indicating that it is not part of a legitimate clinical trial.
5. Risk/benefit disclosures are not necessarily required for advertisement but should be mandatory in consent processes.
While good clinical practice and HSP requires full disclosure of risk/benefit considerations, such information may be too detailed to be included in routine trial advertisements.
6. Public-facing materials should specify if the use of a medicine is off-label or part of a clinical trial.
Describing the objective of treatment is necessary in delineating whether the use of an experimental or unapproved medicine/intervention is part of a clinical trial or off-label use.
7. The use of experimental medicines or off-label use of approved medicines, in the spirit of the "Right-to-Try" act, should not be subject to guidances for clinical trial regulation or oversight.
Off-label use as part of the "Right to Try" Act, should be specified as treatment that is not part of any clinical trial.
8. Disclosure of trial registration, HSP oversight, funding source, and COI for the investigators is necessary.
It is critical that potential participants in any clinical trial understand the regulatory oversight and potential for financial benefit that may be driving the investigator to encourage their participation beyond their primary health interests.
9. The trial should have a protocol in which the trial population (I/E criteria), intervention, duration are prespecified and made available to potential participants.
To avoid statistical bias, changes in trial design should only be made prior to data analysis. Participants should not be coerced into changes into continued participation if trial population indications, study intervention, or duration are changed after consent procedures have been finalized. Such changes should be conveyed and reconsent obtained with full disclosure of why such changes have been made to maintain the legitimacy of the trial.
10. Trial participants should not be unduly influenced by payments, enhanced access to medical services which they may not otherwise receive, or other enticements for engagement.
While HSP protections including regulatory oversight provide such protections, the committee noted that there may be a great deal of variation in compensation for trial engagement. While this may at times be related to degree of funding, scrutiny of significant outliers in compensation may help indicate legitimate versus suspect clinical trial conduct.
11. Participants should be informed that the trial results will be published or otherwise made available to the public and research community, and the investigator should be mandated to do so.
If a trial is legitimate, it should be prepared to share and or publish the data derived from research participation. Preconceived intent to collect data on participants receiving off-label use of unapproved medications or interventions indicates an attempt to bypass regulatory oversight, suggesting a lack of legitimacy for the clinical trial.
Abbreviations: COI, conflict of interest; CONSORT, Consolidated Standards of Reporting Trials; HSP, human subjects protections; I/E, inclusion/exclusion. signal that the trial may not actually be a trial at all, or that it may be of lower quality. Intent to publish or share such results in reputable medical and scientific journals require such registration, and a failure to do so indicates a lower quality study that may be seeking to avoid such requirements. 4 In addition, financial interests including personal or family gain, institutional gain, or other financial conflicts should be appropriately disclosed to participants. 6 Studies involving excessive or unexplained financial gains should indicate a "lower-quality" study.

Public-facing materials
All public materials providing education regarding the trial should be

Important remaining questions and considerations
Although the current consensus panel recommendations address many critical questions inherent in determining the overall quality of clinical trials in aging and dementia, there remain many other important questions that should be recognized, prompt further discussion, and serve as a focus for future efforts to guide high-quality studies in the field. Given the extensive knowledge accumulated through clinical trials and observational studies, there is much debate on the need to include placebo control groups in future Phase II and III studies.
Although the exclusion of placebo controls in Phase I studies is common, it is unclear if current study simulation methods could replace control groups in future studies. Given the variability in disease characteristics and progression across randomized, controlled trials and observational cohorts, it is clear that there remains much work to do in this area of clinical trial design. Additionally, current Food and Drug Administration, European Medicines Agency, and other regulatory guidances maintain requirements for contemporaneous control groups for adjudicating safety and treatment effects in the changing landscape of degenerative disease clinical trials. For now, placebo control groups remain essential for safety and efficacy evaluation.
Other considerations such as standardization of clinical diagnostic criteria and the use of uniform inclusion criteria across trials, controlling for the high number of comorbidities and medications used in older patients, and selection of valid and clinically meaningful outcomes would improve the comparability of study samples and outcomes across trials. Although addressing these considerations would be desirable, this level of uniformity in trial design is currently not feasible for many studies in which the nuances of the sample selection, illness severity, study interventions, and safety concerns may differ broadly. At present, uniform diagnostic criteria, inclusion/exclusion criteria, and outcome measures remain study specific and outside the scope of general recommendations for high-quality aging and dementia clinical trials.
Although the consensus panel appreciated that high-quality trials should maximize inclusion of a wide variety of often frail elderly participants, it is appreciated that depending on the stage of the trial investigation, the type of participant targeted for recruitment, and the oftennuanced risks and benefits of each unique study, general recommendations for maximizing engagement across all studies are not practical. Concerns about the undue influence of caregivers on a participants' and on assessing study outcomes are also important to address, but again general recommendations for judging the quality of a clinical trial in this regard are impractical as most trials conducted in later dementia stages require proxy or surrogate consenting and are dependent on caregiver-reported outcomes. Diversifying trial participants in terms of race/ethnicity and sex is critically important, but diversification can also lead to increased variability as well as small sample size if the analyses have to be conducted separately for each race/ethnic group. Controlling for confounders such as social determinant of health or comorbidities could mitigate the variability to some extent, although the impact of social determinants of health on trial outcomes and efficacy is not well investigated thus far.
Additional important concerns regarding the quality of a clinical trial in aging and dementia include a discussion of the invasiveness and potential risks for study interventions. For each trial we must ask, is this an ethically acceptable treatment for this stage of disease? Given that ADRD are currently incurable, should we only consider oral medications and similar noninvasive treatments as acceptable for high-quality studies, or should we also include injections and infusions, or even invasive stimulation protocols or brain implants? Given the lack of diseasemodifying therapies for a wide range of ADRD stages, general recommendations in this area would be premature, but such considerations should be considered on a trial-by-trial basis.
Further work aimed at developing consensus criteria that guide the recognition of high-quality clinical trials in aging and dementia is needed to further guide investigators, regulatory agencies, and the public in expectations for the highest quality clinical trials for ADRD.
As the number of potential therapeutics in clinical trials continues to grow, the importance of such issues will also increase. At present, the general recommendations developed by this consensus group appear widely applicable across studies and serve as a basis for continued discussion, debate, and growth in the area of ADRD clinical trial research.

General conclusion
There is extensive agreement regarding the characteristics of a highquality ADRD clinical trial. This consensus guidance may be useful in the protocol development and conduct of "high-quality" clinical trials, and may further provide a foundation for the development of outward-facing educational materials to guide clinical trial participation decisions for prospective clinical trial participants and the general public.

ACKNOWLEDGMENTS
The