Adherence Biomarkers, Technologies, and Subject Registries

Transcription

1 Adherence Biomarkers, Technologies, and Subject Registries Phil Skolnick, Ph.D., D.Sc. (hon.) Division of Therapeutics & Medical Consequences National Institute on Drug Abuse, NIH

2 Conflict of Interest Dr. Skolnick is a full time employee of the National Institutes of Health.

3 Noncompliance Precludes Valid Hypothesis Testing In The Clinic I'll share an anecdote related to your compliance article. I had the privilege of working with a very wellknown CRO director in Philadelphia (many of the products on the shelves at CVS were there based on his studies) and he related this story: "The U of Penn had a clinical trials outpatient center, and at some point the hedges out front were removed as part of a landscaping renovation. What do think the workmen discovered? Dozens of bottles of investigational drugs that the study participants over the years were supposed to be taking and recording in their diaries."

4 Self-Report Versus Urinanalysis An ICC of 0.21 indicates a very low agreement between measures From: Anderson, et al., DAD 120:135, 2012

5 Adherence Markers In Clinical Trials To monitor medication adherence in both the placebo and active arms during the trial (and in the ideal, facilitate adherence when it dips) To enable comparison of efficacy based on adherence in all treatment arms

6 Desired Characteristics Of An Adherence Marker Well-behaved PK (once or twice a day dosing) with low variability No drug-drug interactions Urinary excretion (saliva acceptable, especially for on-site assay) Not commonly found in dietary sources, supplements, or pharmaceuticals FDA approved for use (and low toxicity)/gras Bioavailability should not be substantially affected by food Sounds like a molecule with drug-like characteristics! In order to be useful as an adherence marker, there must be no pharmacological effects at dose levels that can be detected in biological matrices

7 Candidate Markers Acetazolamide Carbonic Anhydrase Inhibitor Half-life = 4-8 h (per label) Quinine Antimalarial (& Tonic Water) Half-life = h 100% Bioavailable 80% Bioavailable Therapeutic dose: 125 mg-1 g/day Testing at 15 mg/day Therapeutic Dose: 650 mg/day Testing at 80 mg/day (equivalent to ~1.1 liters of tonic water)

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9 The Rate of Elimination of Acetazolamide Is Predictable and Prolonged Rate of ACZ Elimination in Urine days since last dose is distinct from 1day (ie "not yet today") ug/h ACZ mg ACZ administered Time (h)

10 The Homeopathic Dose Strategy If the study drug has a suitable half-life AND there is a sensitive assay for detection in biological matrices: -Then, the placebo arm is replaced by study drug at doses 1/15 the lowest anticipated active dose. -The informed consent is modified: You will receive one of x doses of drug. We are currently incorporating this strategy in a Ph II POC study: Two arms, receiving 1.5 mg and 40 mg of study drug.

11 Adherence Technologies AiCure: Interactive facial recognition technology to monitor medication administration

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13 Adherence Technologies Xhale Smart: Capsule releases a taggant which is GI metabolized to a volatile breath marker which is then analyzed

14 Xhale

15 Adherence Technologies Proteus Biomedical: Microchip attached to the pill communicates with a patch on the body e-tect: ID-Cap, a microchip in a capsule that communicates with a wearable hub

16 Ingestible Monitors NIDA is promoting development of ingestible systems that monitor medication consumption in real time etect ID-Cap Proteus Raisin Clinical database

17 Subject Registries Dupcheck: An online tool which uses partial identifiers to report when subjects in a study match with subjects in other studies. ClinicalRSVP: Uses fingerprinting hardware/software and partial identifiers to identify matching subjects. CTSdatabase: Uses partial identifiers and an algorithm to determine matches. Provides a printout detailing when, where and for what indication a subject has previously participated in studies. Reports subjects who try to screen elsewhere during the course of a study. Verified Clinical Trials: Uses encrypted identifiers to determine matches and provides a report of whether or not the subject is a match or violates certain protocol criteria. Reports subjects who try to screen elsewhere during the course of a study. SubjectRegistry.com: (as of 2/2016) Allows single access point to CTSdatabase and Verified Clinical Trials databases.

18 Discussion (10 min) Next up: Break David McCann, Ph.D., Associate Director, Division of Therapeutics and Medical Consequences, NIDA, NIH, Bethesda, MD