Adherence Biomarkers,

Technologies, and Subject

Registries

Phil Skolnick, Ph.D., D.Sc. (hon.)

Division of Therapeutics & Medical

Consequences

National Institute on Drug Abuse, NIH

Conflict of Interest

Dr. Skolnick is a full time employee of the

National Institutes of Health.

Noncompliance Precludes Valid

Hypothesis Testing In The ClinicI'll share an anecdote related to your compliance

article. I had the privilege of working with a very well-

known 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."

An ICC of 0.21 indicates a very low agreement between measures

From: Anderson, et al., DAD 120:135, 2012

Self-Report Versus Urinanalysis

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

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

Candidate Markers

Acetazolamide Quinine

Carbonic Anhydrase Inhibitor Antimalarial (& Tonic Water)

Half-life = 4-8 h (per label) Half-life = 10-12 h

100% Bioavailable 80% Bioavailable

Therapeutic dose: 125 mg-1 g/day Therapeutic Dose: 650 mg/dayTesting at 15 mg/day Testing at 80 mg/day

(equivalent to ~1.1 liters of tonic water)

Time (h)

ug/h

AC

Z

0 24 48 72 96 120 144 168 192 216 240 2641

32

1024

15 mg ACZ administered

3 days since last dose isdistinct from 1day (ie "not

yet today")

Rate of ACZ Elimination in Urine

The Rate of Elimination of Acetazolamide Is Predictable and Prolonged

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.

Adherence Technologies

• AiCure: Interactive facial

recognition technology to monitor

medication administration

Adherence Technologies

Xhale Smart: Capsule

releases a taggant which is GI

metabolized to a volatile

breath marker which is then

analyzed

Xhale

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

Ingestible MonitorsNIDA is promoting development of ingestible systems that

monitor medication consumption in real time

Proteus “Raisin”

Clinical database

eTect ID-Cap

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.

Discussion (10 min)

Next up: Break

David McCann, Ph.D.,

Associate Director, Division of Therapeutics

and Medical Consequences, NIDA, NIH,

Bethesda, MD