Development of a DNA Aptamer-Based Electrochemical Assay for Acetazolamide in Urine Using a Handheld Biosensor for Compliance Validation in Clinical Drug Trials Thirty to over eighty percent of patients enrolled in pharmaceutical clinical trials do not comply with trial protocols by discarding the drug under investigation or not using the proper dosages. This common practice compromises the medical treatment decisions during the trials, confounds the interpretation of data from the trials, impacts the regulatory review and could result in inappropriate termination of a drug's development at huge expense to the pharmaceutical industry. Worldwide, this cost has been estimated to be in excess of $560BIL. Furthermore, non-adherence can alter recommended prescription levels of the drug, if approved, and contribute to drug dosing related morbidity and mortality. Existing methods of assessing pharmaceutical adherence during clinical trials include electronic monitoring, and self-reporting, but these methods overestimate protocol compliance. Quantitative assays for the target drug or tagging compounds, such as riboflavin, co-formulated with the drug under investigation are also used, but a missed dose cannot be differentiated from non-adherence to trial protocols. The drug or its marker can be determined quantitatively by techniques such as LC/MS or GC/MS, which can be relatively rapid and accurate, but may require sample preparation and derivatization of the drug or taggant. In addition, because of their size and power requirements, LC/MS and GC/MS methods are generally restricted to central laboratories preventing clinical trial monitors from further questioning enrollees about their lack of compliance. Significant additional costs accrue from transport and cold storage of clinical samples. The solution to these challenging problems is a portable diagnostic system that: 1) can be used by various types of medical professionals with minimal training at the point of care (POC), 2) provides accurate results for the drug or taggant concentration within the timeframe of the patient's in-house clinical trial or periodic clinic visits, and 3) is a versatile platform for evaluating treatment protocol compliance for many different investigational drugs. The ApolloDx-OTC Biotech team assembled for this proposed project has demonstrated the ability to develop a system with all of these characteristics in a simple, inexpensive! handheld diagnostic platform that is widely applicable to quantifying any drug target via custom developed DNA aptamers and closely monitoring trial protocols for enrollees' adherence. The team's diagnostic system and preparation of its prototype consumable has been validated 11 times for six different analytes including small molecule drug analytes. In Phase I, the team will develop a unique DNA aptamer, as it has numerous times in the past, to quantify a sub-therapeutic dose of the non-metabolized taggant acetazolamide (ACZ) in urine samples. Development of an aptamer-based handheld assay for ACZ in urine will enable rapid (within 10 minutes), sensitive determination of ACZ for correlation with target drug levels, thus aiding clinical trials compliance, generating more accurate trial data, improving FDA decisions, and advancing the missions of both the FDA and NIDA. In Phase II, the team will further develop its ACZ aptamer assay and begin seeking FDA approval for it while expanding its repertoire of investigational drug and taggant aptamer assays for use in future clinical trials.
Public Health Relevance Statement: Development of a DNA Aptamer-Based Electrochemical Assay for Acetazolamide in Urine Using a Handheld Biosensor for Compliance Validation in Clinical Drug Trials Noncompliance with clinical trials drug regimens affects the ability of the FDA to fairly judge a candidate drug and costs the pharmaceutical industry significant amounts of money each year which is often passed onto consumers in the form of higher drug prices. By developing rapid, sensitive and highly accurate on site (POC) methods and hardware for determination of sub-therapeutic concentrations of a co-formulated, non-metabolized compliance marker, ACZ, across the relevant dose range, the pharmaceutical industry will be provided the potential of reducing clinical trials costs, increasing FDA drug approval rates and safer prescription of approved drugs.
Project Terms: Acetazolamide; Adenosine Diphosphate; Adherence; Affect; American; aptamer; arm; base; Biological Assay; Biosensor; Biotechnology; Characteristics; Clinic Visits; Clinical; Clinical Protocols; Clinical Trials; commercialization; Compliance behavior; cost; Creatinine; Cryopreservation; Custom; Data; Data Analyses; Data Compromising; Data Quality; Detection; Development; Diagnostic; diagnostic assay; Diagnostic tests; DNA; dosage; Dose; drug candidate; Drug Costs; drug development; drug discovery; Drug Industry; drug quality; Drug Targeting; Economics; Electronics; Enrollment; Ensure; Excretory function; Female; Food and Drug Administration Drug Approval; Future; General Population; Goals; Healthcare; Housing; Human; improved; Ingestion; Inpatients; Investigation; Investigational Drugs; Label; Laboratories; Lead; Link; liquid chromatography mass spectrometry; Mass Fragmentography; Medical; Metabolism; Methods; Mission; Molecular Weight; Monitor; Monitoring Clinical Trials; Morbidity - disease rate; mortality; National Institute of Drug Abuse; non-compliance; Patient Self-Report; Patients; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; pill; Pilot Projects; point of care; point-of-care diagnostics; Preparation; prevent; Price; Program Development; Protocol Compliance; Protocols documentation; prototype; Recruitment Activity; Regimen; Research Personnel; Riboflavin; Sampling; Seminal; Site; small molecule; success; System; Techniques; Test Result; Testing; Theophylline; Therapeutic; Therapeutic Effect; therapy outcome; Time; TimeLine; Tracer; Training; Treatment Protocols; Urea; Urine; Validation; Variant; Work
