Studies in early clinical development

Site: EUPATI Open Classroom
Course: Early Clinical Development
Book: Studies in early clinical development
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Date: Wednesday, 29 June 2022, 2:39 PM

1. Bioavailability (BA) / Bioequivalence (BE) studies

The objectives of bioavailability studies are to evaluate the rate and extent of absorption of a medicine. This is assessed measuring the maximum concentration (Cmax) and time of maximum concentration (Tmax) to evaluate the rate of absorption and area under the curve (AUC) for the extent of absorption.

The same applies to bioequivalence studies but in this case these values are compared with those of a reference formulation.

Bioavailability studies are typically run as crossover, randomised, single dose studies in healthy participants. Researchers measure blood/plasma concentrations of the parent drug and major active metabolites.

Bioequivalence studies are typically run as crossover, randomised studies in fasted healthy participants given single doses of test & reference products administered at the same doses. Researchers measure blood/plasma concentration of parent medicine only.

In order for a medicine to be bioequivalent it must fulfil set criteria.

The information gained from bioavailability and bioequivalent studies:

2. Single Dose/Multiple Dose Escalation Studies (SAD and MAD)

Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies are typically the First-in-Human study (or studies). These are performed as randomised, placebo-controlled trials in healthy volunteers (though, as described above, sometimes in patients). The starting dose is determined by non-clinical toxicology studies and is based on algorithms found in regulatory guidance documents. Common escalation schemes include: 2x, 3.3x (half-long, and modified Fibonacci series). Some stopping rules are: toxicity, absent toxicity (maximised exposure, maximised pharmacodynamics, others).

The information gained from SAD/MAD studies is:

  • Safety/tolerability, identify Maximum Tolerated Dose (MTD)

  • General PK characteristics, variability, linearity, dose proportionality

  • Steady-state parameters (accumulation time-dependency)

  • Preliminary exploration of medicine elimination (metabolite(s) identification)

3. Food Effect Study

The objective of food effect studies is to evaluate the effect of food on the rate and extent of medicine absorption from a given formulation.

Food effect studies are typically run as single dose, crossover studies which compare two conditions: fed with a high-fat high-calorie meal versus fasted volunteers in a two-sequence study in healthy participants (n ≥12) using the highest strength of the medicine.

Researchers conduct a pharmacokinetic assessment similar to bioavailability and determine that there is no food effect if 90% of the fed/fasted Cmax and AUC ratios fall within the 80-125% range. The clinical significance of any observed food effect could be determined based on the medicine’s exposure-response profile.

The information gained from food effect studies:
  • Effect of food on the bioavailability (BA) of oral medicines
  • Labelling instructions [PL: package leaflet] on whether to administer medicine on empty stomach or without regard to meals

4. Renal Impairment Study

The objective of renal impairment studies is to evaluate the medicine in people who have different levels of renal (kidney) function.

Renal impairment studies are typically run as single dose parallel group studies with healthy male and female volunteers (≥ 6 per group) who have varying degrees of renal function. The groups are stratified based on renal function biomarkers (Creatinine Clearance (CrCl)/Glomerular Filtration Rate (GFR)) in to groups for example: normal, mild, moderate, severe impairment, end stage renal disease (dialysis and non-dialysis).

The information gained from renal impairment studies:
  • Effect of renal impairment on medicine clearance
  • Dosage recommendations for various stages of renal impairment

5. Hepatic Impairment Study

The objective of hepatic impairment studies is to evaluate the medicine in people who have different levels of hepatic (liver) impairment.

If Pharmacokinetic results are linear and time-independent, then hepatic impairment studies are typically run as parallel group studies with healthy male and female volunteers (n ≥8 (full study) or n ≥6 (reduced study)) who have varying degrees of impairment of hepatic function. The groups are stratified based on Child-Pugh score classification in to: normal, mild, moderate, and severe impairment.

If the medicine is metabolised by an enzyme that only occurs through genetic variants, then participants should be assessed based on their genotype status.

The information gained from hepatic impairment studies:
  • Effect of hepatic impairment on PK of parent medicine and metabolites
  • Dosage recommendations for various stages of hepatic impairment for efficacy and/or safety reasons

6. Medicines Interaction (Drug-Drug Interaction, DDI) studies

The objective of medicines interaction studies is to evaluate the effect of concomitant medication on the medicines pharmacokinetics, and the effect of the medicine on the pharmacokinetics of concomitant medications. Similar studies can also be conducted to evaluate interaction with substances other than medicines (recreational drugs, opioid substitution therapies, etc) although these studies may pose difficult procedural challenges.

Medicine interaction studies are guided by in vitro effects and are preferably conducted using a crossover trial design, though sometime a parallel group design if the half-life (t1/2) of the medicine is long. The studies are conducted with healthy volunteers or with patients if it is desirable to evaluate pharmacodynamics endpoints or when the medicines are too toxic (e.g. anticancer medicine).

The choice of dosage, dosing intervals, routes and timing of co-administration, and number of doses should maximise the possibility of detecting an interaction and mimic the clinical setting.

The degree of interaction (inhibition/induction) is typically classified by the change in the absorption of one of the drugs, calculated as the area under the curve (AUC) of the substrate.

The information gained from medicine interaction studies:
  • Labelling instructions accordingly for the Package Leaflet (PL) in the section on ‘taking other medicines’

7. Thorough QT Study (TQT)

The QT interval is used as a measure of cardiac rhythm. It comes from the electrocardiography (ECG). The QT interval represents electrical depolarization (contraction) and repolarization (recovery) of the ventricles. A QT prolongation of more than 5 milliseconds in an electrocardiogram (ECG) is a (imperfect) biomarker which can be used to assess the risk that a medicine may provoke arrhythmia.

TQT studies are in vivo safety studies required for all new molecular entities (NMEs) and must take place prior to Phase III trials regardless of in vitro or non-clinical findings. TQT studies are typically conducted as single dose crossover studies with healthy participants. Researchers evaluate therapeutic and supratherapeutic (greater than therapeutic) doses of the medicine versus a positive control (for example commonly antibiotic moxifloxacin) and a negative control (placebo).

The ICH guidelines E14: ‘The Clinical Evaluation of QT/QTc Interval prolongation and Proarrhythmic Potential for Non-Antiarrhythmic medicines’ provide recommendations for the design, conduct, analysis, and interpretation of such clinical studies.

The information gained from TQT studies:

  • To identify medicines that prolong QT, and therefore need a more thorough ECG monitoring in pivotal trials
  • Labelling instructions accordingly