Clinical pharmacology studies
- How can Modeling help in each phase?
General clinical study design
- Population
- Inclusion/Exclusion criteria
- Number of subjects (sample size)
- Intervention
- What is given (Drug/Food, Formulation, Dose), when (regimen), and how (route)?
- Randomization and balance between arms
- Blinding
- Adaptive, cross-over/parallel-group (Study type)
- Control
- What is the control group?
- Placebo, standard-of-care, active comparator?
- Outcome
- What is being measured (Covariates, PK, Clinical/pharmacological outcomes), when (Sampling/visit schedule, baseline and/or time-varying), and how?
- Time
- For how long does the study continue?
- Run-in, active treatment, washout, and follow-up periods
If a cross-over design with a washout period is used, always check that the predose concentration of the second dose is BLQ.
Phases of drug development
A short history of clinical trial “phases”
Prompted by the thalidomide tragedy, the 1962 Kefauver-Harris Amendments to the U.S. Federal Food, Drug, and Cosmetic Act introduced a “proof-of-efficacy” requirement. This led the FDA to introduce structured “phases” in clinical research, describing the progression from First-in-Human trials to confirmatory pivotal trials.
Previously, drug companies only had to show their new products were safe. The way drugs were investigated, a physician from the company would go out in the community with some samples and say to the doctor, “I’ve got this new drug for so-and-so. Here are some samples. Try it out and let us know how you like it”. They would then receive a letter from him stating, “I tried it out on eight patients, and they all got along fine.”
An overview of clinical trial “phases”
Most clinical pharmacology studies are Phase 1 studies, during which we learn about the drug’s PK. In Phase 2, we learn about the PD of the drug. In Phase 3, we confirm our efficacy and safety hypotheses in the target population.
George Box views scientific progress as consisting of and requiring alternating steps of induction and deduction: the former is learning from experience, and the latter confirms what has been learned. A simplified application of this view to clinical drug development would break development into two learn-confirm cycles Figure 1.
- First cycle (Proof-of-Concept)
- Phase 1: Learn what is the tolerated dose? (Max tolerated dose?)
- Phase 2a: Confirm that this dose has the promise of efficacy in a selected group of patients. (Is that dose efficacious?)
- Decision point: Is there a sufficiently positive indication of efficacy (and lack of toxicity) to justify further development? (Go/No go)
- Second cycle
- Phase 2b: Learn how to use the drug in representative patients to make acceptable benefits/risks likely. (Effect on patients?)
- Phase 3/4: Confirm in a large and representative patient population that acceptable benefit/risk is achieved. (Acceptable B/R-ratio?)
- Approval is granted.
Studies within the phases
Phase 1: Human pharmacology
Data from Phase 1 studies are typically well-controlled and provide clean SDTM input datasets.
👨⚕️“First in human” (FIH) PK
- Single ascending dose (SAD)
- Subjects receive a single dose of the investigational drug at one dose level, with dose escalation in subsequent cohorts.
- PK, safety, and/or PD can be of interest.
- Multiple ascending dose (MAD)
- Like SAD, but each subject receives multiple doses at one dose level.
- On some dosing occasions, only pre-dose samples might be taken.
- Dose-adjustment rules can be in place to achieve desirable safety/efficacy.
SAD and MAD studies can be combined under one study, and subjects can participate in both.
🍝Food effect (for oral drugs)
- Typically, a cross-over (fed/fasted), randomized, single-dose (one for each period) in healthy participants.
- Similar to bioequivalence (BE) studies.
💊+💊 Drug-drug interaction (DDI) in vivo
- Evaluate the effect of co-administration with another drug.
- Several study designs are possible in a DDI study, including parallel groups or cross-over designs.
- The study can have either single-dose or multi-dose administration.
☢️ Mass Balance/ADME
- Usually single-dose, open-label trials.
- Small, radiolabeled dose to accurately track drug elimination in biological matrices (blood, plasma, urine, feces).
- Often include metabolite identification and characterization.
- Record the volume of urine, feces’ weight, and collection duration for accurate excretion calculations.
💊=💊 Bioequivalence (BE)
- Typically, a cross-over randomized, single-dose (one for each period) in healthy participants.
- Between formulations or drug combinations.
- Evaluate the rate (Cmax and Tmax) and extent (AUC) of absorption
💓 (T)QT study
- Identifies medicines that prolong QT and thus need more thorough ECG monitoring in Phase 3 pivotal trials.
🧬 Pharmacogenomics (CYP genotyping)
- Often include metabolite identification and characterization.
🚮 Organ dysfunction PK
- Renal impairment (RI)
- Subjects are typically separated into parallel cohorts with varying degrees of impairment (normal, mild, moderate, severe).
- Impairment is often determined by estimated glomerular filtration rate (eGFR), preferably not using Cockcroft-Gault.
- For safety reasons, the dose given to the moderately/severely impaired groups may be lower than that given to the other groups.
- PK/PD and safety can be of interest.
- Hepatic impairment (HI)
- Similar to RI studies.
- Impairment is often determined by Child-Pugh scores or (in oncology) NCI-ODWG scores.
Phase 2: Therapeutic exploratory
Phase 2/3 studies are performed on patients and often consist of separate study parts/cohorts to investigate multiple scenarios (e.g., different patient populations) in one study. In most cases, PD measurements will be part of the analysis (and should be included in the analysis dataset to enable PK-PD evaluations). The study design can be very diverse. Phase 2/3 studies are less controlled than Phase 1, resulting in unrecorded dosing times, missing laboratory measurements, etc.
🤒 Healthy vs Patient PK/PD
- Proof-of-Concept (PoC)
📈 Dose-response
- Typically, randomized parallel group studies
- Three or more dosage levels, one of which may be zero (placebo).
- Including one or more doses of an existing medicine as a control may also be helpful.
- As a rule, PoC is tested at the maximum tolerated doses (MTD) or the maximal administered dose if MTD was not defined.
- Identify a reasonable starting (minimum effective) dose, ideally with specific adjustments.
- Identify response-guided stepwise dose adjustment (titration) and the intervals at which they should be taken.
- Identify a dose, or a response (desirable or undesirable), beyond which titration should not ordinarily be attempted because of lack of further benefit or an unacceptable increase in undesirable effect.
- Identify optimal dose
👩👦 Special populations
- Pediatrics
- Elderly
- Pregnant
- Lactating
- Obese
- Other
Phase 3: Therapeutic confirmatory
- PK and Exposure-Response (efficacy/safety) in the target population
Phase 4: Post-approval
Post-approval studies can, e.g., be studies in new indications.
References
- https://www.wma.net/policies-post/wma-declaration-of-helsinki/
- https://www.ich.org/page/efficacy-guidelines