Phase I - Human Pharmacology

Site: EUPATI Open Classroom
Course: Early Clinical Development
Book: Phase I - Human Pharmacology
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Date: Wednesday, 19 June 2024, 5:43 AM

1. Introduction

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Human pharmacology represents the first stage of testing in human participants, ‘first-in-human’ studies. Although the treatment will have been thoroughly tested in laboratory and animal studies, side-effects in participants cannot be completely known ahead of time. For this reason, phase I studies may involve significant risks. These trials are often conducted in a dedicated inpatient clinic (with/near an intensive care unit) where the participant can be observed by full-time staff, and all possible safety provisions are in place in the event of an unexpected serious adverse reaction. Phase I studies usually have non-therapeutic objectives and are conducted in healthy volunteer participants. A minority of all phase I trials are conducted in patients rather than in healthy volunteers. The reasons for this is that some medicines are too toxic (e.g., anticancer medicine) to be given to healthy participants. Such Phase I trials may provide some early information about efficacy based on surrogate endpoints.

Phase I studies typically involve one or a combination of the following aspects:
  • Estimation of initial safety & tolerability - In order to determine the tolerability of the dose range (single and multiple administrations) expected to be needed for later studies.

  • Pharmacokinetics – Characterises the absorption, distribution, metabolism, and excretion of a medicine by the body. They also assess the clearance of the medicine (measurement of the renal excretion), anticipate possible accumulation, and look at the effects of food on bioavailability. Information is gathered on sub-populations: patient with impaired (renal or hepatic) elimination, the elderly, children, male/female, ethnic subgroups, etc. It is also important to study if any medicines interactions occur. PK may guide the dosage and dose regimens in later studies.

  • Assessment of pharmacodynamics - these data can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimens in later studies.

  • Early measurement of medicine activity - generally performed in later studies. Payment to participants may be provided in Phase I clinical research in accordance with local laws as long as the study has non-therapeutic objectives, multiple procedures and/or long periods of residence, the payments serve as compensation.
Payment must never be related to risk. The amount must be stated in the informed consent document and accepted by the Ethics Committee.

2. First-in-human Clinical Trials – Risk Mitigation

The European Medicines Agency has issued guidelines on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal product (EMEA/CHMP/SWP/28367/07).

The safety of participants in first-in-human clinical trials can be enhanced by identification and planned mitigation of factors associated with risk. Key aspects to mitigate those risk factors includes:
  • Study population
  • Trial sites
  • First dose
  • Route and rate of administration
  • Number of participants per dose increment (cohort)
  • Sequence and interval between dosing of participants within the same cohort
  • Dose escalation increments
  • Transition to next dose cohort
  • Stopping rules
  • Maximum Tolerated Dose (MTD)
The higher the potential risk associated with a medicine, the greater the precautionary measures that should be exercised. Potential risk is identified from animal models (safety-toxicology, PK, PD), previous exposure of humans to medicines that have related modes of action, how new the molecular structure of the active substance(s) is (a novelty), and the nature of the target.

Participants in first-in-human studies are not generally expected to derive any therapeutic benefit from participating in the trial. When making the decision of whether the study population should be composed of healthy participants or patients, several factors should be taken into account, such as:
  • (a) the risks inherent in the type of medicinal product
  • (b) its molecular target
  • (c) immediate and potential long term toxicity
  • (d) the lack of a relevant animal model
  • (e) the relative presence of the target in healthy participants or in patients; e.g. cancer patients
  • (f) the possible higher variability in patients
  • (g) the ability of healthy volunteers to tolerate any potential side effects
  • (h) the potential pharmacogenomic difference between the targeted patient group and healthy participants
  • (i) the patients’ ability to benefit from other products or interventions
  • (j) the predicted therapeutic window of the medication under investigation
When selecting a trial site for first-in-human studies there a number of things to take into consideration.
  1. First-in-human trials should preferably be conducted at a single site.

  2. First-in-human trials should take place in appropriate clinical facilities and be conducted by trained investigators who have acquired the necessary expertise and experience in conducting early phase trials (i.e. Phase I-II) and medical staff with appropriate level of training and previous experience of first-in-human studies.

  3. Units should have immediate access to equipment and staff for an acute emergency and ready availability of Intensive Care Unit facilities.

3. Estimation of the First Dose in Humans

Early non-clinical studies should provide sufficient information to support selection of the initial human dose and safe duration of exposure of a new medicine. In general, the No Observed Adverse Effect Level (NOAEL) determined in non-clinical safety studies performed in the most sensitive and relevant animal species, adjusted with allometric factors or on the basis of pharmacokinetics gives the most important information. The relevant dose is then reduced/adjusted by appropriate safety factors.

An additional approach to dose calculation is “The Minimal Anticipated Biological Effect Level” (MABEL). This is the anticipated dose level leading to a minimal biological effect level in humans. When using this approach, potential differences of sensitivity for the mode of action of the investigational medicinal product between humans and animals need to be taken into consideration, e.g., derived from in vitro studies. A safety factor may be applied for the calculation of the first dose in human from MABEL.

4. Sequence and Interval Between Dosing of Participants

  1. Usually, a single participant receives a single dose of the active investigational medicine.

  2. Further dose administration should be sequential within each cohort to mitigate the risk.

  3. There must be an adequate period of observation between the administration of the medicinal product to the first, second and subsequent participants in a cohort to observe and interpret reactions.

  4. Administration in the next cohort should not occur before participants in the previous cohort have been treated and data/results from those participants are reviewed.

5. Dose Escalation Scheme and Transition to Next Dose Cohort

  1. The dose increment between two dose levels should be guided by the dose/toxicity or dose/effect relationship defined in non-clinical studies, depending on whichever is steeper where this information is available.

  2. The steeper the increase in the dose/toxicity or dose/effect curves, the lower the dose increment that should be selected.

  3. Information on exposure, effect, and safety from the preceding dose in human should be taken into account. Since the initial doses may be very low, it is anticipated that early cohorts may not show any pharmacological effects. Where there is no response in a cohort the precautions for the next cohort should be the same as for the previous cohort.
The protocol should define stopping rules based on safety criteria for the cohort and trial.

6. Maximum Tolerated Dose (MTD)

The maximum tolerated dose (MTD) is the dose at which limited adverse events occur in more participants. The adverse events are defined by objective criteria. The MTD should not by systematically searched for in healthy participants.

If the MTD is set too high, patients could be exposed to unsafe doses, and the resulting intolerance of adverse events may even lead to the discontinuation of the medicine’s development.

If the MTD is set too low, placebo or sub-therapeutic doses could be administered to patients in Phase II efficacy studies, wasting years of development and conducting no-effect studies. This may also lead to the discontinuation of the medicine’s development.