Phase-0 Microdosing Operations

Comparison of Phase-0 Microdosing Operations with Traditional Phase-1 Approaches

Phase-0 microdosing operations have many similar features to traditional Phase-1 programs. However, Phase-0 approaches are usually shorter, smaller, quicker, and therefore cheaper to run. Phase-0 Microdosing operations are primarily defined by the sub-therapeutic exposures to the test drug. This means the exposure is safer than traditional approaches, but also that research participants cannot expect therapeutic benefit. This has ethical, methodological, and technological implications.

Table 1

The table is adapted from: Burt T, Yoshida K, Lappin G, Vuong L, John C, et al. 2016. Microdosing and other Phase-0 Clinical Trials: Facilitating Translation in Drug Development. Clinical and Translational Science 9:74-88.

Phase-0/Microdosing (eIND, ICH M3 guideline)

Traditional Phase-1 (IND)

Therapeutic intent

None

Possible

Study of systemic tolerability

None

Yes

Proof of Mechanism

Possible (e.g., PET receptor binding and displacement)

Possible

Preclinical Package

Limited, variable; depends on extent of exposure to the test article and experimental goals

Full requirements

-     in-vitro Models

Full requirement

Full requirements

-     Toxicology

Limited, variable

Full requirements

-     Genotoxicology

None or limited

Full requirements

GMP

Flexible, depending on available preclinical information and route of administration (e.g., sterility ensured for IV route)

Full requirements

Regulatory Review

30-day

30-day

Usual Duration of Program

4-12 months

12-24 months

Cost of Program

$ 0.5-0.75 M

$ 1.5-2.5 M


Comparison of Phase-0 Microdosing Operations with Traditional Phase-1 Approaches.
Phase-0/Microdosing (eIND, ICH M3 guideline)Traditional Phase-1 (IND)
Therapeutic intentNonePossible
Proof of MechanismPossible (e.g., PET receptor binding and displacement)Possible
Preclinical PackageLimited, variable; depends on extent of exposure to the test article and experimental goalsFull requirements
-       in-vitro ModelsFull requirementFull requirements
-       ToxicologyLimited, variableFull requirements
-       GenotoxicologyNone or limitedFull requirements
GMPFlexible, depending on available preclinical information and route of administration (e.g., sterility ensured for IV route)Full requirements
Regulatory Review30-day30-day
Usual Duration of Program4-12 months12-24 months
Cost of Program$ 0.5-0.75 M$ 1.5-2.5 M

-       Size (Typical)

4-10 participants

6-30 participants

-       Duration (per Participant)

1-14 days*

6-60 days*

-       Number of Study Sites

Single

Single/Multiple

-       Maximal Dose

<MTD

MTD

-       Exposure

Limited

Multiple doses allowed

-       Population

Healthy volunteers or patients

Vulnerable populations

Mostly healthy volunteers (unless toxicity risk is high, e.g., in oncology trials)

* - on Average, Could Be Longer with Longer Half-life Drugs; Mtd – Maximum Tolerated Dose


Studies
-       Size (Typical)4-10 participants6-30 participants
-       Duration (per Participant)1-14 days*6-60 days*
-       Number of Study SitesSingleSingle/Multiple
-       Maximal Dose<MTDMTD
-        ExposureLimitedMultiple doses allowed
-       PopulationHealthy volunteers or patients Vulnerable populationsMostly healthy volunteers (unless toxicity risk is high, e.g., in oncology trials)
* - on Average, Could Be Longer with Longer Half-life Drugs; Mtd – Maximum Tolerated Dose