The Phase-0 Microdosing Regulatory Framework: ICH M3 Guidelines
ICH M3 Guidelines govern the Phase-0 Microdosing regulatory framework. Table 3 below summarizes the guidelines. These guidelines have been internationally harmonized and adopted by USFDA, Europe's EMA, and Japan's PMDA. They specify the definitions and associated requirements of 5 sample approaches (Figure 1) on a range of exposures to the novel drug (See Table 3 in the guidelines). The exposures are defined by dosage and duration and range from a single microdose, to 14 days at the NOAEL (No Observed Adverse Effects Levels). The ICH M3 PHase-0 Microdosing regulatory guidelines use the term 'Exploratory Clinical Trials', which is synonymous with 'Phase-0', and also with 'Exploratory Investigational New Drug (eIND)'.
ICH M3 Table 3. Recommended Non-Clinical Studies to Support Exploratory Clinical Trials.
The 5 examples of Phase-0 Microdosing regulatory approaches are on a range of dosages and duration of exposure. Approaches 1 and 2 are microdosing (#1 is single microdose; #2 is multiple microdoses). Approaches 3, 4, and 5 are non-microdosing Phase-0 approaches. Other approaches are possible as long as there are no exposures consistent with therapeutic intent or intent to study tolerance (e.g., maximum tolerated dose [MTD]).
Clinical:
Non clinical:
Dose to be Administered
Start and Maximum Doses
Pharmacology
General Toxicity Studies a
Genotoxicity b / Other
Approach 1:
Total dose < 100 pg (no inter-dose interval limitations)
AND
Total dose < 1/100th NOAEL and <1/100th pharmacologically active dose (scaled on mg/kg for i.v. and mg/m2 for oral).
Maximal and starting doses can be the same but not exceed a total accumulated dose of 100 pg.
In vitro target/ receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.
Extended single dose
toxicity study (see footnotes c and d in one species, usually rodent, by intended route of administration with toxicokinetic data, or via the i.v. route. A maximum dose of 1000-fold the clinical dose on a mg/kg basis for i.v. and mg/m2 for oral administration can be used.
Genotoxicity studies are not recommended, but any studies or SAR assessments conducted should be included in the clinical trial application.
For highly radioactive agents (e.g., PET imaging agents), appropriate PK and dosimetry estimates should be submitted.
Clinical:
| Dose to be Administered | Start and Maximum Doses |
|---|---|
| Approach 1: Total dose < 100 pg (no inter-dose interval limitations) AND Total dose < 1/100th NOAEL and <1/100th pharmacologically active dose (scaled on mg/kg for i.v. and mg/m2 for oral). | Maximal and starting doses can be the same but not exceed a total accumulated dose of 100 pg. |
Non clinical:
| Pharmacology | General Toxicity Studies a | Genotoxicity b / Other |
|---|---|---|
| In vitro target/ receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection. | Extended single dose toxicity study (see footnotes c and d in one species, usually rodent, by intended route of administration with toxicokinetic data, or via the i.v. route. A maximum dose of 1000-fold the clinical dose on a mg/kg basis for i.v. and mg/m2 for oral administration can be used. | Genotoxicity studies are not recommended, but any studies or SAR assessments conducted should be included in the clinical trial application.
For highly radioactive agents (e.g., PET imaging agents), appropriate PK and dosimetry estimates should be submitted. |
Clinical:
Non clinical:
Dose to be Administered
Start and Maximum Doses
Pharmacology
General Toxicity Studies a
Genotoxicity b / Other
Approach 2:
Total cumulative dose < 500 pg, maximum of 5 administrations with a washout between doses (6 or more actual or predicted half-lives)
AND
each dose < 100 pg
AND
each dose < 1/100th of the NOAEL and < 1/100th of the pharmacologically active dose.
Maximal daily and starting doses can be the same, but not exceed 100 pg.
In vitro target/receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.
7-day repeated-dose toxicity study in one species, usually rodent, by intended route of administration with toxicokinetic data, or via the i.v. route. Hematology, clinical chemistry, necropsy, and histopathology data should be included. A maximum dose of 1000-fold the clinical dose on a mg/kg basis for i.v. and mg/m2 for oral administration can be used.
Genotoxicity studies are not recommended, but any studies or SAR assessments conducted should be included in the clinical trial application.
For highly radioactive agents (e.g., PET imaging agents), appropriate PK and dosimetry estimates should be submitted.
Clinical:
| Dose to be Administered | Start and Maximum Doses |
|---|---|
| Approach 2: Total cumulative dose < 500 pg, maximum of 5 administrations with a washout between doses (6 or more actual or predicted half-lives) AND each dose < 100 pg AND each dose < 1/100th of the NOAEL and < 1/100th of the pharmacologically active dose. | Maximal daily and starting doses can be the same, but not exceed 100 pg. |
Non clinical:
| Pharmacology | General Toxicity Studies a | Genotoxicity b / Other |
|---|---|---|
| In vitro target/receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection. | 7-day repeated-dose toxicity study in one species, usually rodent, by intended route of administration with toxicokinetic data, or via the i.v. route. Hematology, clinical chemistry, necropsy, and histopathology data should be included. A maximum dose of 1000-fold the clinical dose on a mg/kg basis for i.v. and mg/m2 for oral administration can be used. | Genotoxicity studies are not recommended, but any studies or SAR assessments conducted should be included in the clinical trial application.
For highly radioactive agents (e.g., PET imaging agents), appropriate PK and dosimetry estimates should be submitted. |
Clinical:
Non clinical:
Dose to be Administered
Start and Maximum Doses
Pharmacology
General Toxicity Studies a
Genotoxicity b
Approach 3:
Single Dose Studies at Sub- therapeutic Doses or into the Anticipated Therapeutic Range.
Starting dose should be based on the types of toxicity findings observed in the most sensitive species and a consideration of the pharmacologically active dose. For other considerations on initial dosing in humans, regional guidances should be consulted.
Maximum dose can be that yielding up to 1/2 NOAEL exposure in the more sensitive species, in cases where any relevant toxicity observed in animals is anticipated to be monitorable and reversible in humans.
In vitro target/receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.
Core battery of safety pharmacology (see Section 2).
Extended single dose toxicity studies in both the rodent and non-rodent (see footnote c by intended clinical route of administration with toxicokinetics, hematology, clinical chemistry, necropsy, and histopathology data. For this situation the top dose should be MTD, MFD or limit dose (see Section 1.5).
Ames assay (or an alternative assay if Ames is inappropriate, for example, for an antibacterial product).
Clinical:
| Dose to be Administered | Start and Maximum Doses |
|---|---|
| Approach 3: Single Dose Studies at Sub- therapeutic Doses or into the Anticipated Therapeutic Range. | Starting dose should be based on the types of toxicity findings observed in the most sensitive species and a consideration of the pharmacologically active dose. For other considerations on initial dosing in humans, regional guidances should be consulted.
Maximum dose can be that yielding up to 1/2 NOAEL exposure in the more sensitive species, in cases where any relevant toxicity observed in animals is anticipated to be monitorable and reversible in humans. |
Non clinical:
| Pharmacology | General Toxicity Studies a | Genotoxicity b / Other |
|---|---|---|
| In vitro target/receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection. Core battery of safety pharmacology (see Section 2). | Extended single dose toxicity studies in both the rodent and non-rodent (see footnote c by intended clinical route of administration with toxicokinetics, hematology, clinical chemistry, necropsy, and histopathology data. For this situation the top dose should be MTD, MFD or limit dose (see Section 1.5). | Ames assay (or an alternative assay if Ames is inappropriate, for example, for an antibacterial product). |
Clinical:
Non clinical:
Dose to be Administered
Start and Maximum Doses
Pharmacology
General Toxicity Studies a
Genotoxicity b
Approach 4:
Dosing up to 14 days into the therapeutic range but not intended to evaluate clinical MTD.
With toxicity in both species, follow appropriate regional guidance for clinical starting dose. If toxicity is not seen in either species (i.e., the NOAELs are the highest dose tested and doses used were not otherwise limited, e.g., not an MFD), or is seen only in one species, the clinical starting dose should be one that gives a predicted clinical AUC value (based on either interspecies PK modelling or mg/m2 conversion) that is approximately 1/50th of the AUC at the NOAEL from the species yielding the lower exposure. For other considerations on initial dosing in humans, e.g., predicted PD activity, regional guidance should be consulted.
Without toxicity in both species, it is recommended that the maximum clinical dose not exceed 1/10th the lower exposure (AUC) in either species at the highest dose tested in the animals.
When only one species demonstrates toxicity, the maximum clinical dose should not be higher than the NOAEL in the species showing toxicity, or 1/2 the AUC at the highest dose tested in the species not showing toxicity, whichever is lower.
With toxicity in both species, the maximum clinical dose should be based on standard risk assessment approaches and, in this specific case, the clinical MTD can be explored.
In vitro target/receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.
Core battery of safety pharmacology (see Section 2) using doses similar to those used for the toxicity studies.
2-week repeated-dose toxicity studies in rodent and non-rodent with standard parameters assessed and where dose selection in animals is based on exposure multiples of anticipated clinical AUC at maximum dose.
Ames assay (or an appropriate alternative assay if Ames is inappropriate, for example, for an antibacterial product) and an assay (in vitro or in vivo) capable of detecting chromosomal damage in a mammalian system.
Clinical:
| Dose to be Administered | Start and Maximum Doses |
|---|---|
| Approach 4: Dosing up to 14 days into the therapeutic range but not intended to evaluate clinical MTD. | With toxicity in both species, follow appropriate regional guidance for clinical starting dose. If toxicity is not seen in either species (i.e., the NOAELs are the highest dose tested and doses used were not otherwise limited, e.g., not an MFD), or is seen only in one species, the clinical starting dose should be one that gives a predicted clinical AUC value (based on either interspecies PK modelling or mg/m2 conversion) that is approximately 1/50th of the AUC at the NOAEL from the species yielding the lower exposure. For other considerations on initial dosing in humans, e.g., predicted PD activity, regional guidance should be consulted.
Without toxicity in both species, it is recommended that the maximum clinical dose not exceed 1/10th the lower exposure (AUC) in either species at the highest dose tested in the animals. When only one species demonstrates toxicity, the maximum clinical dose should not be higher than the NOAEL in the species showing toxicity, or 1/2 the AUC at the highest dose tested in the species not showing toxicity, whichever is lower. With toxicity in both species, the maximum clinical dose should be based on standard risk assessment approaches and, in this specific case, the clinical MTD can be explored. |
Non clinical:
| Pharmacology | General Toxicity Studies a | Genotoxicity b / Other |
|---|---|---|
| In vitro target/receptor profiling should be conducted.
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection. Core battery of safety pharmacology (see Section 2) using doses similar to those used for the toxicity studies. | 2-week repeated-dose toxicity studies in rodent and non-rodent with standard parameters assessed and where dose selection in animals is based on exposure multiples of anticipated clinical AUC at maximum dose. | Ames assay (or an appropriate alternative assay if Ames is inappropriate, for example, for an antibacterial product) and an assay (in vitro or in vivo) capable of detecting chromosomal damage in a mammalian system. |
Clinical:
Non clinical:
Dose to be Administered
Start and Maximum Doses
Pharmacology
General Toxicity Studies a
Genotoxicity b
Approach 5:
Dosing up to 14 days and not to exceed duration of dosing in non-rodent; into therapeutic range but not intended to evaluate clinical MTD.
Starting dose predicted exposures should not exceed 1/50th the NOAEL in the more sensitive species on a mg/m2 basis. For other considerations on initial dosing in humans, regional guidance should be consulted.
The maximum exposure in humans should not be higher than the AUC at the NOAEL in the non-rodent species or higher than 1/2 the AUC at the NOAEL in the rodent species, whichever is lowers.
In vitro target/receptor profiling should be conducted
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.
Core battery of safety pharmacology (see Section 2) using doses similar to those used for the toxicity studies.
Standard 2-week repeated-dose toxicity study in rodents (with justification of the rodent as an appropriate species). The top dose should be the MTD, MFD or limit dose (see Section 1.5).
Confirmatory study in non-rodent (n=3) at the anticipated NOAEL exposure in rodent, with duration of a minimum of 3 days and at least the intended clinical study duration.
Alternatively, an escalating dose study in the non-rodent with duration of a minimum of 3 days and at least the intended clinical study duration at the anticipated NOAEL exposure in the rodent.
Ames assay (or an appropriate alternative assay if Ames is inappropriate, for example, for an antibacterial product) and an assay (in vitro or in vivo) capable of detecting chromosomal damage in a mammalian system. If an in vivo assessment is used then this could be part of the rodent toxicity study.
Clinical:
| Dose to be Administered | Start and Maximum Doses |
|---|---|
| Approach 5: Dosing up to 14 days and not to exceed duration of dosing in non-rodent; into therapeutic range but not intended to evaluate clinical MTD. | Starting dose predicted exposures should not exceed 1/50th the NOAEL in the more sensitive species on a mg/m2 basis. For other considerations on initial dosing in humans, regional guidance should be consulted.
The maximum exposure in humans should not be higher than the AUC at the NOAEL in the non-rodent species or higher than 1/2 the AUC at the NOAEL in the rodent species, whichever is lowers. |
Non clinical:
| Pharmacology | General Toxicity Studies a | Genotoxicity b / Other |
|---|---|---|
| In vitro target/receptor profiling should be conducted
Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection. Core battery of safety pharmacology (see Section 2) using doses similar to those used for the toxicity studies. | Standard 2-week repeated-dose toxicity study in rodents (with justification of the rodent as an appropriate species). The top dose should be the MTD, MFD or limit dose (see Section 1.5).
Confirmatory study in non-rodent (n=3) at the anticipated NOAEL exposure in rodent, with duration of a minimum of 3 days and at least the intended clinical study duration. Alternatively, an escalating dose study in the non-rodent with duration of a minimum of 3 days and at least the intended clinical study duration at the anticipated NOAEL exposure in the rodent. | Ames assay (or an appropriate alternative assay if Ames is inappropriate, for example, for an antibacterial product) and an assay (in vitro or in vivo) capable of detecting chromosomal damage in a mammalian system. If an in vivo assessment is used then this could be part of the rodent toxicity study. |
Footnotes
a. General toxicity studies should be conducted according to GLP regulations.
b. See Ref. 10 for genotoxicity study design and dose selection.
c. Generally, extended single-dose toxicity studies should be designed to evaluate hematology, clinical chemistry, necropsy, and histopathology data (control and high dose only if no treatment-related pathology is seen at the high dose) after a single administration, with further evaluations conducted 2 weeks later to assess delayed toxicity and/or recovery. The usual design for rodents consists of 10 animals/sex/group to be assessed on the day following dosing, and 5 animals/sex at the dose level(s) selected to be assessed on day 14 post-dose. The usual design for non-rodents consists of 3/sex/group for all groups on day 2 and 2/sex for the dose level(s) assessed on day 14.
d. A single dose level to assess reversibility/delayed toxicity on day 14 can support the microdose approach. The dose level used need not be the high dose but should be a dose that is at least 100 times the clinical dose.
e. In the absence of adverse effects in the clinical trial, escalation above this AUC can be appropriate if the findings in the toxicity studies are anticipated to be monitorable, reversible, and of low severity in humans.