How first-in-human starting doses are set
Regulators set the first human dose from animal data, but the anchor differs by product and population. Healthy-volunteer trials usually start from the animal NOAEL with a safety factor; higher-risk or immune-activating products look to the minimal anticipated biological effect level; anticancer drugs in patients follow ICH S9. Each statement below links to the source sentence.
| Method | Used for | Precedent in Atlas |
|---|---|---|
| NOAEL to human equivalent dose (HED) with a safety factor | New drugs and therapeutic biologics entering healthy-volunteer trials (FDA 2005 algorithm); also cited for oligonucleotides in FDA's 2024 draft | |
| MABEL and pharmacologically active dose (PAD) | Products where pharmacology, not toxicity, may drive the first-dose risk, e.g. novel targets, uncertain animal relevance, or exaggerated-pharmacology classes | |
| Oncology start dose under ICH S9 (1/10 STD10, 1/6 HNSTD) | Anticancer pharmaceuticals in patients with advanced cancer | |
| ADCs and immune-activating products in oncology (ICH S9 and S9 Q&A) | Antibody-drug conjugates and immune agonists (biologic or small molecule) developed for cancer | |
| Cell and gene therapy: dose levels from animal studies | Investigational cell therapy and gene therapy products regulated by FDA CBER |
NOAEL to human equivalent dose (HED) with a safety factor
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
Used for: New drugs and therapeutic biologics entering healthy-volunteer trials (FDA 2005 algorithm); also cited for oligonucleotides in FDA's 2024 draft
For most systemically given drugs, FDA converts each species' NOAEL to a human equivalent dose by normalising to body surface area.
“The NOAEL for each species tested should be identified, and then converted to the HED using appropriate scaling factors. For most systemically administered therapeutics, this conversion should be based on the normalization of doses to body surface area.”The maximum recommended starting dose is the HED divided by a safety factor; FDA says to consider a factor of at least 10.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”The safety factor of 10 is a default: raise it when there is more concern, lower it when available data add assurance of safety.
“The safety factor should be raised when there is reason for increased concern, and lowered when concern is reduced because of available data that provide added assurance of safety.”ICH M3(R2) names the NOAEL in the most appropriate animal species as the most important input to the first human dose.
“In general, the No Observed Adverse Effect Level (NOAEL) determined in nonclinical safety studies performed in the most appropriate animal species gives the most important information.”✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 14Source ↗FDA's 2024 draft oligonucleotide guidance allows justified alternative HED calculations for some oligonucleotides or routes, such as scaling intrathecal doses by CSF volume.
“Alternative approaches to calculation of the human equivalent dose may be appropriate for some classes of ONTs or routes of administration (e.g., intrathecal dose normalized by cerebrospinal fluid volume) with scientific justification.”✓ VerifiedFDA 2024: Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics (draft guidance), p. 12Source ↗
See how each approved product set its first dose: oligonucleotides
MABEL and pharmacologically active dose (PAD)
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
Used for: Products where pharmacology, not toxicity, may drive the first-dose risk, e.g. novel targets, uncertain animal relevance, or exaggerated-pharmacology classes
EMA asks sponsors to use non-clinical pharmacology data, including human in vitro data, to estimate the MABEL and the PAD in humans.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”MABEL and PAD estimates should draw on in vitro target binding and receptor occupancy in human and relevant animal species, plus exposures at pharmacological doses in animals.
“MABEL, PAD and/or ATD should consider target binding and receptor occupancy studies in vitro in target cells from human and the relevant animal species and exposures at pharmacological doses in the relevant animal species.”For healthy volunteers, EMA expects a starting dose giving exposure below the PAD, unless a robust scientific rationale supports a higher dose.
“The starting dose for healthy volunteers should be a dose expected to result in an exposure lower than the PAD, unless a robust scientific rationale can be provided for a higher dose.”If the HED derived from the pharmacologically active dose is below the NOAEL-based MRSD, FDA says lowering the clinical starting dose may be appropriate.
“If this pharmacologic HED is lower than the MRSD, it may be appropriate to decrease the clinical starting dose for pragmatic or scientific reasons.”For classes such as monoclonal antibodies or growth factors, FDA notes that toxicity can come from exaggerated pharmacology, making the PAD potentially more sensitive than the NOAEL.
“Additionally, for certain classes of drugs or biologics (e.g., vasodilators, anticoagulants, monoclonal antibodies, or growth factors), toxicity may arise from exaggerated pharmacologic effects. The PAD in these cases may be a more sensitive indicator of potential toxicity than the NOAEL and might therefore warrant lowering the MRSD.”
See how each approved product set its first dose: bispecific antibodies
Oncology start dose under ICH S9 (1/10 STD10, 1/6 HNSTD)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
Used for: Anticancer pharmaceuticals in patients with advanced cancer
ICH S9 aims for a start dose that is expected to have pharmacologic effects and is reasonably safe to use.
“The goal of selecting the start dose is to identify a dose that is expected to have pharmacologic effects and is reasonably safe to use.”For most systemic small molecules, S9 scales animal doses by body surface area; body weight, AUC or other exposure scaling may be appropriate.
“For most systemically administered small molecules, interspecies scaling of the animal doses to an equivalent human dose is usually based on normalization to body surface area. For both small molecules and biopharmaceuticals, interspecies scaling based on body weight, AUC, or other exposure parameters might be appropriate.”A common small-molecule approach is 1/10 of the rodent STD10, or 1/6 of the non-rodent HNSTD when the non-rodent is the most appropriate species.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”HNSTD means the highest dose without lethality, life-threatening toxicity or irreversible findings.
“The HNSTD is defined as the highest dose level that does not produce evidence of lethality, life-threatening toxicities or irreversible findings.”FDA's 2024 draft oligonucleotide guidance points sponsors of anticancer oligonucleotides to ICH S9 for starting dose.
“Sponsors should consult ICH S9 for appropriate starting dose guidance for ONTs intended to treat cancer.”✓ VerifiedFDA 2024: Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics (draft guidance), p. 12Source ↗
See how each approved product set its first dose: bispecific antibodies · antibody-drug conjugates · oligonucleotides
ADCs and immune-activating products in oncology (ICH S9 and S9 Q&A)
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
Used for: Antibody-drug conjugates and immune agonists (biologic or small molecule) developed for cancer
For ADCs with cytotoxic payloads, the start dose can be 1/10 STD10 in rodents or 1/6 HNSTD in non-rodents for the ADC, scaled by body surface area.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”The S9 Q&A notes that other approaches can be considered for new classes of ADCs.
“Other approaches can be considered for new classes of ADCs.”The HNSTD approach may suit biopharmaceuticals, including ADCs, that are not immune agonists, considering animal-human binding differences.
“The HNSTD may be appropriate in determining a starting dose of a biopharmaceutical (e.g., when drug is not an immune agonist) taking into consideration differences in binding affinity between animals and humans and pharmacological properties of the biopharmaceutical (including ADCs).”For biopharmaceuticals with immune agonistic properties, ICH S9 says a MABEL-based start dose should be considered.
“For biopharmaceuticals with immune agonistic properties, selection of the start dose using a minimally anticipated biologic effect level (MABEL) should be considered.”The S9 Q&A says a MABEL could also be used for small molecules, when risk factors come from the mode of action, the target or model relevance.
“If appropriate, a MABEL could be used for small molecules using in vivo or in vitro data. This approach should be considered if risk factors are derived from knowledge of (1) the mode of action, (2) the nature of the target, and/or (3) the relevance of animal or in vitro models.”
See how each approved product set its first dose: antibody-drug conjugates · bispecific antibodies
Cell and gene therapy: dose levels from animal studies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
Used for: Investigational cell therapy and gene therapy products regulated by FDA CBER
Selecting a potential starting dose level and escalation schedule is a stated objective of the CGT preclinical program.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗Proof-of-concept studies should define the pharmacologically effective dose range, from minimally effective to optimal biological dose.
“The pharmacologically effective dose range (i.e., minimally effective dose and optimal biological dose).”✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 11Source ↗Toxicology studies should test multiple dose levels that bracket the proposed clinical dose range, where feasible.
“Multiple dose levels of the investigational CGT product, which should bracket the proposed clinical dose range, if feasible.”✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 13Source ↗A NOAEL from these toxicology studies helps determine the starting dose level and the dose-escalation scheme.
“(NOAEL), which will help determine selection of the starting dose level and subsequent dose-escalation scheme for the clinical trial.”✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 14Source ↗
See how each approved product set its first dose: gene therapy · cell therapy
Cautions regulators stress
EMA considers it appropriate to dose a single sentinel subject first in each cohort (sentinel dosing).
“It is considered appropriate to design the administration of the first dose in any cohort so that a single subject receives a single dose of the active IMP (often known as sentinel dosing).”Without data on species relevance, FDA defaults to the most sensitive species, the one giving the lowest HED.
“In the absence of data on species relevance, a default position is that the most appropriate species for deriving the MRSD for a trial in adult healthy volunteers is the most sensitive species (i.e., the species in which the lowest HED can be identified).”EMA bases the human exposure estimate on the NOAEL in the most relevant species, which may not be the most sensitive one.
“The exposures achieved at the NOAEL in the most relevant animal species used (which might not necessarily be the most sensitive species) should be used for estimation of an equivalent exposure for humans.”
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