Guidance for Industry
`Estimating the Maximum Safe
`Starting Dose in Initial Clinical Trials
`for Therapeutics in Adult Healthy
`Volunteers
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`July 2005
`Pharmacology and Toxicology
`
`J:\!GUIDANC\5541fnlcln1.doc
`07/06/05
`
`MYLAN - EXHIBIT 1015
`
`

`

`Guidance for Industry
`Estimating the Maximum Safe
`Starting Dose in Initial Clinical Trials
`for Therapeutics in Adult Healthy
`Volunteers
`
`
`
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`July 2005
`Pharmacology and Toxicology
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`INTRODUCTION............................................................................................................. 1
`I.
`BACKGROUND ............................................................................................................... 2
`II.
`III. OVERVIEW OF THE ALGORITHM ........................................................................... 3
`IV.
`STEP 1: NO OBSERVED ADVERSE EFFECT LEVEL DETERMINATION........ 5
`V.
`STEP 2: HUMAN EQUIVALENT DOSE CALCULATION...................................... 6
`A. Conversion Based on Body Surface Area ....................................................................................6
`B. Basis for Using mg/kg Conversions ..............................................................................................7
`C. Other Exceptions to mg/m2 Scaling Between Species .................................................................8
`VI.
`STEP 3: MOST APPROPRIATE SPECIES SELECTION......................................... 9
`VII. STEP 4: APPLICATION OF SAFETY FACTOR....................................................... 9
`A.
`Increasing the Safety Factor .......................................................................................................10
`B. Decreasing the Safety Factor ......................................................................................................11
`VIII. STEP 5: CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE
`DOSE................................................................................................................................ 12
`SUMMARY ..................................................................................................................... 12
`IX.
`REFERENCES............................................................................................................................ 13
`GLOSSARY................................................................................................................................. 15
`APPENDIX A:............................................................................................................................. 16
`Analysis of Allometric Exponent on HED Calculations....................................................................16
`APPENDIX B:............................................................................................................................. 18
`Analysis of Body Weight Effects on HED Calculations ....................................................................18
`APPENDIX C:............................................................................................................................. 24
`Derivation of the Interspecies Scaling Factor (Wa/Wh)(1-b)................................................................24
`APPENDIX D:............................................................................................................................. 25
`Examples of Calculations for Converting Animal Doses to Human Equivalent Doses..................25
`APPENDIX E:............................................................................................................................. 27
`Selection of Maximum Recommended Starting Dose for Drugs Administered Systemically to
`Normal Volunteers ...............................................................................................................................27
`
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`

`

`
`
`Contains Nonbinding Recommendations
`Guidance for Industry1
`Estimating the Maximum Safe Starting Dose in Initial Clinical
`Trials for Therapeutics in Adult Healthy Volunteers
`
`INTRODUCTION
`
`
`
`
`
`This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`number listed on the title page of this guidance.
`
`
`
`
`I.
`
`This guidance outlines a process (algorithm) and vocabulary for deriving the maximum
`recommended starting dose (MRSD) for first-in-human clinical trials of new molecular entities
`in adult healthy volunteers, and recommends a standardized process by which the MRSD can be
`selected. The purpose of this process is to ensure the safety of the human volunteers.
`
`The goals of this guidance are to: (1) establish a consistent terminology for discussing the
`starting dose; (2) provide common conversion factors for deriving a human equivalent dose
`(HED); and (3) delineate a strategy for selecting the MRSD for adult healthy volunteers,
`regardless of the projected clinical use. This process is depicted in a flow chart that presents the
`decisions and calculations used to generate the MRSD from animal data (see Appendix E).
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`
`
`
`1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research
`(CDER) at the Food and Drug Administration.
`
`
`
`1
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`

`

`Contains Nonbinding Recommendations
`
`BACKGROUND
`
`
`II.
`
`The process identified in this guidance pertains to determining the MRSD for adult healthy
`subjects when beginning a clinical investigation of any new drug or biological therapeutic that
`has been studied in animals. This guidance is not pertinent to endogenous hormones and
`proteins (e.g., recombinant clotting factors) used at physiologic concentrations or prophylactic
`vaccines. The process outlined in this guidance pertains primarily to drug products for which
`systemic exposure is intended; it does not address dose escalation or maximum allowable doses
`in clinical trials.
`
`Although the process outlined in this guidance uses administered doses, observed toxicities, and
`an algorithmic approach to calculate the MRSD, an alternative approach could be proposed that
`places primary emphasis on animal pharmacokinetics and modeling rather than dose (Mahmood
`et al. 2003; Reigner and Blesch 2002). In a limited number of cases, animal pharmacokinetic
`data can be useful in determining initial clinical doses.2 However, in the majority of
`investigational new drug applications (INDs), animal data are not available in sufficient detail to
`construct a scientifically valid, pharmacokinetic model whose aim is to accurately project an
`MRSD.
`
`Toxicity should be avoided at the initial clinical dose. However, doses should be chosen that
`allow reasonably rapid attainment of the phase 1 trial objectives (e.g., assessment of the
`therapeutic’s tolerability, pharmacodynamic or pharmacokinetic profile). All of the relevant
`preclinical data, including information on the pharmacologically active dose, the full toxicologic
`profile of the compound, and the pharmacokinetics (absorption, distribution, metabolism, and
`excretion) of the therapeutic, should be considered when determining the MRSD. Starting with
`doses lower than the MRSD is always an option and can be particularly appropriate to meet some
`clinical trial objectives.
`
`
`
`2 If the parent drug is measured in the plasma at multiple times and is within the range of toxic exposures for two or
`more animal species, it may be possible to develop a pharmacokinetic model predicting human doses and
`concentrations and to draw inferences about safe human plasma levels in the absence of prior human data. Although
`quantitative modeling for this purpose may be straightforward, the following points suggest this approach can
`present a number of difficulties when estimating a safe starting dose. Generally, at the time of IND initiation, there
`are a number of unknowns regarding animal toxicity and comparability of human and animal pharmacokinetics and
`metabolism: (1) human bioavailability and metabolism may differ significantly from that of animals; (2)
`mechanisms of toxicity may not be known (e.g., toxic accumulation in a peripheral compartment); and/or (3)
`toxicity may be due to an unidentified metabolite, not the parent drug. Therefore, relying on pharmacokinetic
`models (based on the parent drug in plasma) to gauge starting doses would require multiple untested assumptions.
`Modeling can be used with greatest validity to estimate human starting doses in special cases where few underlying
`assumptions would be necessary. Such cases are exemplified by large molecular weight proteins (e.g., humanized
`monoclonal antibodies) that are intravenously administered, are removed from circulation by endocytosis rather than
`metabolism, have immediate and detectable effects on blood cells, and have a volume of distribution limited to the
`plasma volume. In these cases, allometric, pharmacokinetic, and pharmacodynamic models have been useful in
`identifying the human mg/kg dose that would be predicted to correlate with safe drug plasma levels in nonhuman
`primates. Even in these cases, uncertainties (such as differences between human and animal receptor sensitivity or
`density) have been shown to affect human pharmacologic or toxicologic outcomes, and the use of safety factors as
`described in this guidance is still warranted.
`
`
`
`2
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`

`Contains Nonbinding Recommendations
`
`
`
`The remainder of this guidance focuses on the recommended algorithmic process for starting
`dose extrapolation from animals to humans based on administered doses, since this method will
`likely be useful for the majority of INDs seeking to investigate new drugs in healthy volunteers.
`Some classes of drugs (e.g., many cytotoxic or biological agents) are commonly introduced into
`initial clinical trials in patient volunteers rather than healthy volunteers. Typically, patients are
`used instead of healthy volunteers when a drug is suspected or known to be unavoidably toxic.
`This guidance does not address starting doses in patients. However, many principles and some
`approaches recommended here may be applicable to designing such trials.
`
`
`III. OVERVIEW OF THE ALGORITHM
`
`The recommended process for selecting the MRSD is presented in Appendix E and described in
`this section. The major elements (i.e., the determination of the no observed adverse effect levels
`(NOAELs) in the tested animal species, conversion of NOAELs to HED, selection of the most
`appropriate animal species, and application of a safety factor) are all discussed in greater detail in
`subsequent sections. Situations are also discussed in which the algorithm should be modified.
`The algorithm is intended to be used for systemically administered therapeutics. Topical,
`intranasal, intratissue, and compartmental administration routes and depot formulations can have
`additional considerations, but similar principles should apply.
`
`The process of calculating the MRSD should begin after the toxicity data have been analyzed.
`Although only the NOAEL should be used directly in the algorithm for calculating an MRSD,
`other data (exposure/toxicity relationships, pharmacologic data, or prior clinical experience with
`related drugs) can affect the choice of most appropriate species, scaling, and safety factors.
`
`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. Although body surface area
`conversion is the standard way to approximate equivalent exposure if no further information is
`available, in some cases extrapolating doses based on other parameters may be more appropriate.
`This decision should be based on the data available for the individual case. The body surface
`area normalization and the extrapolation of the animal dose to human dose should be done in one
`step by dividing the NOAEL in each of the animal species studied by the appropriate body
`surface area conversion factor (BSA-CF). This conversion factor is a unitless number that
`converts mg/kg dose for each animal species to the mg/kg dose in humans, which is equivalent to
`the animal’s NOAEL on a mg/m2 basis. The resulting figure is called a human equivalent dose
`(HED). The species that generates the lowest HED is called the most sensitive species.
`
`When information indicates that a particular species is more relevant for assessing human risk
`(and deemed the most appropriate species), the HED for that species may be used in subsequent
`calculations, regardless of whether this species is the most sensitive. This situation is more
`applicable to biologic therapies, many of which have high selectivity for binding to human target
`
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`3
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`Contains Nonbinding Recommendations
`
`
`proteins and limited reactivity in species commonly used for toxicity testing. In such cases, in
`vitro binding and functional studies should be conducted to select an appropriate, relevant
`species before toxicity studies are designed (refer to ICH guidance for industry S6 Preclinical
`Safety Evaluation of Biotechnology-Derived Pharmaceuticals for more details3). (However, if
`serious toxicities are observed in an animal species considered less relevant, those toxicities
`should be taken into consideration in determining the species to be used to calculate an HED.
`For example, in one particular case, dog was selected as the animal species used for calculation
`of an HED because of unmonitorable cardiac lesions, even though the rat was considered the
`most relevant species based on pharmacological activity data.) Additionally, a species might be
`considered an inappropriate toxicity model for a given drug if the dose-limiting toxicity in that
`species was concluded to be of limited value for human risk assessment, based on historical
`comparisons of toxicities in the animal species to those in humans across a therapeutic class (i.e.,
`the dose-limiting toxicity is species-specific). In this case, data from that species should not be
`used to derive the HED. Without any additional information to guide the choice of the most
`appropriate species for assessing human risk, the most sensitive species is designated the most
`appropriate, because using the lowest HED would generate the most conservative starting dose.
`
` A
`
` safety factor should then be applied to the HED to increase assurance that the first dose in
`humans will not cause adverse effects. The use of the safety factor should be based on the
`possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than
`predicted by the animal models, that bioavailability may vary across species, and that the models
`tested do not evaluate all possible human toxicities. For example, ocular disturbances or pain
`(e.g., severe headaches) in humans can be significant dose-limiting toxicities that may go
`undetected in animal studies.
`
`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. Safety concerns or design shortcomings
`noted in animal studies may increase the safety factor, and thus reduce the MRSD further.
`Alternatively, information about the pharmacologic class (well-characterized classes of
`therapeutics with extensive human clinical and preclinical experience) may allay concerns and
`form the basis for reducing the magnitude of the default safety factor and increasing the MRSD.
`Although a dose lower than the MRSD can be used as the actual starting dose, the process
`described in this guidance will derive the maximum recommended starting dose. This algorithm
`generates an MRSD in units of mg/kg, a common method of dosing used in phase 1 trials, but the
`equations and conversion factors provided in this guidance (Table 1, second column) can be used
`to generate final dosing units in the mg/m2 form if desired.
`
`As previously stated, for purposes of initial clinical trials in adult healthy volunteers, the HED
`should ordinarily be calculated from the animal NOAEL. If the HED is based on an alternative
`index of effect, such as the pharmacologically active dose (PAD), this exception should be
`prominently stipulated in descriptions of starting dose calculations.
`
`
`
`3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER
`guidance Web page at http://www.fda.gov/cder/guidance/index.htm.
`
`
`
`4
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`

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`Contains Nonbinding Recommendations
`
`STEP 1: NO OBSERVED ADVERSE EFFECT LEVEL DETERMINATION
`
`
`The remainder of this guidance provides a description of the individual steps in the
`recommended process and the reasoning behind each step.
`
`
`IV.
`
`The first step in determining the MRSD is to review and evaluate the available animal data so
`that a NOAEL can be determined for each study. Several definitions of NOAEL exist, but for
`selecting a starting dose, the following is used: the highest dose level that does not produce a
`significant increase in adverse effects in comparison to the control group. In this context,
`adverse effects that are biologically significant (even if they are not statistically significant)
`should be considered in the determination of the NOAEL. The NOAEL is a generally accepted
`benchmark for safety when derived from appropriate animal studies and can serve as the starting
`point for determining a reasonably safe starting dose of a new therapeutic in healthy (or
`asymptomatic) human volunteers.
`
`The NOAEL is not the same as the no observed effect level (NOEL), which refers to any effect,
`not just an adverse one, although in some cases the two might be identical. The definition of the
`NOAEL, in contrast to that of the NOEL, reflects the view that some effects observed in the
`animal may be acceptable pharmacodynamic actions of the therapeutic and may not raise a safety
`concern. The NOAEL should also not be confused with lowest observed adverse effect level
`(LOAEL) or maximum tolerated dose (MTD). Both of the latter concepts are based on findings
`of adverse effects and are not generally used as benchmarks for establishing safe starting doses
`in adult healthy volunteers. (The term level refers to dose or dosage, generally expressed as
`mg/kg or mg/kg/day.)
`
`Initial IND submissions for first-in-human studies by definition lack in vivo human data or
`formal allometric comparison of pharmacokinetics. Measurements of systemic levels or
`exposure (i.e., AUC or Cmax) cannot be employed for setting a safe starting dose in humans, and
`it is critical to rely on dose and observed toxic response data from adequate and well-conducted
`toxicology studies. However, there are cases where nonclinical data on bioavailability,
`metabolite profile, and plasma drug levels associated with toxicity may influence the choice of
`the NOAEL. One such case is when saturation of drug absorption occurs at a dose that produces
`no toxicity. In this instance, the lowest saturating dose, not the highest (nontoxic) dose, should
`be used for calculating the HED.
`
`There are essentially three types of findings in nonclinical toxicology studies that can be used to
`determine the NOAEL: (1) overt toxicity (e.g., clinical signs, macro- and microscopic lesions);
`(2) surrogate markers of toxicity (e.g., serum liver enzyme levels); and (3) exaggerated
`pharmacodynamic effects. Although the nature and extent of adverse effects can vary greatly
`with different types of therapeutics, and it is anticipated that in many instances, experts will
`disagree on the characterization of effects as being adverse or not, the use of NOAEL as a
`benchmark for dose-setting in healthy volunteers should be acceptable to all responsible
`investigators. As a general rule, an adverse effect observed in nonclinical toxicology studies
`
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`Contains Nonbinding Recommendations
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`STEP 2: HUMAN EQUIVALENT DOSE CALCULATION
`
`
`used to define a NOAEL for the purpose of dose-setting should be based on an effect that would
`be unacceptable if produced by the initial dose of a therapeutic in a phase 1 clinical trial
`conducted in adult healthy volunteers.
`
`
`V.
`
`
`A.
`
`Conversion Based on Body Surface Area
`
`
`After the NOAELs in the relevant animal studies have been determined, they are converted to
`HEDs. A decision should be made regarding the most appropriate method for extrapolating the
`animal dose to the equivalent human dose. Toxic endpoints for therapeutics administered
`systemically to animals, such as the MTD, are usually assumed to scale well between species
`when doses are normalized to body surface area (i.e., mg/m2) (EPA 1992; Lowe and Davis
`1998). The basis for this assumption lies primarily with the work of Freireich et al. (1966) and
`Schein et al. (1970). These investigators reported that, for antineoplastic drugs, doses lethal to
`10 percent of rodents (LD10s) and MTDs in nonrodents both correlated with the human MTD
`when the doses were normalized to the same administration schedule and expressed as mg/m2.
`Despite the subsequent analyses showing that the MTDs for this set of drugs scale best between
`species when doses are normalized to W0.75 rather than W0.67 (inherent in body surface area
`normalization) (Travis and White 1988; Watanabe et al. 1992), normalization to body surface
`area has remained a widespread practice for estimating an HED based on an animal dose.
`
`An analysis of the affect of the allometric exponent on the conversion of an animal dose to the
`HED was conducted (see Appendix A). Based on this analysis and on the fact that correcting for
`body surface area increases clinical trial safety by resulting in a more conservative starting dose
`estimate, it was concluded that the approach of converting NOAEL doses to an HED based on
`body surface area correction factors (i.e., W0.67) should be maintained for selecting starting doses
`for initial studies in adult healthy volunteers. Nonetheless, use of a different dose normalization
`approach, such as directly equating the human dose to the NOAEL in mg/kg, may be appropriate
`in some circumstances. Deviations from the body surface area approach, when describing the
`conversion of animal dose to HED, should be justified. The basis for justifying direct mg/kg
`conversion and examples in which other normalization methods are appropriate are described in
`the following subsection.
`
`Although normalization to body surface area is an appropriate method for extrapolating doses
`between species, consistent factors for converting doses from mg/kg to mg/m2 have not always
`been used. Given that body surface area normalization provides a reasonable approach for
`estimating an HED, the factors used for converting doses for each species should be
`standardized. Since body surface area varies with W0.67, the conversion factors are dependent on
`the weight of the animals in the studies. However, analyses conducted to address the effect of
`body weight on the actual BSA-CF demonstrated that a standard factor provides a reasonable
`estimate of the HED over a broad range of human and animal weights (see Appendix B). The
`conversion factors and divisors shown in Table 1 are therefore recommended as the standard
`
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`6
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`Contains Nonbinding Recommendations
`
`
`values to be used for interspecies dose conversions for NOAELs. (These factors may also be
`applied when comparing safety margins for other toxicity endpoints (e.g., reproductive toxicity
`and carcinogenicity) when other data for comparison (i.e., AUCs) are unavailable or are
`otherwise inappropriate for comparison.)
`
`
`
`
`Species
`
`Table 1: Conversion of Animal Doses to Human Equivalent Doses
`Based on Body Surface Area
`To Convert
`To Convert Animal Dose in mg/kg
`to HEDa in mg/kg, Either:
`Animal Dose in
`mg/kg to Dose in
`Divide
`Multiply
`mg/m², Multiply
`Animal Dose By
`Animal Dose By
`by km
`
`
`
`---
`---
`37
`Human
`Child (20 kg)b
`---
`---
`25
`0.08
`12.3
`3
`Mouse
`0.13
`7.4
`5
`Hamster
`0.16
`6.2
`6
`Rat
`0.19
`5.3
`7
`Ferret
`0.22
`4.6
`8
`Guinea pig
`0.32
`3.1
`12
`Rabbit
`0.54
`1.8
`20
`Dog
`
`
`
`Primates:
`Monkeysc
`0.32
`3.1
`12
`0.16
`6.2
`6
`Marmoset
`0.19
`5.3
`7
`Squirrel monkey
`0.54
`1.8
`20
`Baboon
`0.73
`1.4
`27
`Micro-pig
`0.95
`1.1
`35
`Mini-pig
`a Assumes 60 kg human. For species not listed or for weights outside the standard ranges,
`HED can be calculated from the following formula:
`HED = animal dose in mg/kg x (animal weight in kg/human weight in kg)0.33.
`b This km value is provided for reference only since healthy children will rarely be volunteers
`for phase 1 trials.
`c For example, cynomolgus, rhesus, and stumptail.
`
`
`B.
`
`Basis for Using mg/kg Conversions
`
`
`The factors in Table 1 for scaling animal NOAEL to HEDs are based on the assumption that
`doses scale 1:1 between species when normalized to body surface area. However, there are
`occasions for which scaling based on body weight (i.e., setting the HED (mg/kg) = NOAEL
`(mg/kg)) may be more appropriate. To consider mg/kg scaling for a therapeutic, the available
`data should show that the NOAEL occurs at a similar mg/kg dose across species. The following
`circumstances should exist before extrapolating to the HED on a mg/kg basis rather than using
`
`
`
`7
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`

`

`Contains Nonbinding Recommendations
`
`
`the mg/m2 approach. Note that mg/kg scaling will give a twelve-, six-, and twofold higher HED
`than the default mg/m2 approach for mice, rats, and dogs, respectively. If these circumstances do
`not exist, the mg/m2 scaling approach for determining the HED should be followed as it will lead
`to a safer MRSD.
`
`1. NOAELs occur at a similar mg/kg dose across test species (for the studies with a given
`dosing regimen relevant to the proposed initial clinical trial). (However, it should be
`noted that similar NOAELs on a mg/kg basis can be obtained across species because of
`differences in bioavailability alone.)
`
`2. If only two NOAELs from toxicology studies in separate species are available, one of the
`following should also be true:
`
` •
`
` The therapeutic is administered orally and the dose is limited by local toxicities.
`Gastrointestinal (GI) compartment weight scales by W0.94 (Mordenti 1986). GI
`volume determines the concentration of the therapeutic in the GI tract. It is then
`reasonable that the toxicity of the therapeutic would scale by mg/kg (W1.0).
`
`• The toxicity in humans (for a particular class) is dependent on an exposure parameter
`that is highly correlated across species with dose on a mg/kg basis. For example,
`complement activation by systemically administered antisense oligonucleotides in
`humans is believed to be dependent upon Cmax (Geary et al. 1997). For some
`antisense drugs, the Cmax correlates across nonclinical species with mg/kg dose and in
`such instances mg/kg scaling would be justified.
`
`
`
`• Other pharmacologic and toxicologic endpoints also scale between species by mg/kg
`for the therapeutic. Examples of such endpoints include the MTD, lowest lethal dose,
`and the pharmacologically active dose.
`
`• There is a robust correlation between plasma drug levels (Cmax and AUC) and dose in
`mg/kg.
`
`
`C.
`
`Other Exceptions to mg/m2 Scaling Between Species
`
`
`Scaling between species based on mg/m2 is not recommended for the following categories of
`therapeutics:
`
`1. Therapeutics administered by alternative routes (e.g., topical, intranasal, subcutaneous,
`intramuscular) for which the dose is limited by local toxicities. Such therapeutics should
`be normalized to concentration (e.g., mg/area of application) or amount of drug (mg) at
`the application site.
`
`2. Therapeutics administered into anatomical compartments that have little subsequent
`distribution outside of the compartment. Examples are intrathecal, intravesical,
`
`
`
`8
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`

`

`
`
`Contains Nonbinding Recommendations
`
`intraocular, or intrapleural administration. Such therapeutics should be normalized
`between species according to the compartmental volumes and concentrations of the
`therapeutic.
`
`3. Proteins administered intravascularly with Mr > 100,000 daltons. Such therapeutics
`should be normalized to mg/kg.
`
`STEP 3: MOST APPROPRIATE SPECIES SELECTION
`
`
`
`VI.
`
`After the HEDs have been determined from the NOAELs from all toxicology studies relevant to
`the proposed human trial, the next step is to pick one HED for subsequent derivation of the
`MRSD. This HED should be chosen from the most appropriate species. 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).
`
`Factors that could influence the choice of the most appropriate species rather than the default to
`the most sensitive species include: (1) differences in the absorption, distribution, metabolism,
`and excretion (ADME) of the therapeutic between the species, and (2) class experience that may
`indicate a particular animal model is more predictive of human toxicity. Selection of the most
`appropriate species for certain biological products (e.g., human proteins) involves consideration
`of various factors unique to these products. Factors such as whether an animal species expresses
`relevant receptors or epitopes may affect species selection (refer to ICH guidance for industry S6
`Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals for more details).
`
`When determining the MRSD for the first dose of a new therapeutic in humans, absorption,
`distribution, and elimination parameters will not be known for humans. Comparative
`metabolism data, however, might be available based on in vitro studies. These data are
`particularly relevant when there are marked differences in both the in vivo metabolite profiles
`and HEDs in animals. Class experience implies that previous studies have demonstrated that a
`particular animal model is more appropriate for the assessment of safety for a particular class of
`therapeutics. For example, in the nonclinical safety assessment of the phosphorothioate
`antisense drugs, the monkey is considered the most appropriate species because monkeys
`experience the same dose limiting toxicity as humans (e.g., complement activation) whereas
`rodents do not. For this class of therapeutics, the MRSD would usually be based on the HED for
`the NOAEL in monkeys regardless of whether it was lower than that in rodents, unless unique
`dose limiting toxicities were observed with the new antisense compound in the rodent species.
`
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`VII. STEP 4: APPLICATION OF SAFETY FACTOR
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`Once the HED of the NOAEL in the most appropriate species has been determined, a safety
`factor should then be applied to provide a margin of safety for protection of human subjects
`receiving the initial clinical dose. This safety factor allows for variabil