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`TABLE OF CONTENTS
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`INTRODUCTION............................................................................................................. 1
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`II.
`BACKGROUND ............................................................................................................... 2
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`III.
`OVERVIEW OF THE ALGORITHM ........................................................................... 3
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`IV.
`STEP 1: NO OBSERVED ADVERSE EFFECT LEVEL DETERMINATION ........ 5
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`V.
`STEP 2: HUMAN EQUIVALENT DOSE CALCULATION ...................................... 6
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`A. Conversion Based on Body Surface Area .................................................................................... 6
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`B. Basis for Using mg/kg Conversions .............................................................................................. 7
`Š; Š((#$%&#:( -#,-•–-#4% <"&(% (;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;—
`C. Other Exceptions to mg/m2 Scaling Between Species ................................................................. 8
`B
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`VI.
`STEP 3: MOST APPROPRIATE SPECIES SELECTION......................................... 9
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`VII.
`STEP 4: APPLICATION OF SAFETY FACTOR ....................................................... 9
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`A.
`Increasing the Safety Factor ....................................................................................................... 10
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`B. Decreasing the Safety Factor ...................................................................................................... 11
`Š; 2"!&"( -#)."#1$")*#=!)%&;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;ŽŽ
`VIII. STEP 5: CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE
`9''';15+E#D’##4Œ1'2+>75'Œ#Œ=#58+#E87>/74Œ‹Œ'47‹‹œ#745'9+#
`DOSE ................................................................................................................................ 12
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`IX.
`SUMMARY ..................................................................................................................... 12
`'; 1://7>œ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;ŽB
`REFERENCES ............................................................................................................................ 13
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`GLOSSARY................................................................................................................................. 15
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`APPENDIX A: ............................................................................................................................. 16
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`Analysis of Allometric Exponent on I-IED Calculations .................................................................... 16
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`APPENDIX B: ............................................................................................................................. 18
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`Analysis of Body Weight Effects on HED Calculations .................................................................... 18
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`APPENDIX C: ............................................................................................................................. 24
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`Derivation of the Interspecies Scaling Factor (Wa/Wh)(1'b)................................................................ 24
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`APPENDIX D: ............................................................................................................................. 25
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`Examples of Calculations for Converting Animal Doses to Human Equivalent Doses .................. 25
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`APPENDIX E: ............................................................................................................................. 27
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`Selection of Maximum Recommended Starting Dose for Drugs Administered Systemically to
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`Normal Volunteers ............................................................................................................................... 27
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`
` ';
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`I.
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`Contains Nonbinding Recommendations
`¡¢£¤¥¦£§¨©¢£ª¦£«¦£¬¨­®¯¢°°®£«¥¤¦¢£§¨
`Guidance for Industry1
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`Trials for Therapeutics in Adult Healthy Volunteers
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`INTRODUCTION
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`I.
`
` ±
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`This guidance outlines a process (algorithm) and vocabulary for deriving the maximum
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`recommended starting dose (MRSD) forfirst-in-human clinical trials of new molecular entities
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`in adult healthy volunteers, and recommends a standardized process by which the MRSD can be
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`selected. The purpose of this process is to ensure the safety of the human volunteers.
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` ±
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`The goals of this guidance are to:
`(1) establish a consistent terminology for discussing the
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`starting dose; (2) provide common conversion factors for deriving a human equivalent dose
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`(HED); and (3) delineate a strategy for selecting the MRSD for adult healthy volunteers,
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`regardless of the projected clinical use. This process is depicted in a flow chart that presents the
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`decisions and calculations used to generate the MRSD fiom animal data (see Appendix E).
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`FDA’s guidance documents, including this guidance, do not establish legally enforceable
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`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
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`be Viewed only as recommendations, unless specific regulatory or statutory requirements are
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`cited. The use of the word should in Agency guidances means that something is suggested or
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`recommended, but not required.
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`1 This guidance has been prepared by the Office ofNew Drugs in the Center for Drug Evaluation and Research
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`(CDER) at the Food and Drug Administration.
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`number listed on the title page of this guidance.
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`This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
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`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
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`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
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`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
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`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
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`
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`II.
`BACKGROUND
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`The process identified in this guidance pertains to determining the MRSD for adult healthy
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`subjects when beginning a clinical investigation of any new drug or biological therapeutic that
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`has been studied in animals. This guidance is not pertinent to endogenous hormones and
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`proteins (e.g., recombinant clotting factors) used at physiologic concentrations or prophylactic
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`vaccines. The process outlined in this guidance pertains primarily to drug products for which
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`systemic exposure is intended; it does not address dose escalation or maximum allowable doses
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`in clinical trials.
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`Although the process outlined in this guidance uses administered doses, observed toxicities, and
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`an algorithmic approach to calculate the MRSD, an alternative approach could be proposed that
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`places primary emphasis on animal pharmacokinetics and modeling rather than dose (Mahmood
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`et al. 2003; Reigner and Blesch 2002). In a limited number of cases, animal pharmacokinetic
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`data can be useful in determining initial clinical doses.2 However, in the majority of
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`investigational new drug applications (INDs), animal data are not available in sufficient detail to
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`construct a scientifically valid, pharmacokinetic model whose aim is to accurately project an
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`MRSD.
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`Toxicity should be avoided at the initial clinical dose. However, doses should be chosen that
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`allow reasonably rapid attainment of the phase 1 trial objectives (e.g., assessment of the
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`therapeutic’s tolerability, pharmacodynamic or pharmacokinetic profile). All of the relevant
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`preclinical data, including information on the pharmacologically active dose, the full toxicologic
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`profile of the compound, and the pharmacokinetics (absorption, distribution, metabolism, and
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`excretion) of the therapeutic, should be considered when determining the MRSD. Starting with
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`doses lower than the MRSD is always an option and can be particularly appropriate to meet some
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`clinical trial objectives.
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`2 If the parent drug is measured in the plasma at multiple times and is within the range of toxic exposures for two or
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`more animal species, it may be possible to develop a pharmacokinetic model predicting human doses and
`ÃÀ¼»¸¹³Ã¸Í´½»º³»´Ò³¾Ã¸ËÌ»½À´´³ÌÍ»¾À·»Ï»ÍÀ½¸½²¸¼Ã¸ºÀdz¹»¾³ºÃÀ·»Í½¼»·³º¾³¹µ²¶Ã¸¹·À´»´¸¹·
`concentrations and to draw inferences about safe human plasma levels in the absence of prior human data. Although
`ºÀ¹º»¹¾¼¸¾³À¹´¸¹·¾À·¼¸Ñ³¹Ê»¼»¹º»´¸ÌÀ¶¾´¸Ê»²¶Ã¸¹½Í¸´Ã¸Í»Ï»Í´³¹¾²»¸Ì´»¹º»Àʽ¼³À¼²¶Ã¸¹·¸¾¸ÈÂ;²À¶µ²
`quantitative modeling for this purpose may be straightforward, the following points suggest this approach can
`ж¸¹¾³¾¸¾³Ï»ÃÀ·»Í³¹µÊÀ¼¾²³´½¶¼½À´»Ã¸ËÌ»´¾¼¸³µ²¾ÊÀ¼Ñ¸¼·Ò¾²»ÊÀÍÍÀѳ¹µ½À³¹¾´´¶µµ»´¾¾²³´¸½½¼À¸º²º¸¹
`present a number of difficulties when estimating a safe starting dose. Generally, at the time of IND initiation, there
`½¼»´»¹¾¸¹¶ÃÌ»¼ÀÊ·³Êʳº¶Í¾³»´Ñ²»¹»´¾³Ã¸¾³¹µ¸´¸Ê»´¾¸¼¾³¹µ·À´»È廹»¼¸ÍÍËÒ¸¾¾²»¾³Ã»ÀÊÉáÁ³¹³¾³¸¾³À¹Ò¾²»¼»
`are a number of unknowns regarding animal toxicity and comparability of human and animal pharmacokinetics and
`¸¼»¸¹¶ÃÌ»¼Àʶ¹Ç¹Àѹ´¼»µ¸¼·³¹µ¸¹³Ã¸Í¾ÀÓ³º³¾Ë¸¹·ºÀý¸¼¸Ì³Í³¾ËÀʲ¶Ã¸¹¸¹·¸¹³Ã¸Í½²¸¼Ã¸ºÀdz¹»¾³º´¸¹·
`metabolism: (1) human bioavailability and metabolism may differ significantly fiom that of animals; (2)
`û¾¸ÌÀͳ´ÃØÅÙƲ¶Ã¸¹Ì³À¸Ï¸³Í¸Ì³Í³¾Ë¸¹·Ã»¾¸ÌÀͳ´Ãø˷³ÊÊ»¼´³µ¹³Ê³º¸¹¾ÍËʼÀþ²¸¾Àʸ¹³Ã¸Í´ÚÅÛÆ
`mechanisms of toxicity may not be known (e.g., toxic accumulation in a peripheral compartment); and/or (3)
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`toxicity may be due to an unidentified metabolite, not the parent drug. Therefore, relying on pharmacokinetic
`¾ÀÓ³º³¾ËøËÌ»·¶»¾À¸¹¶¹³·»¹¾³Ê³»·Ã»¾¸ÌÀͳ¾»Ò¹À¾¾²»½¸¼»¹¾·¼¶µÈ±²»¼»ÊÀ¼»Ò¼»Í˳¹µÀ¹½²¸¼Ã¸ºÀdz¹»¾³º
`models (based on the parent drug in plasma) to gauge starting doses would require multiple untested assumptions.
`ÃÀ·»Í´Å̸´»·À¹¾²»½¸¼»¹¾·¼¶µ³¹½Í¸´Ã¸Æ¾Àµ¸¶µ»´¾¸¼¾³¹µ·À´»´ÑÀ¶Í·¼»Ð¶³¼»Ã¶Í¾³½Í»¶¹¾»´¾»·¸´´¶Ã½¾³À¹´È
`Modeling can be used with greatest validity to estimate human starting doses in special cases where few underlying
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`assumptions would be necessary. Such cases are exemplified by large molecular weight proteins (e.g., humanized
`¸´´¶Ã½¾³À¹´ÑÀ¶Í·Ì»¹»º»´´¸¼ËÈÖ¶º²º¸´»´¸¼»»Ó»Ã½Í³Ê³»·ÌË͸¼µ»ÃÀÍ»º¶Í¸¼Ñ»³µ²¾½¼À¾»³¹´Å»ÈµÈÒ²¶Ã¸¹³×»·
`monoclonal antibodies) that are intravenously administered, are removed fiom circulation by endocytosis rather than
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`metabolism, have immediate and detectable effects on blood cells, and have a volume of distribution limited to the
`û¾¸ÌÀͳ´ÃÒ²¸Ï»³Ãû·³¸¾»¸¹··»¾»º¾¸ÌÍ»»ÊÊ»º¾´À¹ÌÍÀÀ·º»ÍÍ´Ò¸¹·²¸Ï»¸ÏÀͶûÀÊ·³´¾¼³Ì¶¾³À¹Í³Ã³¾»·¾À¾²»
`plasma volume. In these cases, allometric, pharmacokinetic, and pharmacodynamic models have been usefiil in
`½Í¸´Ã¸ÏÀͶûÈɹ¾²»´»º¸´»´Ò¸ÍÍÀû¾¼³ºÒ½²¸¼Ã¸ºÀdz¹»¾³ºÒ¸¹·½²¸¼Ã¸ºÀ·Ë¹¸Ã³ºÃÀ·»Í´²¸Ï»Ì»»¹¶´»Ê¶Í³¹
`identifying the human mg/kg dose that would be predicted to correlate with safe drug plasma levels in nonhuman
`³·»¹¾³Ê˳¹µ¾²»²¶Ã¸¹Ãµæǵ·À´»¾²¸¾ÑÀ¶Í·Ì»½¼»·³º¾»·¾ÀºÀ¼¼»Í¸¾»Ñ³¾²´¸Ê»·¼¶µ½Í¸´Ã¸Í»Ï»Í´³¹¹À¹²¶Ã¸¹
`primates. Even in these cases, uncertainties (such as differences between human and animal receptor sensitivity or
`½¼³Ã¸¾»´ÈÝÏ»¹³¹¾²»´»º¸´»´Ò¶¹º»¼¾¸³¹¾³»´Å´¶º²¸´·³ÊÊ»¼»¹º»´Ì»¾Ñ»»¹²¶Ã¸¹¸¹·¸¹³Ã¸Í¼»º»½¾À¼´»¹´³¾³Ï³¾ËÀ¼
`density) have been shown to affect human pharmacologic or toxicologic outcomes, and the use of safety factors as
`·»¹´³¾ËƲ¸Ï»Ì»»¹´²Àѹ¾À¸ÊÊ»º¾²¶Ã¸¹½²¸¼Ã¸ºÀÍÀµ³ºÀ¼¾ÀÓ³ºÀÍÀµ³ºÀ¶¾ºÀû´Ò¸¹·¾²»¶´»ÀÊ´¸Ê»¾Ëʸº¾À¼´¸´
`described in this guidance is still warranted.
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`The remainder of this guidance focuses on the recommended algorithmic process for starting
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`dose extrapolation from animals to humans based on administered doses, since this method will
`·À´»»Ó¾¼¸½À͸¾³À¹Ê¼Àø¹³Ã¸Í´¾À²¶Ã¸¹´Ì¸´»·À¹¸·Ã³¹³´¾»¼»··À´»´Ò´³¹º»¾²³´Ã»¾²À·Ñ³ÍÍ
`likely be useful for the majority of INDs seeking to investigate new drugs in healthy volunteers.
`ͳǻÍËÌ»¶´»Ê¶ÍÊÀ¼¾²»Ã¸ßÀ¼³¾ËÀÊÉáÁ´´»»Ç³¹µ¾À³¹Ï»´¾³µ¸¾»¹»Ñ·¼¶µ´³¹²»¸Í¾²ËÏÀͶ¹¾»»¼´È
`Some classes of drugs (e.g., many cytotoxic or biological agents) are commonly introduced into
`ÖÀûºÍ¸´´»´ÀÊ·¼¶µ´Å»ÈµÈÒø¹ËºË¾À¾ÀÓ³ºÀ¼Ì³ÀÍÀµ³º¸Í¸µ»¹¾´Æ¸¼»ºÀÃÃÀ¹Í˳¹¾¼À·¶º»·³¹¾À
`initial clinical trials in patient volunteers rather than healthy volunteers. Typically, patients are
`³¹³¾³¸ÍºÍ³¹³º¸Í¾¼³¸Í´³¹½¸¾³»¹¾ÏÀͶ¹¾»»¼´¼¸¾²»¼¾²¸¹²»¸Í¾²ËÏÀͶ¹¾»»¼´È±Ë½³º¸ÍÍËÒ½¸¾³»¹¾´¸¼»
`used instead of healthy volunteers when a drug is suspected or known to be unavoidably toxic.
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`This guidance does not address starting doses in patients. However, many principles and some
`±²³´µ¶³·¸¹º»·À»´¹À¾¸··¼»´´´¾¸¼¾³¹µ·À´»´³¹½¸¾³»¹¾´ÈÜÀѻϻ¼Òø¹Ë½¼³¹º³½Í»´¸¹·´Àû
`approaches recommended here may be applicable to designing such trials.
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`OVERVIEW OF THE ALGORITHM
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`The recommended process for selecting the MRSD is presented in Appendix E and described in
`²»¼»ºÀÃû¹·»·½¼Àº»´´ÊÀ¼´»Í»º¾³¹µ¾²»ÔÕÖÁ³´½¼»´»¹¾»·³¹Â½½»¹·³Óݸ¹··»´º¼³Ì»·³¹
`this section. The major elements (i.e., the determination of the no observed adverse effect levels
`¾²³´´»º¾³À¹È±²»Ã¸ßÀ¼»Í»Ã»¹¾´Å³È»ÈÒ¾²»·»¾»¼Ã³¹¸¾³À¹Àʾ²»¹ÀÀÌ´»¼Ï»·¸·Ï»¼´»»ÊÊ»º¾Í»Ï»Í´
`(NOAELs) in the tested animal species, conversion of NOAELs to HED, selection of the most
`ÅáàÂÝç´Æ³¹¾²»¾»´¾»·¸¹³Ã¸Í´½»º³»´ÒºÀ¹Ï»¼´³À¹ÀÊáàÂÝç´¾ÀÜÝÁÒ´»Í»º¾³À¹Àʾ²»ÃÀ´¾
`appropriate animal species, and application of a safety factor) are all discussed in greater detail in
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`subsequent sections. Situations are also discussed in which the algorithm should be modified.
`´¶Ì´»Ð¶»¹¾´»º¾³À¹´ÈÖ³¾¶¸¾³À¹´¸¼»¸Í´À·³´º¶´´»·³¹Ñ²³º²¾²»¸ÍµÀ¼³¾²Ã´²À¶Í·Ì»ÃÀ·³Ê³»·È
`The algorithm is intended to be used for systemically administered therapeutics. Topical,
`±²»¸ÍµÀ¼³¾²Ã³´³¹¾»¹·»·¾ÀÌ»¶´»·ÊÀ¼´Ë´¾»Ã³º¸ÍÍ˸·Ã³¹³´¾»¼»·¾²»¼¸½»¶¾³º´È±À½³º¸ÍÒ
`intranasal, intratissue, and compartmental administration routes and depot formulations can have
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`additional considerations, but similar principles should apply.
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`The process of calculating the MRSD should begin after the toxicity data have been analyzed.
`²»½¼Àº»´´Àʺ¸Íº¶Í¸¾³¹µ¾²»ÔÕÖÁ´²À¶Í·Ì»µ³¹¸Ê¾»¼¾²»¾ÀÓ³º³¾Ë·¸¾¸²¸Ï»Ì»»¹¸¹¸ÍË×»·È
`Although only the NOAEL should be used directly in the algorithm for calculating an MRSD,
`Â;²À¶µ²À¹Í˾²»áàÂÝç´²À¶Í·Ì»¶´»··³¼»º¾Í˳¹¾²»¸ÍµÀ¼³¾²ÃÊÀ¼º¸Íº¶Í¸¾³¹µ¸¹ÔÕÖÁÒ
`other data (exposure/toxicity relationships, pharmacologic data, or prior clinical experience with
`À¾²»¼·¸¾¸Å»Ó½À´¶¼»æ¾ÀÓ³º³¾Ë¼»Í¸¾³À¹´²³½´Ò½²¸¼Ã¸ºÀÍÀµ³º·¸¾¸ÒÀ¼½¼³À¼ºÍ³¹³º¸Í»Ó½»¼³»¹º»Ñ³¾²
`related drugs) can affect the choice of most appropriate species, scaling, and safety factors.
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`The NOAEL for each species tested should be identified, and then converted to the HED using
`±²»áàÂÝçÊÀ¼»¸º²´½»º³»´¾»´¾»·´²À¶Í·Ì»³·»¹¾³Ê³»·Ò¸¹·¾²»¹ºÀ¹Ï»¼¾»·¾À¾²»ÜÝÁ¶´³¹µ
`appropriate scaling factors. For most systemically administered therapeutics, this conversion
`¸½½¼À½¼³¸¾»´º¸Í³¹µÊ¸º¾À¼´È¿À¼ÃÀ´¾´Ë´¾»Ã³º¸ÍÍ˸·Ã³¹³´¾»¼»·¾²»¼¸½»¶¾³º´Ò¾²³´ºÀ¹Ï»¼´³À¹
`should be based on the normalization of doses to body surface area. Although body surface area
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`conversion is the standard way to approximate equivalent exposure if no further information is
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`available, in some cases extrapolating doses based on other parameters may be more appropriate.
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`This decision should be based on the data available for the individual case. The body surface
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`area normalization and the extrapolation of the animal dose to human dose should be done in one
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`step by dividing the NOAEL in each of the animal species studied by the appropriate body
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`surface area conversion factor (BSA-CF). This conversion factor is a unitless number that
`´¶¼Ê¸º»¸¼»¸ºÀ¹Ï»¼´³À¹Ê¸º¾À¼ÅäÖÂèâ¿Æȱ²³´ºÀ¹Ï»¼´³À¹Ê¸º¾À¼³´¸¶¹³¾Í»´´¹¶ÃÌ»¼¾²¸¾
`converts mg/kg dose for each animal species to the mg/kg dose in humans, which is equivalent to
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`the animal’s NOAEL on a mg/m2 basis. The resulting figure is called a human equivalent dose
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`(HED). The species that generates the lowest HED is called the most sensitive species.
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`When information indicates that a particular species is more relevant for assessing human risk
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`(and deemed the most appropriate species), the HED for that species may be used in subsequent
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`calculations, regardless of whether this species is the most sensitive. This situation is more
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`applicable to biologic therapies, many of which have high selectivity for binding to human target
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`Contains Nonbinding Recommendations
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`proteins and limited reactivity in species commonly used for toxicity testing. In such cases, in
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`vitro binding and functional studies should be conducted to select an appropriate, relevant
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`species before toxicity studies are designed (refer to ICH guidance for industry S6 Preclinical
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`Safety Evaluation ofBiotechnology-Derived Pharmaceuticals for more details3). (However, if
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`serious toxicities are observed in an animal species considered less relevant, those toxicities
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`should be taken into consideration in determining the species to be used to calculate an HED.
`´²À¶Í·Ì»¾¸Ç»¹³¹¾ÀºÀ¹´³·»¼¸¾³À¹³¹·»¾»¼Ã³¹³¹µ¾²»´½»º³»´¾ÀÌ»¶´»·¾Àº¸Íº¶Í¸¾»¸¹ÜÝÁÈ
`For example, in one particular case, dog was selected as the animal species used for calculation
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`of an HED because of unmonitorable cardiac lesions, even though the rat was considered the
`Àʸ¹ÜÝÁÌ»º¸¶´»Àʶ¹ÃÀ¹³¾À¼¸ÌÍ»º¸¼·³¸ºÍ»´³À¹´Ò»Ï»¹¾²À¶µ²¾²»¼¸¾Ñ¸´ºÀ¹´³·»¼»·¾²»
`most relevant species based on pharmacological activity data.) Additionally, a species might be
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`considered an inappropriate toxicity model for a given drug if the dose-limiting toxicity in that
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`species was concluded to be of limited value for human risk assessment, based on historical
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`comparisons of toxicities in the animal species to those in humans across a therapeutic class (i.e.,
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`the dose-limiting toxicity is species-specific). In this case, data from that species should not be
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`used to derive the HED. Without any additional information to guide the choice of the most
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`appropriate species for assessing human risk, the most sensitive species is designated the most
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`appropriate, because using the lowest HED would generate the most conservative starting dose.
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`A safety factor should then be applied to the HED to increase assurance that the first dose in
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`humans will not cause adverse effects. The use of the safety factor should be based on the
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`possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than
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`predicted by the animal models, that bioavailability may vary across species, and that the models
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`tested do not evaluate all possible human toxicities. For example, ocular disturbances or pain
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`(e.g., severe headaches) in humans can be significant dose-limiting toxicities that may go
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`undetected in animal studies.
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`In general, one should consider using a safety factor of at least 10. The MRSD should be
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`obtained by dividing the HED by the safety factor. Safety concerns or design shortcomings
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`noted in animal studies may increase the safety factor, and thus reduce the MRSD further.
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`Alternatively, information about the pharmacologic class (well-characterized classes of
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`therapeutics with extensive human clinical and preclinical experience) may allay concerns and
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