Reviewer Guidance
 

Integration of Study Results to Assess
 

Concerns about
 

Human Reproductive and Developmental
 

Toxicities
 

DRAFT GUIDANCE 

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 120 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be 

identified with the docket number listed in the notice of availability that publishes in the Federal 

Register. 

For questions regarding this draft document contact Joseph J. DeGeorge, 301-594-5476. 

U.S. Department of Health and Human Services
 

Food and Drug Administration
 

Center for Drug Evaluation and Research (CDER)
 

October 2001
 

Pharmacology/Toxicology 

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Reviewer Guidance
 

Integration of Study Results to Assess
 

Concerns about
 

Human Reproductive and Developmental
 

Toxicities
 

Additional copies are available from: 

Drug Information Branch (HFD-210)
 

Center for Drug Evaluation and Research (CDER)
 

5600 Fishers Lane, Rockville, MD 20857, (Tel) 301-827-4570
 

Internet at 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)
 

October 2001
 

Pharmacology/Toxicology 

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TABLE OF CONTENTS
 

I. INTRODUCTION....................................................................................................................................................1
 

II. BACKGROUND.......................................................................................................................................................2
 

A. DATA NEEDED TO USE THE INTEGRATION PROCESS................................................................................................2
 

B. TYPES OF REPRODUCTIVE AND DEVELOPMENTAL TOXICITY EVALUATED ............................................................2
 

1. Reproductive Toxicities........................................................................................................................................3
 

2. Developmental Toxicities.....................................................................................................................................3
 

III. DISCUSSION.............................................................................................................................................................4
 

A. OVERALL DECISION TREE (FIG. A).........................................................................................................................5
 

1. Availability of Studies ..........................................................................................................................................5
 

2. Relevance of Studies.............................................................................................................................................5
 

3. Presence or Absence of a Signal.........................................................................................................................6
 

B. NO SIGNAL FOR A REPRODUCTIVE OR DEVELOPMENTAL TOXICITY (FIG. B).......................................................6
 

1. The Model’s Predictive Adequacy.......................................................................................................................7
 

2. Adequacy of Study Doses and Exposure .............................................................................................................7
 

3. Class Alert ............................................................................................................................................................8
 

4. Signals for Related Types of Reproductive and Developmental Toxicity.........................................................8
 

C. ONE OR MORE POSITIVE SIGNALS FOR A CLASS OF REPRODUCTIVE OR DEVELOPMENTAL TOXICITY (FIG. C)...8
 

1. Overview of the Integrative Process...................................................................................................................8
 

2. A Note on Intra- and Inter-Species Concordance ..............................................................................................9
 

a. Signal Strength, Part I ................................................................................................................................... 10
 

b. Signal Strength, Part II.................................................................................................................................. 11
 

c. Pharmacodynamics........................................................................................................................................ 13
 

d. Concordance between the Test Species and Humans.................................................................................. 14
 

e. Relative Exposures....................................................................................................................................... 15
 

f. Class Alerts.................................................................................................................................................... 17
 

g. Summary/Integration of Positive Findings ................................................................................................. 17
 

GLOSSARY...................................................................................................................................................................... 20
 

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1 Reviewer Guidance1 

2 

3 Integration of Study Results to Assess Concerns about 

4 Human Reproductive an 

5 

6 Developmental Toxicities 

7 

8 

9 

10 

11 

12 

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) 13 

14 current thinking on this topic. It does not create or confer any rights for or on any person and does

15 not operate to bind FDA or the public. An alternative approach may be used if such approach 

16 satisfies the requirements of the applicable statutes and regulations. 

17 

18 

19 

20 

21 

22 

23 I. INTRODUCTION 

24 

25 This draft guidance describes a process for estimating the increase in human 

26 developmental and reproductive risks as a result of drug exposure when definitive human 

27 data are unavailable. The overall approach integrates nonclinical information from a 

28 variety of sources (i.e., reproductive toxicology, general toxicology, and toxicokinetic 

29 and pharmacokinetic information, including absorption, distribution, metabolism and 

30 elimination findings) and available clinical information to evaluate a drug’s potential to 

31 increase the risk of an adverse developmental or reproductive outcome in humans. 

32 

33 The integration process focuses on the likelihood a drug will increase the risk of adverse 

34 human developmental or reproductive effects. It does not consider the nature (e.g., 

35 severity, reversibility or repairability) of the adverse response, or otherwise consider the 

36 clinical implications of the response. These risk management issues will be discussed in 

37 separate guidance on how to address the clinical implications of developmental and 

38 reproductive risks in product labeling. Because of inherent differences between drug and 

39 biological products, and resulting differences in the types of preclinical data collected for 

40 drug and biological products, the process described in this guidance will often not be 

41 useful in evaluating potential adverse reproductive or developmental effects for 

1

 This guidance has been prepared by the Office of Review Management in the Center for Drug Evaluation 

and Research (CDER) at the Food and Drug Administration (FDA). 

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42 biological products. However, the general principles described (i.e., a comprehensive 

43 analysis of available data) will typically be of some relevance to biological products.2 

44 

45 

46 II. BACKGROUND 

47 

48 A. Data Needed to Use the Integration Process 

49 

50 Ordinarily, the integration process should be based on an evaluation of a complete 

51 set of the expected general toxicology, reproductive toxicology, and 

52 pharmacokinetics studies.3 This evaluation should include an assessment of the 

53 ability of the drug to produce a positive finding in the relevant animal studies 

54 (e.g., whether doses used were large enough to induce toxicity of some kind). 

55 The evaluation should also compare animal and human pharmacodynamic effects, 

56 animal and human metabolism and disposition, animal and human pharmacologic 

57 and toxic effects, and drug exposures in animal studies in relation to the highest 

58 proposed dose in humans. 

59 

60 The type and extent of available toxicology data may vary depending on the 

61 biological actions of the product, test systems available for studying the 

62 compound, and other factors. In some cases, the data will not include all 

63 desirable general toxicology, reproductive toxicology, and pharmacokinetics 

64 studies. In some of those cases, it may still be possible to use the integration 

65 process without all the desired information. In other cases, limited available data 

66 will preclude the use of the integration process (e.g., often the case for biological 

67 products). Even if the integration process cannot be used, the product should be 

68 evaluated to the greatest extent possible in accordance with sound scientific 

69 principles and the considerations described in this document. 

70 

71 B. Types of Reproductive and Developmental Toxicity Evaluated 

72 

73 For purposes of this document, there are two broad categories of toxicity � 

74 reproductive and developmental toxicity — and, within those categories, seven 

75 classes of toxicity. In the reproductive toxicity category there are three classes of 

76 toxicity: toxic effects on fertility, parturition, and lactation. In the developmental 

77 toxicity category there are four classes of toxicity: mortality, dysmorphogenesis 

78 (structural alterations), alterations to growth, and functional toxicities. For a 

79 given drug, each class of toxicity should ordinarily be assessed. A positive signal 

80 in any class of reproductive or developmental toxicity, whether in valid 

2

 Although this is not a joint CDER/CBER guidance, CBER was consulted during guidance development. 

For more information, contact the Division of Clinical Trials Design and Analysis. 

3

 See the following International Conference on Harmonisation (ICH) guidances for industry: M3 

Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals; S3A 

Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies; S5A Detection of Toxicity to 

Reproduction for Medicinal Products; and S5B Detection of Toxicity to Reproduction for Medicinal 

Products: Addendum on Toxicity to Male Fertility. 

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81 reproductive or general toxicology studies or from human use studies, should be 

82 evaluated using the process described in this guidance to estimate the likelihood 

83 of increased reproductive or developmental risk for humans (see discussion of the 

84 integration process in Section III and schematic representation of the process in 

85 Figure C). 

86 1. Reproductive Toxicities 

87 

88 Reproductive toxicities include structural and functional alterations that 

89 may affect reproductive competence in the F0 generation. The three 

90 classes of reproductive toxicity include effects on fertility, parturition, and 

91 lactation. 

92 

93 • Fertility 

94 

95 Male reproductive toxicity associated with administration of a drug may 

96 be seen as degeneration or necrosis of the reproductive organs, reduction 

97 in sperm count, alterations to sperm motility or morphology, aberrant 

98 mating behavior, altered ability to mate, alterations to endocrine function, 

99 or overall reduction in fertility. 

100 

101 Female reproductive toxicity may be seen as damage to the reproductive 

102 organs, alterations to endocrine regulation of gamete maturation and 

103 release, aberrant mating behavior, altered ability to mate, or overall 

104 reduction in fertility. Diminished fertility in female animals is typically 

105 detected by reductions in the fertility index, the number of implantation 

106 sites, time to mating, or fecundity. 

107 

108 • Parturition 

109 

110 Toxicities affecting labor and delivery in animals may be seen as changes 

111 in the onset or duration of parturition. Changes in the duration of 

112 parturition are frequently reported as mean time elapsed per pup, or total 

113 duration of parturition. 

114 

115 • Lactation 

116 

117 Drugs administered to lactating animals may be a source of unwanted 

118 exposure in the nursing neonate, may alter the process of lactation in the 

119 nursing mother (e.g., the quality or quantity of milk), or may alter 

120 maternal behavior towards the nursing offspring. 

121 

122 2. Developmental Toxicities 

123 

124 Developmental toxicities are generally those that affect the F1 generation. 

125 The four classes of developmental toxicity are mortality, 

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126 dysmorphogenesis (structural alterations), alterations to growth, and 

127 functional toxicities. 

128 

129 • Mortality 

130 

131 Mortality due to developmental toxicity may occur at any time from early 

132 conception to post-weaning, (“embryo-fetal death” is a subset of mortality 

133 due to developmental toxicity). Thus, a positive signal may appear as pre134 or peri-implantation loss, early or late resorption, abortion, stillbirth, 

135 neonatal death or peri-weaning loss. 

136 

137 • Dysmorphogenesis (Structural alterations) 

138 

139 Dysmorphogenic effects are generally seen as malformations or variations 

140 to the skeleton or soft tissues of the offspring, and are commonly referred 

141 to as structural alterations. 

142 

143 • Alterations to Growth 

144 

145 Alterations to growth are generally seen as growth retardation, although 

146 excessive growth or early maturation may also be considered alterations to 

147 growth. Body weight is the most common measurement for assessing 

148 growth rate. Crown-rump length, and ano-genital distance may also be 

149 measured. 

150 

151 • Functional Toxicities 

152 

153 Functional toxicities could include any persistent alteration of normal 

154 physiologic or biochemical function, but typically only developmental 

155 neurobehavioral effects and reproductive function are measured. 

156 Common assessments include locomotor activity, learning and memory, 

157 reflex development, time to sexual maturation, mating behavior, and 

158 fertility. 

159 

160 

161 III. DISCUSSION 

162 

163 The complete data integration process is schematically presented in Figures A-C, 

164 which are attached to this document. To clarify the manner in which data should 

165 be passed through the integration process, the process has been divided into three 

166 components, which are discussed in the following sections A-C. Briefly, Figure 

167 A is applicable to all data-sets, while Figure B is applicable only to data-sets 

168 without evidence of reproductive or developmental toxicity. Figure C is 

169 applicable to data-sets with positive indications of reproductive or developmental 

170 toxicity. 

171 

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172 A. Overall Decision Tree (Figure A). 

173 

174 The decision tree process outlined in Figure A at the end of the document, should 

175 be used for each of the seven classes of reproductive or developmental toxicity 

176 discussed in Section II.B. For a given drug, studies may have been conducted to 

177 evaluate potential effects on none, some, or all of the classes of reproductive and 

178 developmental toxicity. Where studies are available for any of the different 

179 classes, the outcome may be one or more positive signals, or no signal. It is 

180 recognized that in practice one study may address several classes of toxicity and 

181 that a study may be considered adequate to evaluate all, some, or none of the 

182 classes of toxicity addressed. Figure A depicts the sequential decisions that 

183 should be made in evaluating the various situations that may be encountered and 

184 the next steps that should be taken where there are evaluable studies with positive 

185 or negative findings. 

186 

187 1. Availability of Studies 

188 

189 In Figure A, the first question that should be asked for each class of 

190 toxicity is: "Were studies performed that are relevant to an assessment of 

191 the risk of that class of reproductive or developmental toxicity in humans 

192 and are the detailed study results available for comprehensive evaluation?" 

193 

194 If no studies were conducted, or detailed study results are unavailable for 

195 comprehensive evaluation, the review should explain that studies adequate 

196 to assess the risk of that class of toxicity were not done, or are otherwise 

197 unavailable. In such circumstances, risk to humans is considered unknown 

198 or not evaluable and the product labeling should reflect that conclusion: 

199 

200 Example: The risk of [class of reproductive or developmental 

201 toxicity] with [Drug X] is unknown. There are no data to 

202 evaluate its potential to cause [class of reproductive or 

203 developmental toxicity]. 

204 

205 If studies were conducted and are available for comprehensive evaluation, 

206 the assessment process should continue with question 2. 

207 

208 2. Relevance of Studies 

209 

210 The next question that should be asked for each class of toxicity is: "Do 

211 the studies done provide information relevant to assessing the risk of that 

212 type of reproductive or developmental toxicity for the proposed human 

213 use?" If the test system was not relevant, the review should explain why 

214 the studies were not relevant or otherwise appropriate (i.e., inappropriate 

215 test protocol or species, nonrelevant route of drug administration4) and 

4

 This may also apply to information from humans in which the route is inappropriate to provide relevant 

information for the clinical indication. 

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216 should discuss all supporting information that bears on study relevance. If 

217 the test system was not relevant, the risk to humans is considered unknown 

218 or not evaluable and the product labeling should reflect that conclusion: 

219 

220 Example: The risk of [class of reproductive or developmental 

221 toxicity] with [Drug X] is unknown. There are insufficient 

222 data to evaluate its potential to cause [class of reproductive or 

223 developmental toxicity]. 

224 

225 If the studies conducted are relevant to evaluating the risk of the particular 

226 class of toxicity in humans, the risk integration process should continue 

227 with question 3. Note that the processes in Figures B and C (see end of 

228 document) are intended to be used only when studies are considered 

229 adequate to assess the specified risk. They should not be used to evaluate 

230 findings (positive or negative) derived from inadequate studies. 

231 

232 3. Presence or Absence of a Signal 

233 

234 If the test system is relevant and appropriate for assessing the risk of 

235 toxicity in humans, the next question that should be asked for each class of 

236 toxicity is “Was there a positive signal (suggesting toxicity)?” If no signal 

237 was seen, the evaluation process should continue per Section B (Figure B 

238 at end of document). If a positive signal was seen, the evaluation process 

239 should continue per Section C (Figure C at end of document). 

240 

241 B. No Signal (Figure B) 

242 

243 Where there is no positive signal for one of the seven classes of reproductive or 

244 development toxicity, the risk assessment should be a step-wise process leading to 

245 a recommendation about the relevance of the nonfinding in humans. A graphic 

246 representation of this process is presented in Figure B (see end of document). 

247 

248 If multiple studies are available to assess a class of reproductive or developmental 

249 toxicity (e.g., multiple studies would be expected for the evaluation of 

250 dysmorphogenic effects - ICH stage C), the process in Figure B should be used 

251 only if the results of all studies relevant to a particular class of reproductive or 

252 developmental toxicity are negative for that type of toxicity. If any study (general 

253 toxicity, reproductive, or developmental toxicology study) has a positive signal 

254 for that class of reproductive or developmental toxicity, the process in Section C 

255 (Figure C) should be used.5 

256 

257 The following four factors should be considered during the evaluation of each 

258 class of reproductive or developmental toxicity for which there was no signal. 

259 

5

 Studies with conflicting signals and inter-study concordance and nonconcordance are addressed in 

Section C. 

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260 1. The Model/Test Species Predictive Adequacy 

261 

262 To what extent are the models or test species used likely to be predictive 

263 of human response? The following questions bear on the determination of 

264 a model’s predictive adequacy. 

265 

266 • Do any of the models or test species (or systems) demonstrate or have 

267 the capability of responding to the pharmacodynamic effect(s) of the 

268 drug? 

269 

270 • Do any of the model/test species (or systems) demonstrate an overall 

271 toxicity profile that is relevant to the human toxicity profile? 

272 

273 • Do any of the model/test species (or systems) demonstrate 

274 pharmacokinetic (including ADME) profiles for the drug that are 

275 qualitatively similar to those in humans? 

276 

277 If the responses to these questions suggest that the response of the test 

278 species is of little relevance to humans, the review should explain why the 

279 animal study or studies conducted with the drug may not be fully adequate 

280 to evaluate the risk for the particular class of toxicity in humans (i.e., why 

281 the test may have low predictive value). Even if the test system is 

282 determined to be of limited relevance, the review should consider the 

283 remaining factors (2-4 below) and describe any additional uncertainties. 

284 

285 2. Adequacy of Study Doses and Exposure 

286 

287 The following elements should be considered in assessing the relevance to 

288 humans of the drug doses and exposure in the test system: 

289 

290 • Were adequate doses (concentrations) of the drug administered to the 

291 test species or test systems (e.g., MTD, MFD)? 

292 

293 • Were the exposures (based on AUC, Cmax, or other appropriate 

294 systemic exposure metric) achieved in the test species or test systems 

295 adequate relative to those demonstrated in humans at the maximum 

296 recommended human dose? 

297 

298 If the answer to either of these questions is no, the evaluation should state 

299 that the animal studies conducted may be inadequate to fully evaluate the 

300 risk for the particular class of toxicity reported to be negative and explain 

301 in detail why they may be inadequate. Even if the study doses and 

302 exposure are considered inadequate, the evaluation should proceed to the 

303 remaining sections (3-4 below), and any additional uncertainties should be 

304 described. 

305 

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306 3. Class Alert 

307 

308 Class alerts should be based on adverse reproductive or developmental 

309 effects previously demonstrated in humans by closely related chemical 

310 entities or compounds with similar pharmacodynamic effects. If there is a 

311 Class Alert for the drug, based on a related chemical structure of parent or 

312 metabolite or related pharmacologic effect, the class-specific information 

313 relevant to the class of toxicity reported to be negative should be included 

314 in the risk evaluation and discussion of the drug. The basis for the class 

315 alert for adverse effects in humans should be reasonably applicable to the 

316 drug being evaluated. 

317 

318 4. Signals for Related Types of Reproductive and Developmental 

319 Toxicity 

320 

321 The next step in evaluating the relevance of a no signal finding for a 

322 particular class of reproductive or developmental toxicity is to assess 

323 findings for related reproductive and developmental toxicities. A positive 

324 signal for one class of toxicity may suggest some risk in humans for other 

325 toxicities in the same category for which there were no findings in 

326 animals. The issue of related toxicities is most relevant for developmental 

327 toxicities. For example, if there is no signal for fetal mortality, but a 

328 positive signal for alterations to growth or dysmorphogenesis in one (or 

329 more) animal species, it may be inappropriate to conclude there is no risk 

330 of fetal mortality for humans. Related toxicities may also be relevant for 

331 reproductive toxicities where a hormonal mechanism is identified, the 

332 mechanism could be relevant to multiple aspects of reproductive 

333 performance, and the mechanism is relevant to humans. 

334 

335 If positive signals for related classes of toxicity were observed in the 

336 animal studies, the evaluation should state that there was no observed 

337 effect on the type of toxicity being assessed, but positive signals were seen 

338 for related toxicities. If there is no positive signal for any class of 

339 reproductive or developmental toxicity, the evaluation should state that 

340 there is no expected increase in risk for reproductive or developmental 

341 toxicity in humans based on the results of animal studies. 

342 

343 C. One or More Positive Signals (Figure C) 

344 

345 1. Overview of the Integrative Process 

346 

347 There are six factors that may affect the level of concern for a positive 

348 signal in any of the classes of reproductive or developmental toxicity: (1) 

349 signal strength part I, (2) signal strength part II, (3) pharmacodynamics, 

350 (4) concordance (metabolic and toxicologic concordance to the human); 

351 (5) relative exposure; and (6) class alerts. As described in more detail 

352 below, the integration tool considers signal strength in two different ways, 

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353 so signal strength is treated as two separate factors. Each factor has 

354 several contributory elements. The outcomes of the analyses of these six 

355 factors are used in the six columns in the integration tool (see Figure C). 

356 Human data may be considered separately from nonclinical findings and 

357 may greatly influence the overall assessment of human risk of 

358 reproductive or developmental toxicity. 

359 

360 The overall integrative analysis begins with a positive signal in a class of 

361 reproductive or developmental toxicity in one or more of the examined 

362 species. The positive signal may be from a reproductive or developmental 

363 toxicology study or an effect observed on a reproductive tissue, system, or 

364 behavior in a general toxicology study. Each of the six factors should be 

365 analyzed independently. Guidance is provided on what types of 

366 observations for each of the six factors might increase, decrease, or leave 

367 unchanged the level of concern for that factor. These analyses should not 

368 be an arithmetic summation of the contributing elements within each 

369 factor, but a weighted integration that takes into account the quality and 

370 nature of the data under consideration. The assessments of concern for 

371 each of the six factors should be assigned values of +1, -1 or 0, 

372 respectively, if the factor is perceived as increasing, decreasing, or leaving 

373 unchanged the level of concern for a class of reproductive or 

374 developmental toxicity. Conclusions from the six analyses should be 

375 summed to arrive at a comprehensive evaluation of the potential increase 

376 in risk for each class of the seven reproductive or developmental classes 

377 for which there was a positive signal. 

378 

379 2. A Note on Intra- and Inter-Species Concordance 

380 

381 Intra- and interspecies concordance of adverse effects in animals deserves 

382 some special consideration in this risk integration process. Positive 

383 signals in related types of reproductive or developmental toxicity within 

384 the same species indicates intra-species concordance of effects (e.g., a 

385 reduction in normal growth and an increase in developmental mortality). 

386 Positive signals for the same or a related type of toxicity across species 

387 indicates interspecies concordance. In general, findings for which there is 

388 intra- or interspecies concordance are more convincing than a positive 

389 signal in only one toxicity class in only a single species. 

390 

391 In evaluating potential human risk for adverse reproductive or 

392 developmental outcomes, if there is interspecies concordance for a single 

393 adverse effect it may be reasonable to conclude that a similar effect is the 

394 most likely adverse event to be seen in humans treated with the drug. If 

395 different but related adverse effects are seen in multiple test species (e.g., 

396 alterations to growth in one species and developmental mortality in 

397 another, or parturition effects in one species with lactation effects in the 

398 second), it may be reasonable to assume there is some level of risk for 

399 categorically related endpoints in humans. 

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400 

401 A detailed discussion of the overall integrative analysis, the six 

402 individual factors, the contributory elements for each factor, and the 

403 assignment of the level of concern for each factor is presented in 

404 Sections 1-6. 

405 

406 a. Signal Strength, Part I 

407 

408 For the first signal strength factor, a positive signal in any reproductive 

409 or developmental toxicity class should be analyzed with respect to 

410 three contributory elements that examine whether the finding is 

411 present in more than one setting: (a) whether there is cross-species 

412 concordance (where more than one species has been studied), (b) 

413 whether there is multiplicity of effects, and (c) whether adverse effects 

414 are seen at more than one time. 

415 

416 Cross-Species Concordance 

417 

418 The defining characteristic of cross-species concordance is a 

419 positive signal in the same class of reproductive or developmental 

420 toxicity in more than one species. Cross-species concordance is 

421 most likely to be identified for structural abnormalities 

422 (dysmorphogenesis) or developmental mortality because these 

423 toxicities are frequently detected in the organogenesis testing 

424 paradigm, in which multiple species are typically evaluated. In 

425 addition, alterations to endocrine function or gonadal 

426 histopathology (which may alter fertility) may be indirectly 

427 detected in subchronic and chronic toxicity studies in rodents and 

428 nonrodents. When cross-species concordance is observed, there is 

429 increased concern for reproductive or developmental toxicity in 

430 humans. In contrast, there is decreased concern when a signal is 

431 detected in only one species (with the proviso that the negative 

432 species is an appropriate animal model and the studies were 

433 adequate in design, dosing, and implementation). 

434 

435 For alterations to parturition or lactation, it’s often not possible to 

436 assess cross-species concordance because peri- and postnatal studies to 

437 assess these classes of toxicity are usually done in only a single 

438 species. 

439 

440 Multiplicity of Effects 

441 

442 Multiplicity of effects refers to observation, in a single species or 

443 animal model, of two or more positive signals within one of the two 

444 general categories of toxicity (reproductive or developmental ) or 

445 within one of the seven classes of reproductive or developmental 

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446 toxicities. The observation of increased embryo-fetal death and 

447 structural abnormalities (dysmorphogenesis) in an animal test species 

448 is an example of multiple positive signals within a general category. 

449 The observation of two or more positive signals for structural 

450 abnormalities in tissues of multiple embryonic origin (e.g., defects 

451 affecting soft tissue, skeletal tissue, and/or neural tissue) is an example 

452 of multiple positive signals in a toxicity class. 

453 

454 If all species examined demonstrate multiplicity of effects, there is 

455 increased concern for reproductive or developmental toxicity in 

456 humans. If there are positive signals in two or more species, but 

457 multiplicity of effects is observed in only one species, concern is 

458 unchanged for this element. If no species studied exhibits multiplicity 

459 of effects, there is decreased concern. 

460 

461 Adverse Effects at Different Stages 

462 of the Reproductive or Developmental Process 

463 

464 Evidence of toxicity may arise during any stage of the reproductive or 

465 development process. For example, developmental mortality may be 

466 reported as early or late resorptions, abortions, or stillbirths. If a positive 

467 signal in animals is observed in multiple stages of development, there is 

468 generally greater concern for adverse human reproductive outcomes. If a 

469 positive signal is observed only during a single, discreet interval, the level 

470 of concern is unchanged. If the positive signal occurs only during 

471 processes that are of limited relevance to humans (rare), there would be 

472 less concern for adverse human reproductive outcomes. In addition to its 

473 relevance to this evaluation process, it is also important to define the 

474 timing of the period of susceptibility for the observed positive signal to 

475 provide a context for the human risk. 

476 

477 b. Signal Strength, Part II 

478 

479 In assessing the second signal strength factor, a positive signal should be 

480 analyzed with respect to the following three contributory elements: (a) co481 existence of maternal toxicity, (b) presence of a dose-response 

482 relationship, and (c) the observation of rare events. 

483 

484 Maternal Toxicity 

485 

486 In weighing a signal of toxicity, the magnitude of adverse effects in 

487 the offspring versus the severity of maternal (and, for fertility studies, 

488 paternal) toxicity should be considered when drawing a conclusion 

489 about the relevance of the F0 toxicity to effects observed in the 

490 offspring. This assessment is relevant to all seven classes of 

491 reproductive and developmental toxicity. A positive signal occurring 

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492 at doses that are not maternally toxic increases concern for human 

493 reproductive or developmental toxicity. If a positive signal is 

494 observed only in the presence of frank maternal toxicity, there is 

495 decreased concern, provided that the positive signal may be reasonably 

496 attributed to maternal toxicity. 6 

497 

498 When evaluating a positive signal in two or more species, 

499 assessment of the implications of maternal or paternal toxicity 

500 should be based on a composite analysis of the data from all 

501 adequately studied species. If a positive signal is seen in two 

502 or more species in the absence of maternal toxicity, there is 

503 increased concern for adverse human reproductive outcomes. 

504 If a positive signal is seen only in the presence of clear relevant 

505 maternal toxicity in multiple species, there is decreased 

506 concern. If there is nonconcordance between test species as to 

507 the presence and relevance of maternal toxicity, there may be 

508 no change in the overall level of concern for this contributory 

509 element. 

510 

511 If any species is considered inappropriate to assessing the 

512 implications of maternal or paternal toxicity, the evaluation 

513 should be performed using the remaining available data. 

514 

515 Dose-Response Relationship 

516 

517 Concern for human reproductive or developmental toxicity is 

518 increased when a positive signal is characterized by any of the 

519 following: (1) increased severity of adverse effects with an 

520 increase in dose, (2) increased incidence of adverse effects with 

521 an increase in dose, or (3) a high incidence of adverse effects 

522 across all dosed groups. Conversely, the absence of all three of 

523 these indicia of dose-response would be cause for unchanged 

524 or decreased concern. 

525 

526 If multiple species are evaluated, a clear dose response across 

527 all tested species increases concern. If a positive signal occurs 

528 in more than one species, only one of which demonstrates one 

529 of the dose-response relationships described above, the level of 

530 concern will generally be unchanged. If there is no dose531 response in any species, there is decreased concern for this 

532 contributory element. 

533 

534 Rare Events 

535 

6

 The attribution of adverse fetal effects to maternal (or paternal) toxicity can be based on previously 

collected data demonstrating the relationship between the maternal/paternal and reproductive effects. 

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536 Developmental toxicity studies usually lack the statistical power to 

537 detect subtle increases in rare events. Thus, an increased frequency of 

538 positive signals for rare events in drug-exposed animals increases 

539 concern for reproductive or developmental toxicity in humans. The 

540 absence of an increased frequency of rare events, however, does not 

541 decrease concern. 

542 

543 When multiple species (more than two) are studied, an increased 

544 frequency of positive signals for rare events in more than one species 

545 increases concern for adverse outcomes in humans even if not all 

546 species have an increased frequency of positive signals. 

547 

548 c. Pharmacodynamics 

549 

550 A positive signal should be analyzed with respect to the following 

551 three pharmacodynamic elements: (a) the therapeutic index, (b) 

552 biomarkers as a benchmark, and (c) the similarity between the 

553 pharmacologic and toxicologic mechanisms. 

554 

555 Therapeutic Index (TI) 

556 

557 The TI is used to identify the extent to which there is overlap 

558 between therapeutic doses and doses that cause reproductive or 

559 developmental toxicity. It is unusual to obtain well-defined dose560 response curves for toxicity and efficacy from a single species. 

561 Thus, the use of estimations or surrogate endpoints (related to the 

562 therapeutic mechanism) for this evaluation may be warranted. To 

563 reduce the impact of variation in the slope of the dose-response 

564 curves, estimation of the TI should generally be based on 

565 comparison of the TD10 and the ED90 concentrations.7 

566 

567 If the TI10/90 is < 5, there is increased concern for reproductive or 

568 developmental toxicity in humans, as there is limited separation in the 

569 doses causing adverse effects from those responsible for efficacy. If 

570 the TI10/90 ratio falls between 5 and 20, the level of concern is 

571 unchanged. If the TI10/90 ratio is > 20, there is decreased concern 

7

 The TD10 (toxic dose or concentration) should be defined by the Cmax (or other appropriate exposure 

metric) that produced the toxic reproductive or developmental response in 10% of a responsive or sensitive 

species, whereas the ED90 (efficacious dose or concentration) should be defined by the Cmax (or other 

appropriate exposure metric) that produced the desired effect in 90% of the test species. These parameters 

can be estimated. Preferably, both the TD10 and ED90 would be defined in the same species. In some 

instances estimation of the ED90 can be based on in vitro cell inhibition studies (frequently seen for 

antibiotics and antineoplastic agents). Although less desirable, efficacy data can be derived from another 

species, but caution should be exercised in such situations. The same exposure metric should be used in the 

estimation of the TD10 and ED90 values. Scientific justification for the drug exposure metrics used for 

comparison should be provided. 

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572 because of the wide separation in doses causing adverse effects from 

573 those resulting in efficacy. 

574 

575 If there are data available to determine the TI10/90 ratio in multiple 

576 species, assessment of the level of concern for this element should 

577 be based on an integrated analysis of data from all adequately 

578 studied species. The extent of concordance in the size of the TI10/90 

579 between species may increase, decrease, or leave unchanged the 

580 level of concern (i.e., the greater the concordance, the more likely 

581 concern will be increased). In the event of nonconcordance of the 

582 TI ratios between multiple test species, the nature of the positive 

583 signals observed and the relevance of the endpoint and test species 

584 to the human condition should be considered before making an 

585 assessment. In the event that one species is considered 

586 inappropriate to the analysis, the evaluation should be performed 

587 without reference to that species. 

588 

589 Biomarkers as a Benchmark 

590 

591 There may be circumstances in which an effect on a biomarker is 

592 consistently seen in multiple species at doses lower than the NOEL for 

593 demonstrable reproductive/developmental toxicity. If there is an effect 

594 on this biomarker at or below the therapeutic dose in humans, there is 

595 increased concern for reproductive or developmental toxicity in 

596 humans. If this biomarker is responsive to the drug in humans, can be 

597 monitored, and is not affected at the therapeutic dose, there may be 

598 decreased concern. 

599 

600 Similarity between Pharmacologic and 

601 Reproductive Developmental Toxicologic Mechanisms 

602 

603 If a positive signal is an extension of, progression of, or related 

604 response to the intended pharmacologic effect of the drug (e.g., delay 

605 of parturition by drugs known to suppress uterine smooth muscle 

606 contractility or hypotension in the offspring of dams treated during late 

607 gestation with a drug known to lower blood pressure), there is 

608 increased concern for reproductive or developmental toxicity in 

609 humans. There is less concern if the positive signal is attributed to an 

610 animal-specific pharmacological response, even though it may be an 

611 extension of the pharmacologic effect of the drug (e.g., pregnancy loss 

612 in rats due to hypo-prolactinemia). 

613 

614 d. Concordance between the Test Species and Humans 

615 

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616 Concordance between the test species and humans should be evaluated 

617 with respect to: (a) the metabolic and drug distribution profiles, and (b) 

618 the general toxicity profiles, and (c) biomarker profiles. 

619 

620 Metabolic and Drug Distribution Profiles 

621 

622 Drug distribution, elimination, and biotransformation (pathways and 

623 metabolites) in the test species and in humans should be compared. 

624 Quantitative differences in metabolic/drug distribution profiles 

625 between the test species and humans are often seen, and may not have 

626 important implications and should not be overemphasized. 

627 Reproductive and developmental toxicities induced by compounds 

628 whose metabolic and distribution profiles are very similar in animals 

629 and humans increases concern for reproductive or developmental 

630 toxicity in humans. For compounds with highly dissimilar metabolic 

631 or tissue distribution profiles in animals and humans, there is less 

632 concern if the toxic effect seen in the test species can be attributed to a 

633 metabolite or tissue distribution profile not seen in humans. For any 

634 other scenario, concern is unchanged. 

635 

636 When there are significant differences in drug distribution or metabolic 

637 profiles between several species, yet each test species demonstrates a 

638 positive signal for a reproductive or developmental toxicity, the toxicity is 

639 assumed to be attributable to the parent drug or a common bio640 transformed product and concern is increased. 

641 

642 General Toxicity Profiles 

643 

644 If the overall toxicity profile of a drug in one or more test species with 

645 a positive signal is similar to that in humans, there is increased concern 

646 for reproductive or developmental toxicity in humans. If the overall 

647 toxicity profiles are dissimilar, there may be decreased concern. When 

648 general toxicology data are available for more than one species, the 

649 determination of the level of concern (increased, decreased, or 

650 unchanged) should be based on an assessment of each test species’ 

651 ability to indicate human adverse effects in response to the drug. 

652 

653 Biomarker Profiles 

654 

655 When biomarker profiles are available for comparison, an approach 

656 similar to that described in the assessment of General Toxicity Profiles 

657 (previous section) may be useful. 

658 

659 e. Relative Exposures 

660 

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661 When considering the relative exposure comparisons discussed below, 

662 more emphasis should be placed on a parameter within this factor 

663 when there is a scientifically plausible link between the exposure 

664 metric (or biomarker) and the adverse reproductive (or developmental) 

665 effect. 

666 

667 Kinetic Comparison of Relative Exposure 

668 

669 Comparison of systemic drug exposure at the NOEL for the 

670 reproductive or toxicity class in the test species to that in humans at 

671 the maximum recommended dose is a critical determination. This 

672 comparison should be based on the most relevant metric (e.g., AUC, 

673 Cmax, Cmin, BSA [body surface area] adjusted dose). In general, there 

674 is increased concern for reproductive or developmental toxicity in 

675 humans for relative exposure ratios (animal:human) that are <10, 

676 decreased concern for exposure ratios >25, and no change in concern 

677 for ratios between 10 and 25. When applicable, the relative exposure 

678 ratio should consider both the parent compound and its metabolites. 

679 For example, it is appropriate to combine parent and metabolite when 

680 both are pharmacologically active and the activity relates to the 

681 reproductive or developmental toxicity. 

682 

683 Where there are exposure data for multiple test species, the NOEL 

684 exposure for each should be compared to human exposure at the 

685 maximum recommended dose. If the exposure ratios are low (<10 fold) in 

686 multiple species with a positive signal, there is increased concern. If the 

687 exposure ratios are high (>25 fold), there is decreased concern. In the 

688 event a significant difference in relative exposures is observed between 

689 multiple test species, the appropriateness of the metric (for example, AUC, 

690 Cmax) being used to define the inter-species exposure comparisons should 

691 be re-assessed. If an alternative metric fails to reduce the disparity 

692 between species, the assessment of concern should be based on the lowest 

693 ratio (i.e., in the most sensitive species). 

694 

695 Relative interspecies exposure data should be evaluated in light of species 

696 differences in protein binding (free drug concentration), receptor affinity 

697 (if related to the positive signal) or site specific drug concentrations. In the 

698 absence of meaningful differences between the test species and humans in 

699 these parameters, the interspecies comparisons should be based on total 

700 drug exposure. 

701

702 Biomarkers as a Measure of Relative Exposure 

703 

704 The purpose of this relative exposure metric is to compare the dose 

705 causing a reproductive toxic effect in the test species to the 

706 therapeutic dose in humans, normalized to the doses causing a 

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707 response common to both species. In practice, this is done by 

708 taking the NOEL for the adverse reproductive or developmental 

709 effect and dividing by the dose at which the biomarker response is 

710 seen in the test species. This is compared to the human therapeutic 

711 dose divided by the dose at which the biomarker response is seen 

712 in the human. The ratio calculated for animals is then divided by 

713 the ratio calculated for humans. When this ratio of relative 

714 biomarker exposure (animal:human) is < 10, there is increased 

715 concern for human reproductive or developmental toxicity. When 

716 this ratio is > 25, there is less concern. When this ratio falls 

717 between 10 and 25, the level of concern is unchanged. 

718 

719 Where there are data to compute relative biomarker exposure ratios 

720 for multiple species, the level of concern assessment should be 

721 based on an integrated analysis of data from all adequately studied 

722 species. Where there are nonconcordant biomarker ratios between 

723 multiple test species, the relevance of the biomarker as expressed 

724 in the various species should be considered before making an 

725 assessment. If there is no scientific rationale for the disparity 

726 between species, the biomarker, as a measure of exposure, will be 

727 of questionable utility. 

728 

729 f. Class Alerts 

730 

731 Consideration of a class associated effect should be based on prior human 

732 experience for a drug with related chemical structure (parent or 

733 metabolite) or related pharmacologic effect, and with known reproductive 

734 or developmental outcomes in humans. There is increased concern for 

735 reproductive or developmental toxicity in humans when the drug is from a 

736 class of compounds known to produce adverse effects in the same toxicity 

737 class in humans and animals. There is decreased concern only in 

738 circumstances in which a class of compounds, although demonstrating 

739 adverse effects in animals, has been previously shown to have no related 

740 adverse effects on human reproduction or development. In the absence of 

741 adequate human reproduction or developmental data for a class, the level 

742 of concern is unchanged. 

743 

744 g. Summary/Integration of Positive Findings 

745 

746 Notes on the use of the Integration Tool (see Figure C end of 

747 document): 

748 

749 The factors discussed below are derived from a limited sample of 

750 pharmaceuticals where the clinical outcomes are reasonably well 

751 defined. CDER believes that using specific factors and benchmark 

752 values to assess the potential to increase risk to humans for adverse 

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753 reproductive and developmental outcomes will result in a more 

754 unbiased and uniform evaluation. CDER also believes this approach 

755 will help identify specific areas of additional information about a 

756 pharmaceutical that would be useful in more fully defining risk and 

757 allow specific analysis of areas of disagreement that influence the risk 

758 evaluation. 

759 

760 1. Where there is a positive finding in nonclinical or general 

761 toxicology studies for one of the seven classes of reproductive or 

762 developmental toxicity, there is a potential for increased human 

763 risk. In evaluating the level of increased risk, positive findings 

764 from each of the seven classes of reproductive and developmental 

765 toxicity should be assessed separately. All relevant information 

766 should be considered. 

767 

768 2. In evaluating the level of concern for each of the six factors in the 

769 overall assessment, the analysis should reflect the weight of 

770 evidence taking into account the quality and type of data under 

771 consideration for each factor (i.e., should not be merely an 

772 arithmetic summation of the contributory elements for each factor). 

773 For each factor there should be a determination of increased (+1), 

774 decreased (-1), or no change (0) in the level of concern. 

775 

776 3. The values for the six factors should then be summed to arrive at 

777 one of the following overall conclusions for each class of 

778 reproductive or developmental toxicity: (1) the drug is predicted to 

779 increase risk, (2) the drug may increase risk, or (3) the drug does 

780 not appear to increase risk of that class of reproductive or 

781 developmental toxicity in humans. Where there is sufficient 

782 information about the drug to assess each of the six factors within 

783 Figure C, a net value of > +3 suggests a drug is predicted to 

784 increase risk for that class of toxicity in humans, a value between 

785 +2 and –2 suggests that the drug may increase the risk, and a value 

786 < -3 suggests the drug does not appear to increase the risk. 

787 

788 

789 The summary risk conclusions for the outcomes of analyses using 

790 Figure “C” are: 

791 

792 Does Not Appear to Increase Risk: The drug is not anticipated to 

793 increase the incidence of adverse reproductive (or developmental) effects 

794 above the background incidence discussed in humans when used in 

795 accordance with dosing information in the product label. 

796 

797 May Increase Risk: The drug may increase the incidence of adverse 

798 reproductive (or developmental) events above the background incidence in 

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799 humans when used in accordance with the dosing information in the 

800 product label. 

801 

802 Predicted to Increase Risk: The drug is expected to increase the 

803 incidence of adverse reproductive (or developmental) events above the 

804 background incidence in humans when used in accordance with the dosing 

805 information in the product label. 

806 

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807 

808 GLOSSARY 

809 

810 ADME - absorption, distribution, metabolism, and elimination 

811 

812 Biomarker - a clinical or laboratory parameter that is known, or thought, to correlate 

813 with a toxicity outcome or with exposure 

814 

815 Class Alert – an adverse reproductive or developmental effect previously demonstrated 

816 in humans by closely related chemical entities or compounds with similar 

817 pharmacodynamic effects 

818 

819 Contributory Elements - specific items of information that contribute to the overall 

820 evaluation and conclusion for each factor of Figure C 

821 

822 Developmental Toxicity - any adverse effect induced prior to attainment of adult life. It 

823 includes effects induced or manifested in the embryonic or fetal period and those induced 

824 or manifested postnatally. These are generally adverse effects that affect the F1 

825 generation and are divided into four endpoints, mortality, dysmorphogenesis, alterations 

826 to growth, and functional toxicities. 

827 

828 Factor – for purposes of this guidance, a factor is one of the six components used to 

829 evaluate the level of concern for a positive signal in a class of developmental or 

830 reproductive toxicity to determine whether there is an increase (assigned value of +1), a 

831 decrease (-1), or no change (0) in the overall concern for that class of toxicity. There are 

832 six factors: (1) signal strength, part I; (2) signal strength, part 2; (3) pharmacodynamics; 

833 (4) concordance between the test species and humans; (5) relative exposures; and (6) 

834 class alerts. They are all portions of the Integration Tool (Figure C) and are discussed in 

835 Section 4. 

836 

837 Fertility – reproductive competence 

838 

839 Lactation - the secretion of milk or the period of milk secretion 

840 

841 Malformation - a permanent alteration (anomaly) in which there is a morphologic defect 

842 of an organ or a larger region of the body, resulting from an abnormal developmental 

843 process. They generally occur at a low frequency in the control population and/or will 

844 adversely affect survival, growth, or development of functional competence. 

845 

846 Maternal (Paternal) Toxicity – toxicity to the mother (maternal) or the father (paternal) 

847 in a reproductive toxicology study, but not necessarily a toxicity to reproductive function 

848 

849 Parturition – labor and delivery 

850 

851 Positive Signal - a treatment related reproductive or developmental toxicity 

852 

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853 Rare Event – an endpoint that occurs in less than 1 percent of the control animals in a 

854 study and in historical control animals 

855 

856 Reproductive Toxicity - structural and/or functional alterations that may affect 

857 reproductive competence of the F0 generation. These are divided into three classes� 

858 fertility, parturition, and lactation. 

859 

860 Therapeutic Index - for the purpose of this document, the ratio of the dose that induces 

861 a toxicologic effect in approximately 10 percent of the treated animals (TD10) compared 

862 to the dose that brings about the intended result of the therapeutic in 90 percent of the 

863 treated animals (ED90) 

864 

865 Toxicologic Effect - any adverse effect of a therapeutic 

866 

867 Variation - an alteration that may occur at a relatively high frequency and/or represents a 

868 retardation in development, a transitory alteration, or a permanent alteration not believed 

869 to adversely affect survival, growth, development, or functional competence. 

870 

871 

872 

873 

874 

875 

876 

877 

878 

879 

880 

881 

882 

883 

884 

885 

886 

887 

888 

889 

890 

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891 APPENDIX A 

892 

893 

894 SAMPLE SCENARIOS AND RISK CONCLUSIONS FOR SITUATIONS IN 

895 WHICH THERE ARE NO POSITIVE FINDINGS FOR A CLASS OF 

896 REPRODUCTIVE OR DEVELOPMENTAL TOXICITY 

897 (ASSESSMENTS USING FIGURE B) 

898 

899 

900 Case 1. The animal species and dose selections were considered appropriate, there 

901 is no class alert for the drug, and no positive signals were observed for any class 

902 of developmental toxicity. 

903 

904 Summary Risk Conclusion 1. Based on studies in animals, there does not appear 

905 to be an increased risk for adverse developmental effects in humans. 

906 

907 Case 2. No positive signals were observed for any class of reproductive toxicity 

908 and there are no human data for the drug. However, other drugs in the same 

909 pharmacologic class have demonstrated adverse reproductive effects in humans 

910 (i.e., a class alert). 

911 

912 Summary Risk Conclusion 2. The risk for adverse reproductive effects in humans 

913 is unknown. Although no effects were observed in adequately conducted 

914 reproductive toxicity studies in animals, and there is no information about adverse 

915 reproductive effects of the drug in humans, adverse reproductive effects have 

916 been observed in humans with related drugs. (should specify the type of adverse 

917 effects observed in humans with other members of the class and the basis for the 

918 class designation�e.g., chemically or pharmacologically related ). 

919 

920 Case 3. The available developmental toxicity studies are considered to lack 

921 predictive value because exposures to the drug in animal studies conducted at the 

922 MTD were not considered adequate when compared to the maximum exposure in 

923 humans. 

924 

925 Summary Risk Conclusion 3. The risk for adverse developmental effects in 

926 humans is unknown. Although there were no observed adverse developmental 

927 effects in adequately conducted toxicity studies in animals, exposures achieved in 

928 the animal studies may not have been adequate to fully evaluate the potential for 

929 the drug to increase the risk of reproductive or developmental toxicity in humans. 

930 

931 Case 4. The animal models were not considered adequate to test the drug because 

932 the test species in the reproductive toxicity studies lacked the cellular receptor 

933 responsible for the pharmacologic activity of the drug in humans, or did not 

934 demonstrate a toxicity or metabolite profile similar to that in humans. 

935 

936 

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937 Summary Risk Conclusion 4. The risk for adverse reproductive effects in humans 

938 is unknown. Although there were no observed adverse effects in animal 

939 reproductive toxicity studies, there remains some concern for increased risk of 

940 adverse reproductive effects in humans exposed to the drug because the test 

941 species may not be predictive of the human condition. 

942 

943 Case 5. In animal studies considered appropriate for predicting the human 

944 response, and at exposure levels significantly greater than expected in humans, 

945 there was a positive signal in one class of developmental toxicity and no observed 

946 adverse effects in a related class of developmental toxicity. The positive signal 

947 was evaluated using Figure C and it was concluded that the drug may increase the 

948 risk of that class of toxicity in humans. 

949 

950 Summary Risk Conclusion 5. Based on studies in animals, the drug may increase 

951 the risk of [the class of developmental toxicity in which toxicity was observed] in 

952 humans. Although no findings were observed for [type of developmental toxicity 

953 in same category] there may be some relationship between the incidence of [the 

954 class of toxicity in which toxicity was observed] and [the related class of toxicity 

955 not observed]. 

956 

957 

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1. AVAILABILITY OF STUDIES? 

NO 

YES 

2. RELEVANCE OF STUDIES
 NO

(TEST SYSTEM AND ROUTE)
 

YES 

YES 

3. PRESENCE OF A SIGNAL 

FOR AN ENDPOINT? 

“POSITIVE EFFECT OBSERVED” 

USE FIGURE C FOR INTEGRATION OF DATA 

FOR ENDPOINTS WITH POSITIVE RESULTS 

NO
 

“UNKNOWN” OR “NOT EVALUABLE” RISK 

INFORMATION IS NOT AVAILABLE TO 

ASSESS RISK 

“UNKNOWN” OR “NOT EVALUABLE” RISK 

DEFINE NON-RELEVANCE OF TEST SYSTEM 

OR STUDY 

(DO NOT USE FIGURE C) 

“NO OBSERVED EFFECT” 

USE FIGURE B FOR INTEGRATION OF DATA 

FOR ENDPOINTS WITH NO SIGNAL 

24
 

FIGURE A. OVERALL DECISION TREE FOR EVALUATION OF
 

REPRODUCTIVE/DEVELOPMENTAL TOXICITIES
 
SYSTEM?

 

 

1. ADEQUACY OF MODEL 

NO SIGNAL 

NO 

2. ADEQUATE STUDY DOSES/EXPOSURE? 

3. CLASS ALERT? 

YES 

NO 

“UNKNOWN RISK” OR “POSSIBLE RISK 

BASED ON RELATED DRUG” 

INADEQUATE INFORMATION EXISTS TO 

ASSESS RISK TO HUMAN 

REPRODUCTION, SINCE ... THE TEST 

SYSTEM OR TEST CONDUCT WERE 

DEEMED LACKING (DESCRIBE 

SITUATION) OR, THE COMPOUND WAS 

SUBJECT TO A CLASS ALERT (DESCRIBE 

SITUATION AND INCLUDE CLASS 

INFORMATION). 

4. ANY ENDPOINT POSITIVE YES 

IN RELATED REPRO/DEVEL. 

CATEGORY? 

NO 

“NO OBSERVED EFFECT ON ...” 

“NO PREDICTED RISK”
 

25
 

FIGURE B. DECISION TREE FOR REPRODUCTIVE/DEVELOPMENTAL
 

TOXICITIES WITH NO SIGNAL 
26 

CLASSES OF TOXICITY 

OR SIGNALS 

REPRODUCTIVE

TOXICITY

1. Fertility 

2. Parturition 

3. Lactation 

DEVELOPMENTAL

TOXICITY

1. Mortality 

2. Dysmorphogenesis 

3. Alterations to growth 

4. Functional toxicity 

SIGNAL 

STRENGTH 

I 

PD 

ADME 

TOX 

EXPOSURE 

CLASS, 

ALERTS 

POSITIVE 

SIGNAL 

SIGNAL 

STRENGTH 

I 

ANIMAL DATA 

PD 

ADME 

TOX 

EXPOSURE 

CLASS 

ALERTS 

PROGRESS TO NEXT STEP 

MAY 

INCREASE 

HUMAN 

REPRO. RISK 

PREDICTED 

TO INCREASE 

HUMAN 

REPRO. RISK 

DOES NOT 

APPEAR TO 

INCREASE 

HUMAN 

REPRO. 

RISK 

HUMAN 

DATA 

HUMAN 

DATA 

SIGNAL 

STRENGTH 

II 

SIGNAL 

STRENGTH 

II 

FIGURE C - INTEGRATION TOOL FOR REPRODUCTIVE OR 

DEVELOPMENTAL TOXICITIES WITH A POSITIVE SIGNAL 

HUMAN DATA 

DATA INTEGRATION PROCESS