Regulatory Toxicology and Pharmacology 70 (2014) 572–573
Contents lists available at ScienceDirect
Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
Letter to the Editor What constitutes scientific justification for inclusion of recovery assessment in pre-clinical studies supporting first time in man (FTIM)? We recently published an analysis of the likelihood of reversibility of toxic effects with respect to target organs after a terminal dose free period in rodent and non-rodent toxicity studies conducted to support first time in man (FTIM) dosing for 68 AstraZeneca candidate drugs (CDs) (Horner et al., 2014). Our analysis demonstrated that (i) 86% of all effects observed at the end of dosing recovered (where this was defined as partial or full recovery), (ii) where recovery was not observed this could largely be explained by the nature of the lesion or by the relatively short recovery period and (iii) that demonstrating lack of recovery did not necessarily prevent progression into clinical trials. On this basis we questioned the need to include a recovery assessment in these FTIM studies other than on an individual case-by-case basis driven by scientific rationale. In this respect we are in broad agreement with Pandher et al. (2012) and with the NC3Rs (2012) who concluded that in general, the inclusion of recovery groups should follow a case-by-case approach in line with rational scientific in vivo study design. These conclusions are also in line with International guidelines; the ICH M3 (R2) guideline on non-clinical studies for the conduct of human clinical trials simply states that reversibility should be assessed ‘when appropriate’. ICH S9 (Nonclinical Evaluation for Anticancer Pharmaceuticals) offers more in that it states that ‘A study that includes a terminal non-dosing period is called for if there is severe toxicity at approximate clinical exposure and recovery cannot be predicted by scientific assessment’ and this is further expanded on in the ICH M3 (R2) (2011) Questions and Answers document where scientific assessment could be based on ‘the extent and severity of the lesion, the regenerative capacity of the organ and knowledge of other drugs causing the effect’. Although this concordance in conclusions is encouraging, the case by case approach is not particularly useful to an individual toxicologist who needs to decide in advance of conducting the study what ‘when appropriate’ or ‘if recovery cannot be predicted by scientific assessment’ actually means in the context of their toxicology package. This has led to recovery groups being included more routinely than not, probably following individual company default positions that usually include a recovery assessment in the pivotal Good Laboratory Practice (GLP) studies supporting FTIM. It is important to challenge these default positions. Including recovery assessment in pivotal GLP studies supporting FTIM uses additional animals and resources at a time in the drug development process that may not be scientifically optimal or beneficial to clinical trial design. So, what constitutes scientific justification for inclusion of recovery assessment in GLP studies supporting FTIM? We propose http://dx.doi.org/10.1016/j.yrtph.2014.09.005 0273-2300/Ó 2014 Elsevier Inc. All rights reserved.
3 main points to be considered assuming (as is normally the case) that the site and severity of the lesions and hence whether they can be predicted to recover is not yet known: 1. Target effects – from published literature or previous practical experience. 2. Chemistry (or related chemistry) effects – from structural data bases or prior experience. 3. Prior in vivo experience – data obtained from earlier work such as dose range finding, efficacy or DMPK studies. In practical terms, guidelines suggest that if a scientific rationale can be provided that a lesion will recover then there is no need to assess experimentally. Put another way, there is no need to demonstrate recovery in every study; with the extensive experience and expertise of our pathologists and toxicologists, we can provide a rationale for the likelihood of recovery for most lesions. Experience has shown that even moderate or severe lesions may recover. Are there any arguments for including a recovery assessment even in the absence of prior information that would justify inclusion? It is clear there is reassurance to be gained in having actual data showing recovery rather than using professional judgment, knowing that one will be held accountable. But this argument applies to all the decisions we make as professionals in the absence of incomplete information. Of course, we do need to be confident in our predictions of recovery to ensure we minimize risk of inducing irreversible damage. Although limited, the dataset used in our analysis (Horner et al., 2014) represents a range of chemistries and therapy areas. The outcome of the analysis provides us with the data to enable us to make an informed decision to stop including recovery assessment as a default in our GLP studies supporting FTIM; the majority of lesions recover and where they do not they can be explained rationally. This rationale is independent of the therapy area in question and includes FTIM studies for anticancer agents. In addition, we have recently extended the in vivo data sets we obtain prior to conducting pivotal GLP studies to support FTIM (Roberts et al., 2014). The main reasons for this were to bring drug candidate safety attrition forward, delivering the opportunity for a reduction in attrition in the GLP phase and beyond thus increasing efficiency by avoiding progressing unsuitable compounds, reducing animal use overall and delivering an overall improvement in the quality of the drug discovery and development pipeline. However, this extended in vivo data set also gives additional confidence that we will detect rare and/or severe toxicities where reversibility cannot be predicted. This would then indicate the need for a follow up recovery assessment in the pivotal GLP studies supporting FTIM. In summary, we would advocate that recovery is not routinely included in the pivotal GLP studies supporting FTIM. We do
Letter to the Editor / Regulatory Toxicology and Pharmacology 70 (2014) 572–573
anticipate rare occasions where there will be a scientific need to include recovery; this may be more common in the oncology area where the observed target organ profile was slightly different, with a larger range of organs not recovering fully within the off-dose period in both species (Horner et al., 2014). This approach presents an opportunity to streamline current practices without impact on patient and volunteer safety. References Horner, S., Robinson, S., Lees, D., Callander, R., Roberts, R., 2014. Target organ profiles in toxicity studies supporting human dosing: an assessment of recovery and chronic dosing. Regul. Toxicol. Pharmacol. 70 (1), 270–285. http:// dx.doi.org/10.1016/j.yrtph.2014.07.008. ICH Guideline M3(R2), 2009. Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. . ICH Guideline S9, 2009. Nonclinical evaluation for anticancer pharmaceuticals. . ICH M3(R2) Q&A, 2011. Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. European Medicines Agency. Committee for medicinal products for human use (CHMP). ICH guidelines
573
M3(R2) Q&A. . NC3Rs, 2012: National Centre for the Replacement, Refinement & Reduction of Animals in Research, 2012. Reducing the use of recovery animals in pharmaceutical development. . Pandher, K., Leach, N.W., Burns-Naas, L.A., 2012. Appropriate uses of recovery groups in nonclinical toxicity studies: value in a science-driven case-by-case approach. Vet. Pathol. 49, 357–361. Roberts, R., Kavanagh, S., Mellor, H., Pollard, C., Robinson, S., Platz, S., 2014. Reducing attrition in drug development: smart loading preclinical safety assessment. Drug Discov. Today 19, 341–347.
Sally Robinson ⇑ Ruth Roberts Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, UK ⇑ Corresponding author. Fax: +44 1625 513779. E-mail address: [email protected] (R. Roberts) Available online 16 September 2014
Contents lists available at ScienceDirect
Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
Letter to the Editor What constitutes scientific justification for inclusion of recovery assessment in pre-clinical studies supporting first time in man (FTIM)? We recently published an analysis of the likelihood of reversibility of toxic effects with respect to target organs after a terminal dose free period in rodent and non-rodent toxicity studies conducted to support first time in man (FTIM) dosing for 68 AstraZeneca candidate drugs (CDs) (Horner et al., 2014). Our analysis demonstrated that (i) 86% of all effects observed at the end of dosing recovered (where this was defined as partial or full recovery), (ii) where recovery was not observed this could largely be explained by the nature of the lesion or by the relatively short recovery period and (iii) that demonstrating lack of recovery did not necessarily prevent progression into clinical trials. On this basis we questioned the need to include a recovery assessment in these FTIM studies other than on an individual case-by-case basis driven by scientific rationale. In this respect we are in broad agreement with Pandher et al. (2012) and with the NC3Rs (2012) who concluded that in general, the inclusion of recovery groups should follow a case-by-case approach in line with rational scientific in vivo study design. These conclusions are also in line with International guidelines; the ICH M3 (R2) guideline on non-clinical studies for the conduct of human clinical trials simply states that reversibility should be assessed ‘when appropriate’. ICH S9 (Nonclinical Evaluation for Anticancer Pharmaceuticals) offers more in that it states that ‘A study that includes a terminal non-dosing period is called for if there is severe toxicity at approximate clinical exposure and recovery cannot be predicted by scientific assessment’ and this is further expanded on in the ICH M3 (R2) (2011) Questions and Answers document where scientific assessment could be based on ‘the extent and severity of the lesion, the regenerative capacity of the organ and knowledge of other drugs causing the effect’. Although this concordance in conclusions is encouraging, the case by case approach is not particularly useful to an individual toxicologist who needs to decide in advance of conducting the study what ‘when appropriate’ or ‘if recovery cannot be predicted by scientific assessment’ actually means in the context of their toxicology package. This has led to recovery groups being included more routinely than not, probably following individual company default positions that usually include a recovery assessment in the pivotal Good Laboratory Practice (GLP) studies supporting FTIM. It is important to challenge these default positions. Including recovery assessment in pivotal GLP studies supporting FTIM uses additional animals and resources at a time in the drug development process that may not be scientifically optimal or beneficial to clinical trial design. So, what constitutes scientific justification for inclusion of recovery assessment in GLP studies supporting FTIM? We propose http://dx.doi.org/10.1016/j.yrtph.2014.09.005 0273-2300/Ó 2014 Elsevier Inc. All rights reserved.
3 main points to be considered assuming (as is normally the case) that the site and severity of the lesions and hence whether they can be predicted to recover is not yet known: 1. Target effects – from published literature or previous practical experience. 2. Chemistry (or related chemistry) effects – from structural data bases or prior experience. 3. Prior in vivo experience – data obtained from earlier work such as dose range finding, efficacy or DMPK studies. In practical terms, guidelines suggest that if a scientific rationale can be provided that a lesion will recover then there is no need to assess experimentally. Put another way, there is no need to demonstrate recovery in every study; with the extensive experience and expertise of our pathologists and toxicologists, we can provide a rationale for the likelihood of recovery for most lesions. Experience has shown that even moderate or severe lesions may recover. Are there any arguments for including a recovery assessment even in the absence of prior information that would justify inclusion? It is clear there is reassurance to be gained in having actual data showing recovery rather than using professional judgment, knowing that one will be held accountable. But this argument applies to all the decisions we make as professionals in the absence of incomplete information. Of course, we do need to be confident in our predictions of recovery to ensure we minimize risk of inducing irreversible damage. Although limited, the dataset used in our analysis (Horner et al., 2014) represents a range of chemistries and therapy areas. The outcome of the analysis provides us with the data to enable us to make an informed decision to stop including recovery assessment as a default in our GLP studies supporting FTIM; the majority of lesions recover and where they do not they can be explained rationally. This rationale is independent of the therapy area in question and includes FTIM studies for anticancer agents. In addition, we have recently extended the in vivo data sets we obtain prior to conducting pivotal GLP studies to support FTIM (Roberts et al., 2014). The main reasons for this were to bring drug candidate safety attrition forward, delivering the opportunity for a reduction in attrition in the GLP phase and beyond thus increasing efficiency by avoiding progressing unsuitable compounds, reducing animal use overall and delivering an overall improvement in the quality of the drug discovery and development pipeline. However, this extended in vivo data set also gives additional confidence that we will detect rare and/or severe toxicities where reversibility cannot be predicted. This would then indicate the need for a follow up recovery assessment in the pivotal GLP studies supporting FTIM. In summary, we would advocate that recovery is not routinely included in the pivotal GLP studies supporting FTIM. We do
Letter to the Editor / Regulatory Toxicology and Pharmacology 70 (2014) 572–573
anticipate rare occasions where there will be a scientific need to include recovery; this may be more common in the oncology area where the observed target organ profile was slightly different, with a larger range of organs not recovering fully within the off-dose period in both species (Horner et al., 2014). This approach presents an opportunity to streamline current practices without impact on patient and volunteer safety. References Horner, S., Robinson, S., Lees, D., Callander, R., Roberts, R., 2014. Target organ profiles in toxicity studies supporting human dosing: an assessment of recovery and chronic dosing. Regul. Toxicol. Pharmacol. 70 (1), 270–285. http:// dx.doi.org/10.1016/j.yrtph.2014.07.008. ICH Guideline M3(R2), 2009. Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. . ICH Guideline S9, 2009. Nonclinical evaluation for anticancer pharmaceuticals. . ICH M3(R2) Q&A, 2011. Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. European Medicines Agency. Committee for medicinal products for human use (CHMP). ICH guidelines
573
M3(R2) Q&A. . NC3Rs, 2012: National Centre for the Replacement, Refinement & Reduction of Animals in Research, 2012. Reducing the use of recovery animals in pharmaceutical development. . Pandher, K., Leach, N.W., Burns-Naas, L.A., 2012. Appropriate uses of recovery groups in nonclinical toxicity studies: value in a science-driven case-by-case approach. Vet. Pathol. 49, 357–361. Roberts, R., Kavanagh, S., Mellor, H., Pollard, C., Robinson, S., Platz, S., 2014. Reducing attrition in drug development: smart loading preclinical safety assessment. Drug Discov. Today 19, 341–347.
Sally Robinson ⇑ Ruth Roberts Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, UK ⇑ Corresponding author. Fax: +44 1625 513779. E-mail address: [email protected] (R. Roberts) Available online 16 September 2014
