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A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development
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Regulatory Toxicology and Pharmacology 50 (2008) 345–352 www.elsevier.com/locate/yrtph
A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development Sally Robinson a,*, Jean-Luc Delongeas b, Elizabeth Donald c, David Dreher d, Matthias Festag e, Sophie Kervyn f,1, Ann Lampo g, Kamil Nahas h, Vicente Nogues i, Deborah Ockert j,2, Kirsty Quinn k, Sally Old l,3, Nigel Pickersgill m, Kev Somers n, Claudia Stark o, Peter Stei p, Lynne Waterson q, Kathryn Chapman r,* a
AstraZeneca, Alderley Park, UK Servier, Neuilly Sur Seine, France c Charles River Laboratories, Edinburgh, UK d Covance Laboratories, Harrogate, UK e Roche, Basel, Switzerland f Eli Lilly and Company, UCB Pharma SA, Braine-l’Alleud, Belgium g Johnson and Johnson, Beerse, Belgium h Pfizer, Amboise, France i Novartis, Basel, Switzerland j Nycomed GmbH, Hamburg, Germany k Aptuit, Edinburgh, UK l Sanofi-Aventis, Alnwick, UK m MDS Pharma Services, Lyon, France n GlaxoSmithKline, Ware, UK o Bayer Schering Pharma AG, Berlin, Germany p Boehringer Ingelheim, Biberach, Germany q Huntingdon Life Sciences, Huntingdon, UK UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (UK NC3RS), London, UK b
r
Received 24 October 2007 Available online 5 December 2007
Abstract Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose. A European initiative including 18 companies has undertaken an evidencebased review of acute toxicity studies and assessed the value of the data generated. Preclinical and clinical information was shared on 74 compounds. The analysis indicated acute toxicity data was not used to (i) terminate drugs from development (ii) support dose selection for repeat dose studies in animals or (iii) to set doses in the first clinical trials in humans. The conclusion of the working group is that acute toxicity studies are not needed prior to first clinical trials in humans. Instead, information can be obtained from other studies,
*
1 2 3
Corresponding authors. Fax: +44 01625 516809 (S. Robinson), +44 0 207 670 5178 (K. Chapman). E-mail addresses: [email protected] (S. Robinson), [email protected] (K. Chapman). Represented Eli Lilly until the end of 2006 prior moving to UCB Pharma SA. As of 1 July 2007. Previously ALTANA Pharma AG. Sanofi-Aventis were represented separately as their former legacy companies prior to the merger in 2005.
0273-2300/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2007.11.009
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which are performed at more relevant doses for humans and are already an integral part of drug development. The conclusions have been discussed and agreed with representatives of regulatory bodies from the US, Japan and Europe. 2007 Elsevier Inc. All rights reserved. Keywords: Acute toxicity; Pharmaceuticals; Regulatory guidelines
1. Introduction 1.1. Background The pharmaceutical industry recognises the need to reassess the design and conduct of toxicology studies as new scientific practices and knowledge develop. The assessment often includes the consideration of the 3Rs principles (Russell and Burch, 1959) such that studies that are not providing optimal information are challenged and opportunities for replacing or reducing animal use are identified. Acute toxicity studies in animals are considered necessary for any pharmaceutical intended for human use. Historically, the first toxicity test performed has been the acute toxicity study (Casarett and Doull, 1999). The main objective of these studies is to identify a single dose causing major adverse effects/life threatening toxicity, which often involves an estimation of the minimum dose causing lethality. The studies are usually carried out in rodents, and consist of a single dose up to a limit of 2000 mg/kg, or the maximum technically achievable. In pharmaceutical drug development this is the only study type where lethality/ life-threatening toxicity is an endpoint as documented in current regulatory guidelines (Commission Directive, 2003; Center for Drug Evaluation and Research, 1996; ICH Japan, 1999). Scientists and animal protection groups have criticized the conduct of acute toxicity studies (Langley, 2005). The predictivity of rodent acute toxic effects for human acute toxic effects has long been disputed but never proven. In addition, in recent years there has been a change in strategy in the pharmaceutical industry such that early toxicology information is used to identify the most promising compounds to progress as potential human medicines. Acute toxicity tests are often no longer the first toxicology studies conducted therefore prompting this reassessment of acute toxicity tests in pharmaceutical drug development. In this paper we present evidence-based arguments to demonstrate that these studies have limited value in terms of preclinical and human safety assessment compared to the substantial adverse effects experienced by some of the animals. 1.2. Current regulatory climate In recent years, progress has been made in refining acute toxicity studies. Alternatives to the traditional LD50 test, designed in 1927 (Trevan, 1927) have been developed that significantly improve animal welfare. These are the fixed dose procedure, the acute toxic class method, and the up and down procedure (Botham, 2002) and these are partic-
ularly used in the hazard classification of chemicals. In 2002, the Organisation for Economic Co-Operation and Development (OECD) eliminated the oral LD50 (lethal dose in 50% of animals) test from its guidelines for the testing of chemicals. The International Conference on Harmonisation of the Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) has also provided the opportunity to refine acute toxicity tests, with the acceptance of data from dose escalation studies (ICH M3, 1997). However, ICH refers to national guidelines where they exist and these still indicate the requirement for acute toxicity data for pharmaceutical drugs. The requirements in terms of the species, exposure route and observation period vary between geographical regions as shown in Table 1. The European and US guidelines specify a second route that ensures exposure. It is worth noting that acute toxicity is the only study type where a route other than the clinical route is routinely required. Evidence of exposure in other study types is provided by a toxicokinetic assessment. 1.3. Working group objectives A European industry-working group was established in 2003 and currently represents 13 pharmaceutical companies and 5 contract research organisations (see author affiliations). Aptuit, HLS and UCB Pharma SA joined in 2007 and their data has been added to the survey retrospectively. The aim of the working group is to facilitate cooperation and data sharing on conventional acute toxicity studies in rodents. The objectives were (a) to review how acute toxicity data are gathered and used across the pharmaceutical industry and (b) to develop a strategy for challenging the guidelines on the requirement for acute toxicity where lethality/life threatening toxicity is an endpoint. The ultimate goal of the working group is to assess the relevance of acute toxicity data in the drug development process and to provide recommendations for alternative testing strategies to replace acute toxicity studies by using information derived from other studies. Acute toxicity testing of chemicals and intermediates by the pharmaceutical and chemical industries was not addressed as this is carried out for a different purpose and under different regulatory guidance. In addition, specifically designed extended single dose studies (e.g., microdosing, CHMP, 2004) and single dose studies for biotechnology products (ICH S6, 1997) are not part of the scope of this initiative as again the purpose and regulatory guidance for these studies are different to those for standard therapeutic agents and regimens.
S. Robinson et al. / Regulatory Toxicology and Pharmacology 50 (2008) 345–352 Table 1 Regulatory framework EEC
US a
2 Species 2 Routes, clinical route plus a route ensuring exposurec 7–14-Day observation
Japan b
2 Species 2 Routes (as EEC) 14-Day observation
2 Speciesb Clinical 14-Day observation
a
Usually rat and mouse. US/Japan: specify a non-rodent. Dose-escalation is acceptable alternative for non-rodents; no region mentions dose-escalation as alternative for rodents. c Only study type where a second route (parenteral, usually intravenous) is routinely required. b
This initiative has the full support of the European Federation of Pharmaceutical Industries and Associations (EFPIA), in particular the preclinical safety group.
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An initial data sharing exercise was undertaken by the working group to compare the design of acute toxicity studies and to review how internal regulatory and clinical colleagues use the data generated. All of the companies involved in the working group completed a questionnaire on study designs for pharmaceutical drugs at the time they joined the working group. This included questions on standard acute toxicity package and the timing and purpose of the studies. Detail was also gathered on specific study designs and numbers of animals used for acute toxicity studies. Data were collected from all companies able to supply the information. One contract research organisation has no set policy on acute toxicity studies and no information was included for this company. Therefore, in some of the figures presented in this paper the total number of companies may not equal 18. 2.2. Results
2. Obtaining information on current practice 2.1. Initial discussions and data sharing Historically, there were preclinical (Sections 2.1.1 & 2.1.2) and clinical (Section 2.1.3) objectives proposed for conducting acute toxicity studies in the development of new medicines. 2.1.1. Dose selection Preclinically, it was often assumed that the data from acute toxicity studies might be used to aid dose selection for other studies and provide preliminary target organ toxicity. However, initial discussions within the working group indicated that for many companies the acute study is no longer the first toxicology study performed and dose-selection information is gained from many other study types, including non-GLP (Good Laboratory Practice) exploratory studies. 2.1.2. Identification of target organs of toxicity It is also often stated that such studies support identification of target organs of toxicity. However, since microscopic pathology is not routinely performed on acute toxicology studies they of very limited value to identify target organs. 2.1.3. Assessment of acute overdose situation Clinically, it is assumed that the data obtained from acute toxicity studies is used to give information on the likely effects of acute overdose in humans. Initial discussions indicated that the studies do not include clinical pathology, microscopic pathology or toxicokinetic evaluation and that the clinical observations seen in rodents at high doses are often non-specific and may help in assessing the lethal dose-range, but they do not add information that would support measures to be taken in overdose situations in humans. Therefore, studies evaluating vital organ functions in more detail, such as safety pharmacology studies, might be appropriate to support assessment of acute overdose.
At the start of the initiative there was variability in the acute toxicity packages conducted by the companies represented on the working group (Fig. 1a). For the majority of the companies the acute studies conducted were consistent with the European guideline, using two species (rat and mouse) and two routes of administration i.e. the intended human route of administration and a parenteral route (four rodent studies in total). The current European Guidelines do not specifically request a non-rodent species where (a) lethality is not an acceptable endpoint and (b) dose-escalation studies are an acceptable alternative. Several companies were using minimised study packages successfully within the confines of the current regulatory guidelines. This variability in acute toxicity packages is not unique to Europe. Six US companies completed the questionnaire and the results showed that there was a similar variability in acute toxicity packages from one rodent study to four rodent studies. The data from the US companies is not included in the figures in this paper. From current study designs, in general only very limited data, other than maximum non-lethal dose and minimum lethal doses, are provided (Fig. 2). The microscopic evaluation of selected tissues is extremely rare and done on a case-by-case basis. It is clear from the information collected that these studies are not used to identify target organs. There was large inter-company variability in the numbers of rodents used at the start of the initiative (Fig. 3a/ b). This is particularly evident in the use of mice, with four companies not using any mice and six companies using 60 to 100 or more mice per compound. The companies not using mice were those that had already employed a minimised approach to acute toxicity testing. The data also illustrated that the majority of the companies (13/17) conducted acute toxicity studies prior to the first clinical trial in humans. This timing appeared to be driven by the ICH M3, 1997 guideline that specifies the requirement for data prior to first clinical trial in humans,
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Fig. 1. (a) Survey of standard acute toxicity packages (2003–2005). (b) Survey of standard acute toxicity packages (2006). (c) Survey of standard acute toxicity packages (2007).
first clinical trial in humans. This approach places the acute toxicity studies later in the development programme resulting in a reduction in the number of compounds tested due to attrition during the development process. From the information collected it is clear there is inconsistency in the approach to providing acute toxicity data within the pharmaceutical industry. By sharing information the working group was able to demonstrate there was both the scope and willingness to agree upon a harmonised approach to reduce the number of studies and refine the design in the short term. In addition, an assessment of the scientific value of the data generated would form the basis to challenging the requirement for these studies in the longer term. Fig. 2. Data provided in toxicity studies.
although the guideline indicates dose escalation data are an acceptable alternative. Interestingly, one company conducted no acute toxicity studies at all. Two companies conducted studies prior to registration rather than prior to the
3. Obtaining information on how acute toxicity data are used prior to the first clinical trial in humans 3.1. Compound specific data sharing As the majority of companies conducted acute toxicity studies prior to the first clinical trial in humans, a data
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Data were collected on 34 compounds for which development was terminated prior to administration to humans and 40 compounds that entered into clinical trials in humans. An example of the types of data collected for a compound that was given in clinical trials is illustrated in Tables 2a and 2b. The types of information collected included therapeutic class, toxicological effects of concern, species and study type effects were identified in, dose levels required for effects of concern, reasons for termination of the compound, or justification for dose levels in man. Available acute toxicity data were also summarised. The following therapy areas were covered by the data on compounds that entered clinical trials in humans: cardiovascular, CNS/PNS, metabolic disorders, urology, inflammatory disorders, endocrine, gastro-intestinal, respiratory and anti-infective (Table 3). The data sharing demonstrated the following keypoints:
Fig. 3. a and b show the downward shift in number of rodents used per project in each company between 2003–2005 and 2007.
sharing exercise was conducted to assess how acute toxicity data are used at this stage in drug development. In this data sharing exercise two questions were addressed. (a) Are acute toxicity data used to stop development of compounds prior to the first clinical trial in humans? (b) Are acute toxicity data used to help define dose levels or to identify additional clinical monitoring required for the first clinical trial in humans?
- Acute toxicity studies were never responsible for termination of a compound. The most common reason for termination of compounds prior to the first clinical trial in humans was the identification of dose limiting target organ toxicity in the 2 or 4 week repeat dose toxicity studies (Table 4). - No additional information was gained from studies in a second rodent species. Data from 28 compounds given orally in both the rat and the mouse showed similar effects (e.g., either in terms of clinical observations or lethality) for 22 compounds at comparable doses (less than 20% difference in dose between the two species). For the remaining six compounds there was no more than a twofold difference in doses showing similar clinical observations or lethality between the two species. The picture was similar for 22 compounds given parenterally in both the rat and the mouse. - For approximately 25% of the compounds assessed, the data indicated non-rodents were more sensitive in detecting effects that determined dose levels in the first human clinical trials and therefore data from short term non-rodent studies already conducted as part of drug development may provide more useful information than acute studies in rodents.
Table 2a Data showing effects of concern for compound X and the studies where these were identified Therapeutic class
Toxicological effect(s) of concern
Species effect(s) were identified in
Primary study type(s) in which effect(s) were identified
Doses at which the effects of concern were seen (mg/kg)
Justification for starting dose in man
Justification for maximum dose administered in man
Reason for stopping dose escalation in man
Comments
Gastrointestinal
Cytochrome P4501A1 induction
Rat
One month study
19, 88, 38. No no-adverse effect level (NOAEL)
Cytochrome P4501A1 induction not considered relevant to man. Effects in the dog were used to limit doses/ exposure in man
Exposure at the NOAEL in the dog
—
—
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Table 2b Summary of acute toxicity data for compound X Therapeutic class
Effects of concern observed in acute toxicity (clinical route, oral)
Dose range in mg/kg (clinical route)
Effects of concern observed in acute toxicity (parenteral route)
Dose range in mg/kg (parenteral route)
Comments
Was the acute data used to set or justify human dose levels
Gastrointestinal
Mouse: not performed Rat acute: increased salivation, ploughing, pilo-erection, ataxia and hunched posture on the day of dosing Dog dose-escalation study: Emesis
Mouse: not performed Rat: minimum lethal dose >2000 mg/kg Dog: 25–300 mg/kg. Emesis with no increase in systemic exposure with dose
Mouse: not performed Rat: not performed
Mouse: not performed Rat: not performed
No mouse data. No parenteral route Dog dose escalation data used as an alternative to acute data
No
Table 3 Numbers of compounds for which data was shared within each therapy area Therapy area
Compounds terminated prior to the first clinical trial in humans
Compounds that entered clinical trials in humans
Cardiovascular Central/peripheral nervous system Metabolic Inflammatory Respiratory Endocrine Gastrointestinal Anti-infective Urology Oncology
5 9
3 9
4 5 7 1 0 2 0 1 Total = 34
7 5 4 3 5 1 3 — Total = 40
Table 4 The reasons for termination of the 34 compounds prior to the first clinical trial in humans Reason for termination
Number of compounds
Insufficient bioavailability Chemical stability issues Safety pharmacology issues Genetic toxicity issues Dose-limiting target organ effects in 2 and 4 week repeat dose studies with no margin of safety, and/or no biomarker Business reasons (e.g. class discontinued, switch to molecule with better safety or efficacy profile) Potential for developmental toxicity
1 1 2 2 22
5 1
- Acute toxicity studies were never used to set the dose levels for the first clinical trials in humans, identify target organs or to indicate markers for monitoring in the clinical trials. This information was obtained from the two to four week repeat dose toxicity studies where full bio-
chemical and histopathological evaluations were performed along with the measurement of plasma concentrations of drug. - No additional information was obtained from the parenteral route. The most common parenteral route was bolus intravenous injection giving a pattern of exposure completely different from that anticipated for the clinical route and often leading to a rapid onset of both clinical observations and substantial adverse effects. In addition, 19 of the 40 compounds that were given in clinical trials to humans did not have acute studies conducted by the parenteral route, demonstrating that this information was not essential. 3.2. Working group recommendations based on data-sharing Based upon the review of the 40 compounds that proceeded to human clinical trials, the following recommendations are made by the working group: • Acute toxicity studies should not be required prior to the first clinical trial in humans. • Any short term or dose-escalation data (including from non-GLP studies) should be considered acceptable to allow assessment of acute toxicity and this should be by the clinical route only. • In situations where overdosing may be a cause for concern (e.g., where there may be uncontrolled access to drug as in Phase 3 clinical trials or at registration) establish, by reviewing both the pre-clinical and clinical dataset, whether additional high dose information is necessary. In the majority of cases a stand-alone acute toxicity study should not be required. • Lethality should not be the primary endpoint. • Rather than using a second rodent species, data should be provided from a rodent and a non-rodent species preferably from short duration studies that are already an integral part of drug development and that include parameters in the study design that assist risk assessment. In November 2006 a workshop that included representatives of the European, Japanese and United States regula-
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tory bodies was held to discuss this topic. The participants, including the regulatory representatives, fully supported the recommendations of the working group (Chapman and Robinson, 2007). 4. Repeat survey of working group on current practice The questionnaire on acute toxicity packages and study design was repeated in May 2006 and June 2007. From the results of the repeat surveys, it was clear that the ongoing discussions within the working group and other working group activities had already facilitated the review of acute toxicity strategy within some of the working group companies. The working group members have adopted a minimised approach within the current regulatory requirements based on other companies experience in providing limited or no data from acute toxicity studies to regulators. During the time the working group has been reviewing the value of acute toxicity studies, the number of companies providing the full four-study package has significantly decreased. By 2007, the majority of companies now provide only one acute study plus other data, or no acute studies at all (Fig. 1b and c). These minimised strategies are within the constraints of the current regulatory guidelines. In addition, companies conducting acute toxicity studies prior to first clinical trial in humans have reduced from 13/17 initially to 6/17 in 2007 thus reducing the numbers of compounds for which acute toxicity studies are conducted. The number of rodents used in acute toxicity studies has also significantly decreased (Fig. 3). This is predominantly due to the fact that the majority of companies are conducting few if any acute toxicity studies. Where they are still conducted there has also been a reduction in the number of rodents used per study due to the sharing of best practice within the group. ICH M3 is currently undergoing revision (Section 6) and it will take time to finalise the guideline. In the meantime the working group is continuing to communicate its recommendations more widely to regulators, colleagues and companies not involved in the working group. This dissemination strategy has included leaflets, posters, presentations at conferences and an international regulatory workshop. Through the CROs on the working group, smaller companies are receiving information packs containing the information on the initiative and its recommendations. The significant changes in acute toxicity packages between 2006 and 2007 (Fig. 1b and c) indicate that the regulatory workshop and other dissemination activities during 2006 have had an impact on the number of acute toxicity studies carried out. 5. Discussion It is clear that the strategy for toxicity testing during pharmaceutical development has changed significantly over the years such that early toxicology information is used to identify the most promising compounds to progress as
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potential human medicines. Acute toxicity tests are often no longer the first tests performed and more useful data for dose setting in other animal studies are obtained from studies that are already an integral part of drug development and that do not have lethality or life threatening toxicity as an endpoint. Additionally it is clear from the sharing of data and analysis of 40 compounds that went into human clinical trials that acute toxicity data should not be required before first clinical trial in humans. Regulatory bodies in all regions support this recommendation. The only possible clinical reason for conducting acute toxicity studies is to support risk assessment in humans at a time when patients will have uncontrolled access to large quantities of drug, although the usefulness of the limited animal data set provided from acute toxicity studies is still questionable. The recommendations from this work are specifically focussed on the development of new medicines and regulatory guidance for pharmaceuticals. However, in Zbinden and Flury-Roversi (1981) reviewed the significance of the LD50 test for the toxicological evaluation of chemical substances. Some of the points made then have been clearly re-emphasised by the recent work e.g. that the data is extremely limited without laboratory diagnostic and histopathological assessments and that the data may not be that useful in dose setting for other animal studies. Given that this work is nearly 30 years old and the fact that the original ICH M3 clearly tried to reduce acute toxicity testing for pharmaceuticals over 10 years ago it might be questioned why there has not been more impact in the pharmaceutical industry. The section on single dose/acute toxicity in the current ICH M3 guideline is extremely brief and lacking in detail and therefore refers to national guidelines for more detail. It is possible that the lack of clarity in the national guidelines underpinning ICH M3 has been an inadvertent barrier to the implementation of the 3Rs. The approach taken by the working group has demonstrated the value of sharing and collating data in order to harmonise study designs and implement the 3Rs. More importantly the group have analysed how toxicological data on active pharmaceuticals are practically used to support the safety of potential new medicines given in human clinical trials. It has been the use of relevant data sets that has provided the evidence needed to convince both the pharmaceutical companies involved and the regulatory bodies that acute toxicity studies are clearly of limited value in pharmaceutical drug development. This has allowed the final steps to be taken to implement the reduction and replacement of acute toxicity testing in pharmaceutical drug development. Establishing whether acute toxicity studies are required for predicting human overdose is the next stage and an ongoing collaboration with the Lyon Poison Centre will be pivotal in determining whether acute toxicity information is needed to provide information that assists in the management of overdose situations. This initiative illustrates the benefits that can be achieved in terms of implementing the 3Rs by a coordinated
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approach and sharing data within the pharmaceutical industry and with regulatory bodies to reach a common position based on evidence and science. It is important to consider where else a similar strategy could be applied to enhance the application of the 3Rs.
to be acceptable supporting information on single high dose toxicity. The results show that there should be no requirement for stand-alone acute toxicity studies as these are not pivotal in human safety assessment. References
6. Conclusion Acute toxicity data are: • Extremely limited with regard to the parameters examined, concentrating on minimum lethal and maximum non-lethal doses. • Of less use than other, less harmful animal tests that are superior for deciding appropriate doses for further studies using animals. • Do not provide information on the nature of toxic effects, which are better evaluated in other routine studies. • Not, in practice, used to set doses in the first human clinical trials because other routine studies provide more informative data. The topic of acute toxicity requirements is currently being addressed via the revision of ICH M3 and this has been an opportunity to incorporate the recommendations made by the working group into the new guidance. The recommendations were supported by representatives of the international regulatory bodies at the workshop held in November 2006 (Chapman and Robinson, 2007). At this stage the draft ICH guidance has incorporated all the recommendations of the working group. Acceptance of the recommendations will effectively lead to ‘replacement’ of acute studies in time as non-GLP dose-range finding information from rodent and non-rodents should be considered
Commission Directive 2003/63/EC of the 25th June 2003 amending directive 2001/83/EC of the European parliament and of the council on the community code relating to medicinal products for human use, Annex I. Official Journal of the European Communities L159 27/6/ 2003, pp. 46–94, Brussels. Botham, P.A., 2002. Acute Systemic Toxicity. ILAR J, 2002;43 Suppl:S27–30. Review. Casarett and Doull’s Toxicology. The basic science of poisons. (Fifth Edition). Companion Handbook. Edited by C.D. Klaassen and J.B. Watkins III. Published by McGraw-Hill. 1999. Center for Drug Evaluation and Research (CDER) Guidance for Industry, August 1996. Single dose acute toxicity testing for pharmaceuticals. Pt 1.. Chapman, K., Robinson, S., 2007. Challenging the regulatory requirement for acute toxicity studies in the development of new medicines. A workshop report. . EMEACHMP/SWP/2599/02/Rev 1, 23 June 2004. Position paper on nonclinical safety studies to support clinical trials with a single microdose. London. (CHMP adopted June 2004). ICH Japan, 1999. Guidelines for New Drug Registration with Harmonized Tripartite Guidelines. Yakuji Nippo Ltd, Japan. ICH M3, 1997. Guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. . ICH S6, 1997. Preclinical safety assessment of biotechnology-derived pharmaceuticals. . Langley, G., 2005. European coalition to end animal experiments: acute toxicity testing without animals. ECEAE, London. Russell, W.M.S., Burch, R.L., 1959 (reprinted 1992). The principles of humane experimental technique. Universities Federation for Animal Welfare, Wheathamsted, UK. Trevan, J., 1927. The error of determination of Toxicity. Proc. R. Soc. 101, 483–514. Zbinden, G., Flury-Roversi, M., 1981. Significance of the LD50-test for the toxicological evaluation of chemical substances. Arch. Toxicol. 47, 77–99.
Regulatory Toxicology and Pharmacology 50 (2008) 345–352 www.elsevier.com/locate/yrtph
A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development Sally Robinson a,*, Jean-Luc Delongeas b, Elizabeth Donald c, David Dreher d, Matthias Festag e, Sophie Kervyn f,1, Ann Lampo g, Kamil Nahas h, Vicente Nogues i, Deborah Ockert j,2, Kirsty Quinn k, Sally Old l,3, Nigel Pickersgill m, Kev Somers n, Claudia Stark o, Peter Stei p, Lynne Waterson q, Kathryn Chapman r,* a
AstraZeneca, Alderley Park, UK Servier, Neuilly Sur Seine, France c Charles River Laboratories, Edinburgh, UK d Covance Laboratories, Harrogate, UK e Roche, Basel, Switzerland f Eli Lilly and Company, UCB Pharma SA, Braine-l’Alleud, Belgium g Johnson and Johnson, Beerse, Belgium h Pfizer, Amboise, France i Novartis, Basel, Switzerland j Nycomed GmbH, Hamburg, Germany k Aptuit, Edinburgh, UK l Sanofi-Aventis, Alnwick, UK m MDS Pharma Services, Lyon, France n GlaxoSmithKline, Ware, UK o Bayer Schering Pharma AG, Berlin, Germany p Boehringer Ingelheim, Biberach, Germany q Huntingdon Life Sciences, Huntingdon, UK UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (UK NC3RS), London, UK b
r
Received 24 October 2007 Available online 5 December 2007
Abstract Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose. A European initiative including 18 companies has undertaken an evidencebased review of acute toxicity studies and assessed the value of the data generated. Preclinical and clinical information was shared on 74 compounds. The analysis indicated acute toxicity data was not used to (i) terminate drugs from development (ii) support dose selection for repeat dose studies in animals or (iii) to set doses in the first clinical trials in humans. The conclusion of the working group is that acute toxicity studies are not needed prior to first clinical trials in humans. Instead, information can be obtained from other studies,
*
1 2 3
Corresponding authors. Fax: +44 01625 516809 (S. Robinson), +44 0 207 670 5178 (K. Chapman). E-mail addresses: [email protected] (S. Robinson), [email protected] (K. Chapman). Represented Eli Lilly until the end of 2006 prior moving to UCB Pharma SA. As of 1 July 2007. Previously ALTANA Pharma AG. Sanofi-Aventis were represented separately as their former legacy companies prior to the merger in 2005.
0273-2300/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2007.11.009
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S. Robinson et al. / Regulatory Toxicology and Pharmacology 50 (2008) 345–352
which are performed at more relevant doses for humans and are already an integral part of drug development. The conclusions have been discussed and agreed with representatives of regulatory bodies from the US, Japan and Europe. 2007 Elsevier Inc. All rights reserved. Keywords: Acute toxicity; Pharmaceuticals; Regulatory guidelines
1. Introduction 1.1. Background The pharmaceutical industry recognises the need to reassess the design and conduct of toxicology studies as new scientific practices and knowledge develop. The assessment often includes the consideration of the 3Rs principles (Russell and Burch, 1959) such that studies that are not providing optimal information are challenged and opportunities for replacing or reducing animal use are identified. Acute toxicity studies in animals are considered necessary for any pharmaceutical intended for human use. Historically, the first toxicity test performed has been the acute toxicity study (Casarett and Doull, 1999). The main objective of these studies is to identify a single dose causing major adverse effects/life threatening toxicity, which often involves an estimation of the minimum dose causing lethality. The studies are usually carried out in rodents, and consist of a single dose up to a limit of 2000 mg/kg, or the maximum technically achievable. In pharmaceutical drug development this is the only study type where lethality/ life-threatening toxicity is an endpoint as documented in current regulatory guidelines (Commission Directive, 2003; Center for Drug Evaluation and Research, 1996; ICH Japan, 1999). Scientists and animal protection groups have criticized the conduct of acute toxicity studies (Langley, 2005). The predictivity of rodent acute toxic effects for human acute toxic effects has long been disputed but never proven. In addition, in recent years there has been a change in strategy in the pharmaceutical industry such that early toxicology information is used to identify the most promising compounds to progress as potential human medicines. Acute toxicity tests are often no longer the first toxicology studies conducted therefore prompting this reassessment of acute toxicity tests in pharmaceutical drug development. In this paper we present evidence-based arguments to demonstrate that these studies have limited value in terms of preclinical and human safety assessment compared to the substantial adverse effects experienced by some of the animals. 1.2. Current regulatory climate In recent years, progress has been made in refining acute toxicity studies. Alternatives to the traditional LD50 test, designed in 1927 (Trevan, 1927) have been developed that significantly improve animal welfare. These are the fixed dose procedure, the acute toxic class method, and the up and down procedure (Botham, 2002) and these are partic-
ularly used in the hazard classification of chemicals. In 2002, the Organisation for Economic Co-Operation and Development (OECD) eliminated the oral LD50 (lethal dose in 50% of animals) test from its guidelines for the testing of chemicals. The International Conference on Harmonisation of the Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) has also provided the opportunity to refine acute toxicity tests, with the acceptance of data from dose escalation studies (ICH M3, 1997). However, ICH refers to national guidelines where they exist and these still indicate the requirement for acute toxicity data for pharmaceutical drugs. The requirements in terms of the species, exposure route and observation period vary between geographical regions as shown in Table 1. The European and US guidelines specify a second route that ensures exposure. It is worth noting that acute toxicity is the only study type where a route other than the clinical route is routinely required. Evidence of exposure in other study types is provided by a toxicokinetic assessment. 1.3. Working group objectives A European industry-working group was established in 2003 and currently represents 13 pharmaceutical companies and 5 contract research organisations (see author affiliations). Aptuit, HLS and UCB Pharma SA joined in 2007 and their data has been added to the survey retrospectively. The aim of the working group is to facilitate cooperation and data sharing on conventional acute toxicity studies in rodents. The objectives were (a) to review how acute toxicity data are gathered and used across the pharmaceutical industry and (b) to develop a strategy for challenging the guidelines on the requirement for acute toxicity where lethality/life threatening toxicity is an endpoint. The ultimate goal of the working group is to assess the relevance of acute toxicity data in the drug development process and to provide recommendations for alternative testing strategies to replace acute toxicity studies by using information derived from other studies. Acute toxicity testing of chemicals and intermediates by the pharmaceutical and chemical industries was not addressed as this is carried out for a different purpose and under different regulatory guidance. In addition, specifically designed extended single dose studies (e.g., microdosing, CHMP, 2004) and single dose studies for biotechnology products (ICH S6, 1997) are not part of the scope of this initiative as again the purpose and regulatory guidance for these studies are different to those for standard therapeutic agents and regimens.
S. Robinson et al. / Regulatory Toxicology and Pharmacology 50 (2008) 345–352 Table 1 Regulatory framework EEC
US a
2 Species 2 Routes, clinical route plus a route ensuring exposurec 7–14-Day observation
Japan b
2 Species 2 Routes (as EEC) 14-Day observation
2 Speciesb Clinical 14-Day observation
a
Usually rat and mouse. US/Japan: specify a non-rodent. Dose-escalation is acceptable alternative for non-rodents; no region mentions dose-escalation as alternative for rodents. c Only study type where a second route (parenteral, usually intravenous) is routinely required. b
This initiative has the full support of the European Federation of Pharmaceutical Industries and Associations (EFPIA), in particular the preclinical safety group.
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An initial data sharing exercise was undertaken by the working group to compare the design of acute toxicity studies and to review how internal regulatory and clinical colleagues use the data generated. All of the companies involved in the working group completed a questionnaire on study designs for pharmaceutical drugs at the time they joined the working group. This included questions on standard acute toxicity package and the timing and purpose of the studies. Detail was also gathered on specific study designs and numbers of animals used for acute toxicity studies. Data were collected from all companies able to supply the information. One contract research organisation has no set policy on acute toxicity studies and no information was included for this company. Therefore, in some of the figures presented in this paper the total number of companies may not equal 18. 2.2. Results
2. Obtaining information on current practice 2.1. Initial discussions and data sharing Historically, there were preclinical (Sections 2.1.1 & 2.1.2) and clinical (Section 2.1.3) objectives proposed for conducting acute toxicity studies in the development of new medicines. 2.1.1. Dose selection Preclinically, it was often assumed that the data from acute toxicity studies might be used to aid dose selection for other studies and provide preliminary target organ toxicity. However, initial discussions within the working group indicated that for many companies the acute study is no longer the first toxicology study performed and dose-selection information is gained from many other study types, including non-GLP (Good Laboratory Practice) exploratory studies. 2.1.2. Identification of target organs of toxicity It is also often stated that such studies support identification of target organs of toxicity. However, since microscopic pathology is not routinely performed on acute toxicology studies they of very limited value to identify target organs. 2.1.3. Assessment of acute overdose situation Clinically, it is assumed that the data obtained from acute toxicity studies is used to give information on the likely effects of acute overdose in humans. Initial discussions indicated that the studies do not include clinical pathology, microscopic pathology or toxicokinetic evaluation and that the clinical observations seen in rodents at high doses are often non-specific and may help in assessing the lethal dose-range, but they do not add information that would support measures to be taken in overdose situations in humans. Therefore, studies evaluating vital organ functions in more detail, such as safety pharmacology studies, might be appropriate to support assessment of acute overdose.
At the start of the initiative there was variability in the acute toxicity packages conducted by the companies represented on the working group (Fig. 1a). For the majority of the companies the acute studies conducted were consistent with the European guideline, using two species (rat and mouse) and two routes of administration i.e. the intended human route of administration and a parenteral route (four rodent studies in total). The current European Guidelines do not specifically request a non-rodent species where (a) lethality is not an acceptable endpoint and (b) dose-escalation studies are an acceptable alternative. Several companies were using minimised study packages successfully within the confines of the current regulatory guidelines. This variability in acute toxicity packages is not unique to Europe. Six US companies completed the questionnaire and the results showed that there was a similar variability in acute toxicity packages from one rodent study to four rodent studies. The data from the US companies is not included in the figures in this paper. From current study designs, in general only very limited data, other than maximum non-lethal dose and minimum lethal doses, are provided (Fig. 2). The microscopic evaluation of selected tissues is extremely rare and done on a case-by-case basis. It is clear from the information collected that these studies are not used to identify target organs. There was large inter-company variability in the numbers of rodents used at the start of the initiative (Fig. 3a/ b). This is particularly evident in the use of mice, with four companies not using any mice and six companies using 60 to 100 or more mice per compound. The companies not using mice were those that had already employed a minimised approach to acute toxicity testing. The data also illustrated that the majority of the companies (13/17) conducted acute toxicity studies prior to the first clinical trial in humans. This timing appeared to be driven by the ICH M3, 1997 guideline that specifies the requirement for data prior to first clinical trial in humans,
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Fig. 1. (a) Survey of standard acute toxicity packages (2003–2005). (b) Survey of standard acute toxicity packages (2006). (c) Survey of standard acute toxicity packages (2007).
first clinical trial in humans. This approach places the acute toxicity studies later in the development programme resulting in a reduction in the number of compounds tested due to attrition during the development process. From the information collected it is clear there is inconsistency in the approach to providing acute toxicity data within the pharmaceutical industry. By sharing information the working group was able to demonstrate there was both the scope and willingness to agree upon a harmonised approach to reduce the number of studies and refine the design in the short term. In addition, an assessment of the scientific value of the data generated would form the basis to challenging the requirement for these studies in the longer term. Fig. 2. Data provided in toxicity studies.
although the guideline indicates dose escalation data are an acceptable alternative. Interestingly, one company conducted no acute toxicity studies at all. Two companies conducted studies prior to registration rather than prior to the
3. Obtaining information on how acute toxicity data are used prior to the first clinical trial in humans 3.1. Compound specific data sharing As the majority of companies conducted acute toxicity studies prior to the first clinical trial in humans, a data
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Data were collected on 34 compounds for which development was terminated prior to administration to humans and 40 compounds that entered into clinical trials in humans. An example of the types of data collected for a compound that was given in clinical trials is illustrated in Tables 2a and 2b. The types of information collected included therapeutic class, toxicological effects of concern, species and study type effects were identified in, dose levels required for effects of concern, reasons for termination of the compound, or justification for dose levels in man. Available acute toxicity data were also summarised. The following therapy areas were covered by the data on compounds that entered clinical trials in humans: cardiovascular, CNS/PNS, metabolic disorders, urology, inflammatory disorders, endocrine, gastro-intestinal, respiratory and anti-infective (Table 3). The data sharing demonstrated the following keypoints:
Fig. 3. a and b show the downward shift in number of rodents used per project in each company between 2003–2005 and 2007.
sharing exercise was conducted to assess how acute toxicity data are used at this stage in drug development. In this data sharing exercise two questions were addressed. (a) Are acute toxicity data used to stop development of compounds prior to the first clinical trial in humans? (b) Are acute toxicity data used to help define dose levels or to identify additional clinical monitoring required for the first clinical trial in humans?
- Acute toxicity studies were never responsible for termination of a compound. The most common reason for termination of compounds prior to the first clinical trial in humans was the identification of dose limiting target organ toxicity in the 2 or 4 week repeat dose toxicity studies (Table 4). - No additional information was gained from studies in a second rodent species. Data from 28 compounds given orally in both the rat and the mouse showed similar effects (e.g., either in terms of clinical observations or lethality) for 22 compounds at comparable doses (less than 20% difference in dose between the two species). For the remaining six compounds there was no more than a twofold difference in doses showing similar clinical observations or lethality between the two species. The picture was similar for 22 compounds given parenterally in both the rat and the mouse. - For approximately 25% of the compounds assessed, the data indicated non-rodents were more sensitive in detecting effects that determined dose levels in the first human clinical trials and therefore data from short term non-rodent studies already conducted as part of drug development may provide more useful information than acute studies in rodents.
Table 2a Data showing effects of concern for compound X and the studies where these were identified Therapeutic class
Toxicological effect(s) of concern
Species effect(s) were identified in
Primary study type(s) in which effect(s) were identified
Doses at which the effects of concern were seen (mg/kg)
Justification for starting dose in man
Justification for maximum dose administered in man
Reason for stopping dose escalation in man
Comments
Gastrointestinal
Cytochrome P4501A1 induction
Rat
One month study
19, 88, 38. No no-adverse effect level (NOAEL)
Cytochrome P4501A1 induction not considered relevant to man. Effects in the dog were used to limit doses/ exposure in man
Exposure at the NOAEL in the dog
—
—
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Table 2b Summary of acute toxicity data for compound X Therapeutic class
Effects of concern observed in acute toxicity (clinical route, oral)
Dose range in mg/kg (clinical route)
Effects of concern observed in acute toxicity (parenteral route)
Dose range in mg/kg (parenteral route)
Comments
Was the acute data used to set or justify human dose levels
Gastrointestinal
Mouse: not performed Rat acute: increased salivation, ploughing, pilo-erection, ataxia and hunched posture on the day of dosing Dog dose-escalation study: Emesis
Mouse: not performed Rat: minimum lethal dose >2000 mg/kg Dog: 25–300 mg/kg. Emesis with no increase in systemic exposure with dose
Mouse: not performed Rat: not performed
Mouse: not performed Rat: not performed
No mouse data. No parenteral route Dog dose escalation data used as an alternative to acute data
No
Table 3 Numbers of compounds for which data was shared within each therapy area Therapy area
Compounds terminated prior to the first clinical trial in humans
Compounds that entered clinical trials in humans
Cardiovascular Central/peripheral nervous system Metabolic Inflammatory Respiratory Endocrine Gastrointestinal Anti-infective Urology Oncology
5 9
3 9
4 5 7 1 0 2 0 1 Total = 34
7 5 4 3 5 1 3 — Total = 40
Table 4 The reasons for termination of the 34 compounds prior to the first clinical trial in humans Reason for termination
Number of compounds
Insufficient bioavailability Chemical stability issues Safety pharmacology issues Genetic toxicity issues Dose-limiting target organ effects in 2 and 4 week repeat dose studies with no margin of safety, and/or no biomarker Business reasons (e.g. class discontinued, switch to molecule with better safety or efficacy profile) Potential for developmental toxicity
1 1 2 2 22
5 1
- Acute toxicity studies were never used to set the dose levels for the first clinical trials in humans, identify target organs or to indicate markers for monitoring in the clinical trials. This information was obtained from the two to four week repeat dose toxicity studies where full bio-
chemical and histopathological evaluations were performed along with the measurement of plasma concentrations of drug. - No additional information was obtained from the parenteral route. The most common parenteral route was bolus intravenous injection giving a pattern of exposure completely different from that anticipated for the clinical route and often leading to a rapid onset of both clinical observations and substantial adverse effects. In addition, 19 of the 40 compounds that were given in clinical trials to humans did not have acute studies conducted by the parenteral route, demonstrating that this information was not essential. 3.2. Working group recommendations based on data-sharing Based upon the review of the 40 compounds that proceeded to human clinical trials, the following recommendations are made by the working group: • Acute toxicity studies should not be required prior to the first clinical trial in humans. • Any short term or dose-escalation data (including from non-GLP studies) should be considered acceptable to allow assessment of acute toxicity and this should be by the clinical route only. • In situations where overdosing may be a cause for concern (e.g., where there may be uncontrolled access to drug as in Phase 3 clinical trials or at registration) establish, by reviewing both the pre-clinical and clinical dataset, whether additional high dose information is necessary. In the majority of cases a stand-alone acute toxicity study should not be required. • Lethality should not be the primary endpoint. • Rather than using a second rodent species, data should be provided from a rodent and a non-rodent species preferably from short duration studies that are already an integral part of drug development and that include parameters in the study design that assist risk assessment. In November 2006 a workshop that included representatives of the European, Japanese and United States regula-
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tory bodies was held to discuss this topic. The participants, including the regulatory representatives, fully supported the recommendations of the working group (Chapman and Robinson, 2007). 4. Repeat survey of working group on current practice The questionnaire on acute toxicity packages and study design was repeated in May 2006 and June 2007. From the results of the repeat surveys, it was clear that the ongoing discussions within the working group and other working group activities had already facilitated the review of acute toxicity strategy within some of the working group companies. The working group members have adopted a minimised approach within the current regulatory requirements based on other companies experience in providing limited or no data from acute toxicity studies to regulators. During the time the working group has been reviewing the value of acute toxicity studies, the number of companies providing the full four-study package has significantly decreased. By 2007, the majority of companies now provide only one acute study plus other data, or no acute studies at all (Fig. 1b and c). These minimised strategies are within the constraints of the current regulatory guidelines. In addition, companies conducting acute toxicity studies prior to first clinical trial in humans have reduced from 13/17 initially to 6/17 in 2007 thus reducing the numbers of compounds for which acute toxicity studies are conducted. The number of rodents used in acute toxicity studies has also significantly decreased (Fig. 3). This is predominantly due to the fact that the majority of companies are conducting few if any acute toxicity studies. Where they are still conducted there has also been a reduction in the number of rodents used per study due to the sharing of best practice within the group. ICH M3 is currently undergoing revision (Section 6) and it will take time to finalise the guideline. In the meantime the working group is continuing to communicate its recommendations more widely to regulators, colleagues and companies not involved in the working group. This dissemination strategy has included leaflets, posters, presentations at conferences and an international regulatory workshop. Through the CROs on the working group, smaller companies are receiving information packs containing the information on the initiative and its recommendations. The significant changes in acute toxicity packages between 2006 and 2007 (Fig. 1b and c) indicate that the regulatory workshop and other dissemination activities during 2006 have had an impact on the number of acute toxicity studies carried out. 5. Discussion It is clear that the strategy for toxicity testing during pharmaceutical development has changed significantly over the years such that early toxicology information is used to identify the most promising compounds to progress as
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potential human medicines. Acute toxicity tests are often no longer the first tests performed and more useful data for dose setting in other animal studies are obtained from studies that are already an integral part of drug development and that do not have lethality or life threatening toxicity as an endpoint. Additionally it is clear from the sharing of data and analysis of 40 compounds that went into human clinical trials that acute toxicity data should not be required before first clinical trial in humans. Regulatory bodies in all regions support this recommendation. The only possible clinical reason for conducting acute toxicity studies is to support risk assessment in humans at a time when patients will have uncontrolled access to large quantities of drug, although the usefulness of the limited animal data set provided from acute toxicity studies is still questionable. The recommendations from this work are specifically focussed on the development of new medicines and regulatory guidance for pharmaceuticals. However, in Zbinden and Flury-Roversi (1981) reviewed the significance of the LD50 test for the toxicological evaluation of chemical substances. Some of the points made then have been clearly re-emphasised by the recent work e.g. that the data is extremely limited without laboratory diagnostic and histopathological assessments and that the data may not be that useful in dose setting for other animal studies. Given that this work is nearly 30 years old and the fact that the original ICH M3 clearly tried to reduce acute toxicity testing for pharmaceuticals over 10 years ago it might be questioned why there has not been more impact in the pharmaceutical industry. The section on single dose/acute toxicity in the current ICH M3 guideline is extremely brief and lacking in detail and therefore refers to national guidelines for more detail. It is possible that the lack of clarity in the national guidelines underpinning ICH M3 has been an inadvertent barrier to the implementation of the 3Rs. The approach taken by the working group has demonstrated the value of sharing and collating data in order to harmonise study designs and implement the 3Rs. More importantly the group have analysed how toxicological data on active pharmaceuticals are practically used to support the safety of potential new medicines given in human clinical trials. It has been the use of relevant data sets that has provided the evidence needed to convince both the pharmaceutical companies involved and the regulatory bodies that acute toxicity studies are clearly of limited value in pharmaceutical drug development. This has allowed the final steps to be taken to implement the reduction and replacement of acute toxicity testing in pharmaceutical drug development. Establishing whether acute toxicity studies are required for predicting human overdose is the next stage and an ongoing collaboration with the Lyon Poison Centre will be pivotal in determining whether acute toxicity information is needed to provide information that assists in the management of overdose situations. This initiative illustrates the benefits that can be achieved in terms of implementing the 3Rs by a coordinated
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approach and sharing data within the pharmaceutical industry and with regulatory bodies to reach a common position based on evidence and science. It is important to consider where else a similar strategy could be applied to enhance the application of the 3Rs.
to be acceptable supporting information on single high dose toxicity. The results show that there should be no requirement for stand-alone acute toxicity studies as these are not pivotal in human safety assessment. References
6. Conclusion Acute toxicity data are: • Extremely limited with regard to the parameters examined, concentrating on minimum lethal and maximum non-lethal doses. • Of less use than other, less harmful animal tests that are superior for deciding appropriate doses for further studies using animals. • Do not provide information on the nature of toxic effects, which are better evaluated in other routine studies. • Not, in practice, used to set doses in the first human clinical trials because other routine studies provide more informative data. The topic of acute toxicity requirements is currently being addressed via the revision of ICH M3 and this has been an opportunity to incorporate the recommendations made by the working group into the new guidance. The recommendations were supported by representatives of the international regulatory bodies at the workshop held in November 2006 (Chapman and Robinson, 2007). At this stage the draft ICH guidance has incorporated all the recommendations of the working group. Acceptance of the recommendations will effectively lead to ‘replacement’ of acute studies in time as non-GLP dose-range finding information from rodent and non-rodents should be considered
Commission Directive 2003/63/EC of the 25th June 2003 amending directive 2001/83/EC of the European parliament and of the council on the community code relating to medicinal products for human use, Annex I. Official Journal of the European Communities L159 27/6/ 2003, pp. 46–94, Brussels. Botham, P.A., 2002. Acute Systemic Toxicity. ILAR J, 2002;43 Suppl:S27–30. Review. Casarett and Doull’s Toxicology. The basic science of poisons. (Fifth Edition). Companion Handbook. Edited by C.D. Klaassen and J.B. Watkins III. Published by McGraw-Hill. 1999. Center for Drug Evaluation and Research (CDER) Guidance for Industry, August 1996. Single dose acute toxicity testing for pharmaceuticals. Pt 1.