Section II: Benefit-Risk Management Principles and Practices
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
94
Conclusion
The safety-monitoring process for a novel
drug begins in the preclinical phase before
the first human dose is administered. The data
produced in this process are used to support
the safety-related conclusions put forward in
the investigator’s brochure, informed consent
document, clinical trial protocols, and other
regulatory submission documents, such as the
IND application and the new drug application.
The overall goal is to have strategies in place for
managing any identified toxicology risks and to
estimate a safe starting dose and dose escalation
plan for the FIH clinical trial. Taking an exam-
ple from the previously discussed hypothetical
GLP-1 analog drug candidate where the ETLA
identified several potential toxicology liabilities
(Appendix 6-1), the ensuing preclinical studies
validated these concerns and identified new
issues, including the potential for thyroid C-cell
carcinoma, for which a risk management or
minimization strategy was formulated to enable
the IND application and the FIH study (Table
6-3). Therefore, a thoughtful and purposeful pre-
clinical safety assessment provides a foundation
for an integrative interpretation of all relevant
information to establish a safe starting dose and
minimize the potential for adverse clinical events
during subsequent clinical trials.
References
All URLs were accessed on 25 October 2022.
1. Dean JH, Olson HM. The integration of investigative
toxicology in the drug discovery process. Biol Cell.
1993 77:3-8.
2. Bass AS, et al. Exploratory drug safety: A discovery
strategy to reduce attrition in development. J Pharmacol
Toxicol Methods. 2009 60: 69-78.
3. Caldwell GW, et al. The new pre-preclinical paradigm:
Compound optimization in early and late phase drug
discovery. Cur Top Med Chem. 2001 1:353-66.
4. Kramer JA, et al. The application of discovery
toxicology and pathology towards the design of safe
pharmaceutical lead candidates. Nat Rev Drug Discov.
2007 6:636-49.
5. Jacobson-Kram D, et al. Leveraging exploratory
investigational new drug studies to accelerate drug
development. Clin Cancer Res. 2008 14:3670-74.
6. Stevens JL. Future of toxicology-mechanisms of toxicity
and drug safety: Where do we go from here? Chem Res
Toxicol. 2006 19:1393-401.
7. International Conference on Harmonisation. Safety
Pharmacology Studies for Human Pharmaceuticals
S7A Step 4. 08 November 2000. https://database.ich.
org/sites/default/files/S7A_Guideline.pdf
8. Claude JR, Claude N. Safety pharmacology: An essen-
tial interface of pharmacology and toxicology in the
non-clinical assessment of new pharmaceuticals. Toxicol
Lett. 2004 151:25-28.
9. Kinter LB, Valentin J-P. Safety pharmacology and risk
assessment. Fundam Clin Pharmacol. 2002 16:175–82.
10. Luft J, Bode G. Integration of safety pharmacology
endpoints into toxicology studies. Fundam Clin
Pharmacol. 2002 16:91–103.
11. Strauss DG., et al. Translational models and tools to
reduce clinical trials and improve regulatory decision-
making for QTc and proarrhythmia risk (ICH E14/
S7B updates). Clin Pharmacol Ther. 2021 109.2:319-33.
12. Williams PD. The role of pharmacological profil-
ing in safety assessment. Regul Toxicol Pharmacol.
1990 12:238-52.
13. Gad SC. Safety Evaluation of Pharmaceuticals and
Medical Devices. Springer 2011:23-44.
14. European Medicines Agency. ICH S6 (R1) Preclinical
safety evaluation of biotechnology-derived pharma-
ceuticals. Last updated 25 July 2011. https://www.
ema.europa.eu/en/ich-s6-r1-preclinical-safety-evalua-
tion-biotechnology-derived-pharmaceuticals
15. Bussiere JL, et al. Alternative strategies for toxicity
testing of species-specific biopharmaceuticals. Intl J
Toxicol. 2009 28:230-53.
16. European Medicines Agency. Guideline on strate-
gies to identify and mitigate risks for first-in-human
clinical trials with investigational medicinal prod-
ucts. Revision 1. Dated 20 July 2017. https://www.
ema.europa.eu/en/documents/scientific-guideline/
guideline-strategies-identify-mitigate-risks-first-hu-
man-early-clinical-trials-investigational_en.pdf
17. Food and Drug Administration. Estimating the
maximum safe starting dose in initial clinical trials for
therapeutics in adult healthy volunteers [guidance].
Current as of 24 August 2018. https://www.fda.gov/reg-
ulatory-information/search-fda-guidance-documents/
estimating-maximum-safe-starting-dose-initial-clini-
cal-trials-therapeutics-adult-healthy-volunteers
18. Horvath CJ, Milton MN. The Tegenero incident
and the Duff Report conclusions: A series of unfor-
tunate events or an avoidable event? Toxicol Pathol.
2009 37:372-83.
19. Agoram BM. Use of pharmacokinetic/pharmaco-
dynamic modeling for starting dose selection in
first-in-human trials of high-risk biologics. Br J Clin
Pharmacol. 2009 67:153-60.
20. Buckley LA, et al. “Estimation of human starting
dose for phase I clinical programs. In: Cayen MN, ed.
Strategies and Routes to First-in-Human Trials. John
Wiley and Sons NY: 2011:423-463.
21. Mager DE, et al. Scaling pharmacodynamics from in
vitro and preclinical animal studies to humans. Drug
Metab Pharmacokinet. 2009 24(1):16-24.
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
94
Conclusion
The safety-monitoring process for a novel
drug begins in the preclinical phase before
the first human dose is administered. The data
produced in this process are used to support
the safety-related conclusions put forward in
the investigator’s brochure, informed consent
document, clinical trial protocols, and other
regulatory submission documents, such as the
IND application and the new drug application.
The overall goal is to have strategies in place for
managing any identified toxicology risks and to
estimate a safe starting dose and dose escalation
plan for the FIH clinical trial. Taking an exam-
ple from the previously discussed hypothetical
GLP-1 analog drug candidate where the ETLA
identified several potential toxicology liabilities
(Appendix 6-1), the ensuing preclinical studies
validated these concerns and identified new
issues, including the potential for thyroid C-cell
carcinoma, for which a risk management or
minimization strategy was formulated to enable
the IND application and the FIH study (Table
6-3). Therefore, a thoughtful and purposeful pre-
clinical safety assessment provides a foundation
for an integrative interpretation of all relevant
information to establish a safe starting dose and
minimize the potential for adverse clinical events
during subsequent clinical trials.
References
All URLs were accessed on 25 October 2022.
1. Dean JH, Olson HM. The integration of investigative
toxicology in the drug discovery process. Biol Cell.
1993 77:3-8.
2. Bass AS, et al. Exploratory drug safety: A discovery
strategy to reduce attrition in development. J Pharmacol
Toxicol Methods. 2009 60: 69-78.
3. Caldwell GW, et al. The new pre-preclinical paradigm:
Compound optimization in early and late phase drug
discovery. Cur Top Med Chem. 2001 1:353-66.
4. Kramer JA, et al. The application of discovery
toxicology and pathology towards the design of safe
pharmaceutical lead candidates. Nat Rev Drug Discov.
2007 6:636-49.
5. Jacobson-Kram D, et al. Leveraging exploratory
investigational new drug studies to accelerate drug
development. Clin Cancer Res. 2008 14:3670-74.
6. Stevens JL. Future of toxicology-mechanisms of toxicity
and drug safety: Where do we go from here? Chem Res
Toxicol. 2006 19:1393-401.
7. International Conference on Harmonisation. Safety
Pharmacology Studies for Human Pharmaceuticals
S7A Step 4. 08 November 2000. https://database.ich.
org/sites/default/files/S7A_Guideline.pdf
8. Claude JR, Claude N. Safety pharmacology: An essen-
tial interface of pharmacology and toxicology in the
non-clinical assessment of new pharmaceuticals. Toxicol
Lett. 2004 151:25-28.
9. Kinter LB, Valentin J-P. Safety pharmacology and risk
assessment. Fundam Clin Pharmacol. 2002 16:175–82.
10. Luft J, Bode G. Integration of safety pharmacology
endpoints into toxicology studies. Fundam Clin
Pharmacol. 2002 16:91–103.
11. Strauss DG., et al. Translational models and tools to
reduce clinical trials and improve regulatory decision-
making for QTc and proarrhythmia risk (ICH E14/
S7B updates). Clin Pharmacol Ther. 2021 109.2:319-33.
12. Williams PD. The role of pharmacological profil-
ing in safety assessment. Regul Toxicol Pharmacol.
1990 12:238-52.
13. Gad SC. Safety Evaluation of Pharmaceuticals and
Medical Devices. Springer 2011:23-44.
14. European Medicines Agency. ICH S6 (R1) Preclinical
safety evaluation of biotechnology-derived pharma-
ceuticals. Last updated 25 July 2011. https://www.
ema.europa.eu/en/ich-s6-r1-preclinical-safety-evalua-
tion-biotechnology-derived-pharmaceuticals
15. Bussiere JL, et al. Alternative strategies for toxicity
testing of species-specific biopharmaceuticals. Intl J
Toxicol. 2009 28:230-53.
16. European Medicines Agency. Guideline on strate-
gies to identify and mitigate risks for first-in-human
clinical trials with investigational medicinal prod-
ucts. Revision 1. Dated 20 July 2017. https://www.
ema.europa.eu/en/documents/scientific-guideline/
guideline-strategies-identify-mitigate-risks-first-hu-
man-early-clinical-trials-investigational_en.pdf
17. Food and Drug Administration. Estimating the
maximum safe starting dose in initial clinical trials for
therapeutics in adult healthy volunteers [guidance].
Current as of 24 August 2018. https://www.fda.gov/reg-
ulatory-information/search-fda-guidance-documents/
estimating-maximum-safe-starting-dose-initial-clini-
cal-trials-therapeutics-adult-healthy-volunteers
18. Horvath CJ, Milton MN. The Tegenero incident
and the Duff Report conclusions: A series of unfor-
tunate events or an avoidable event? Toxicol Pathol.
2009 37:372-83.
19. Agoram BM. Use of pharmacokinetic/pharmaco-
dynamic modeling for starting dose selection in
first-in-human trials of high-risk biologics. Br J Clin
Pharmacol. 2009 67:153-60.
20. Buckley LA, et al. “Estimation of human starting
dose for phase I clinical programs. In: Cayen MN, ed.
Strategies and Routes to First-in-Human Trials. John
Wiley and Sons NY: 2011:423-463.
21. Mager DE, et al. Scaling pharmacodynamics from in
vitro and preclinical animal studies to humans. Drug
Metab Pharmacokinet. 2009 24(1):16-24.