Risk Assessment in Drug Development (or How much of compound X is safe? ) (EYP 2006) Colin Fish

Risk Assessment in Drug Development (or How much of compound X is safe? ) (EYP 2006) Colin Fish

History All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy. Philippus Aureolus Theophrastus Bombastus von Hohenheim- Paracelsus (1493-1541)

Comparison of lethal doses of well known agents Agent LD50 (mg/kg) Ethyl alcohol 10,000 Sodium chloride 4,000 Ferrous sulphate 1,500 Morphine sulphate 900 Phenobarbital sodium 150 Picrotoxin 5 Strychnine sulphate 2 Nicotine 1 d-tubocurarine 0.5 Hemicholinium-3 0.2 Tetrodotoxin 0.10 Dioxin (TCDD) 0.001 Botulinum toxin 0.00001 From Casarett and Doull s Toxicology

Principles For new drugs, Preclinical Safety Assessment conducts a set of animal and in vitro studies with the active ingredient Defined by regulatory guidelines General expectation is to induce toxicity or show diligent attempts to maximise exposure Purpose: identify and characterise hazards establish dose-response and exposure-response relationships allow informed assessment of risks

isk Assessment: Pre-Test his scenario has high risk. (Agree/Disagree)

HAZARD - the inherent potential for harm RISK - the probability of harm under specific conditions

Risk Assessment and Drug Development Hazard Identification Scientific Processes Risk Assessment Process Hazard Characterisation Exposure Assessment Dose Response Science and Policy Risk Evaluation Modified from Haschek and Rousseaux Toxicologic Pathology Risk Management Technology and Social Decisions

Hazard identification and characterisation Cascade of studies, based on: Regulatory guidelines Internal harmonisation Acceptability to internal and external ethics boards Scientific rationale Not as simple as just following a recipe

Core Hazard Identification Studies Before Candidate Selection (CS) Early Safety Prediction ( target liability, QSAR) Compound activity profiling (e.g., receptors, enzymes) Screens for genetic toxicity and arrhythmogenic potential Acute in vivo toxicology (e.g., rat 7-day toxicology study) CS to First Time in Man (FTIH) Definitive genetic toxicity tests Dose-range and definitive 14-28 day toxicology Safety Pharmacology (CV, CNS, respiratory) FTIH to Proof-of-Concept (PoC) 3 to 12 month toxicology Reproductive toxicology (fertility, teratology) PoC to Launch Immunotoxicology Juvenile / postnatal development studies 2 year rodent carcinogenicity studies Additional specialized studies to characterize hazards Often modified by prior knowledge

Risk Assessment Multifactorial, multidisciplinary approach: Nature of the hazard (i.e. seriousness of the toxicity) Dose-response and exposure-response relationship Therapeutic Index ( safety margin ) Mechanism species specificity / relative sensitivity metabolism / tissue distribution Reversibility Availability of early markers Target population Risk/benefit ratio (depends on target disease) Comparison with existing therapy concept of acceptability of class effects

Clinical trials Drug development: clinical trials are progressive: Clinical trials sequence: Phase I: safety and tolerability in normal volunteers (small numbers, closely monitored) Phase II: safety and dose ranging / efficacy in patient volunteers (small numbers, closely monitored) Phase III: definitive efficacy in patients (large numbers, more extensive)

Progressive preclinical support Extended duration and scale of clinical trials: Studies to support Phase I and II (and III in US only) Duration of Clinical Duration of Repeated Dose Toxicity Studies Trial Rodent Non-rodent Single dose 2-4 weeks 2 weeks Up to 2 weeks 2-4 weeks 2 weeks Up to 1 month 1 month 1 month Up to 3 months 3 months 3 months Up to 6 months 6 months 6 months More than 6 months 6 months 6-9 months From ICH, topic M3

Importance of drug measurements Animal and human Sequence of blood samples at intervals after dose Limit of quantification required may depend on dose µg/ml ng/ml pg/ml For some drugs, total administered dose in man may be 25µg For some study types (e.g., PET biodistribution studies), dose might be <10µg May also need to track metabolites that are >10% of circulating drug-related material

Use of exposure measurements Exposure: plot for single animal Plasma concentration C max Area under curve (AUC) Time: 0 hours 12 hours 24 hours

Principles Prime focus is on the drug itself, and safety in volunteers and patients Also look at: impurities, extractables, solvents, degradation products, intermediates, metabolites etc safety of manufacturing staff, animal dosing technicians etc implications for accidental or deliberate overdose

Typical Sources of Impurities Starting materials Intermediates Processing Formulation Dosing devices Sterilisation Excess materials By-products Drug substance Drug Product Catalysts Storage? Solvents Impurities Excess reagents Starting materials By-products etc Leachables Degradation products

ICH Guidelines Some ICH guidance exists and is contained under Quality (Q) Topics - i.e., those relating to chemical and pharmaceutical Quality Assurance. Q3A Q3B Q3C Impurities in Drug Substances Impurities in Drug Products Residual Solvents Official ICH webpage: http://www.ich.org/

Q3A(R): Impurities in New Drug Substances Provides information on the qualification of impurities in new drug substances produced by chemical synthesis Applies to NDAs/MAAs and, retrospectively, to marketed drugs Maximum daily dose Qualification Threshold Identification Threshold 2 g/day 0.15% 0.10 % or 1 mg TDI 1,2 or 1 mg TDI 1,2 >2g/day 0.05% 0.05% 1 TDI = Total daily intake 2 Whichever is lower Note: Does not apply to biological or biotechnological substances - more specialised guidelines are available. Revised version adopted in EU - Feb 02

Genotoxic impurities Could argue there is no safe dose of a genotoxic agent (especially gene mutagens) FDA has asked for 1 ppm limit in some cases Recent EU guidance on genotoxic impurities Draft EMEA guideline (see http://www.emea.eu.int/) Document ref: CPMP/SWP/5199/02 Concept of threshold of toxicological concern 1.5µg total daily dose for life considered safe Suggestions of flexibility for short duration of treatment

Genetic toxicology Perspective on in vitro Positives Cytotoxicity Mutation frequency Increase Mutation frequency Increase Cytotoxicity Dose Dose LOW CONCERN HIGH CONCERN

Genotoxic impurities the conundrum 1.5ug daily dose, in a 50mg/day drug = 0.003% But according to ICH Q3A(R) threshold for identification of impurities is 0.1% There might be impurities below the threshold for identification that might be genotoxic but remain untested and not controlled to 1.5ug daily dose

Genotoxic impurities the conundrum Solution: assessment of synthetic route and chemical structure for potential impurities and degradation products Screening of predicted structures in silico for potential genotoxicity Analytical issues: Have to work up sensitive assays for theoretical impurities, to prove they are not there! Chemistry issues: If there are suspect impurities, they have to be controlled

Genotoxic impurities the conundrum Other ways out: Less problematic for low dose drugs for a 25ug/day drug anything <6% will be below 1.5ug limit Others: might show that amount potentially present does not significantly add to background exposure Example: formaldehyde Classified as probable human carcinogen and as a likely mutagen, but EPA limit in drinking water 1ppm 1 litre of water might contain 1mg formaldehyde Also can be formed from aspartamine A can of diet cola could contain >1.5mg

Principles

Principles

Principles

Principles

Backup slides

Q3B(R): Impurities in New Drug Products Degradation products of the active ingredient on storage Reaction products of the active ingredient with an excipient, container or closure system Maximum daily dose Qualification Threshold < 10 mg 1% or 50μg TDI 10 mg - 100 mg 0.5% or 200 μg TDI >100 mg - 2 g 0.2% or 3 mg TDI > 2g 0.15% Note: Less stringent than Q3A because easier to attain lower LOD/LOQ in drug substance, and because degradants are more likely to be similar to parent or metabolites. Revised version adopted in EU - Mar 03

Q3C: Residual Solvents Solvents have no therapeutic benefit But often critical part of synthesis as can enhance yield, or determine some characteristics (eg, crystal form, purity + solubility) Remove or limit content sufficiently in order to meet product specification good manufacturing practices safety requirements Three categories based on their safety (i.e. Permissible Daily Exposures ) Adopted in EU Sept 97. Also see CPMP/QWP/450/3 Apr 03

Categories of Solvent Class 1: unacceptable toxicity (includes known carcinogens) should be avoided unless product gives significant therapeutic benefit (anti-cancer) e.g. benzene (2ppm), carbon tetrachloride (4ppm) Class 2: irreversible toxicity including neurotoxicity, teratogenicity and non-genotoxic carcinogens, exposure limited to <50 mg/day (5000ppm), eg, cyclohexane, pyridine, methanol Class 3: low toxicity, exposure should be limited to 50 mg/day, but higher exposure may be justifiable on case by case basis eg acetic acid, ethanol, DMSO

Permissible Daily Exposures (PDE) The maximum acceptable daily intake of residual solvent in pharmaceutical products Literature reviewed and NOEL (or LOEL) from most relevant toxicity studies used to calculate PDE, where: PDE = NOEL x Weight adjustment F1 x F2 x F3 x F4 x F5 The weight adjustment assumes a standard 50kg patient Connelly et al, Pharmeuropa, 1997, 9 (1 - Suppl.) S1-68

Metals / Catalysts Draft CPMP/EFPIA guideline (CPMP/SWP/4446-2nd version released for consultation in June 02) Acceptable limits for residual metals arising from use of catalysts in synthesis of pharmaceuticals (e.g. Ni, Cu, Cr) As no therapeutic benefit, limit on safety & quality-based criteria Being developed using same rationale as for Q3C (i.e. PDE s - but taking dietary exposure into account) Not yet considered by ICH, but good starting point if needed If not listed, use 10 ppm default, unless data suggests otherwise Available on EMEA website http://www.emea.eu.int/pdfs/human/swp/444600en.pdf

Metals / Catalysts Concentration limits (ppm) Elements Oral Parenteral Pt, Pd, Ir, Rh, Ru, Os 5 (group) 0.5 (group) Mo, V, Ni, Cr 10 1.0 Cu, Mn 15 1.5 Zn, Fe 20 2.0 If 2 or more present, the total oral limit should not exceed 20 ppm; and parenteral 2 ppm For intakes >10 g/day, reduce limits pro rata Group limit applies for platinoids. If 2 or more are present, the group conc limit is applied to the total amount For other routes of administration use parenteral values, unless absorption will never exceed oral absorption, in which case use oral value