Epidemiology 260Drug and Device Development

April 15, 2010Leslie Z. Benet, PhD

Department of Bioengeering and Therapeutic Sciences

Schools of Pharmacy and Medicine A good portion of the material presented in my

presentation comes from the American Course in Drug Development and Regulatory Science (ACDRS) http://bts.ucsf.edu/ACDRS/

ACTIVE CONSULTANCIES AND CONFIDENTIALITY AGREEMENTS • AGILE THERAPEUTICS INC. • INTEKRIN THERAPEUTICS • ALLERGAN • JOHNSON & JOHNSON • AMGEN • MILLENNIUM PHARMACEUTICALS • ASTELLAS PHARMA • PRECISIONMED • BOEHRINGER INGELHEIM • RIGEL, INC. • CHEMDIV INC. • SAVIENT PHARMACEUTICALS • GENENTECH • S*BIO PTE LTD • HOFFMANN-LAROCHE • VERTEX PHARMACEUTICALS • IMMUNE CONTROL INC.

CONFLICT OF INTEREST STATEMENTLeslie Z. Benet, Ph.D.

4/10

CORPORATE AND SCIENTIFIC ADVISORY BOARDS • CNSBIO PTY., LTD. • MEDICINES360 • HUREL CORP. • OPTIVIA BIOTECHNOLOGY INC. • IMPAX LABORATORIES INC. • PANACEA BIOTEC • LIMERICK BIOPHARMA • SILICO INSIGHTS • LIPOCINE, INC. • VIRAL GENETICS

                                                                                                                                                                                                                                                                    

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      

FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA

                                                                                                                                                                                                                                                             

                                                                                                                          

     

                                                                                                 

                                                                                                                                                            

  

     

                                                                                                                                                                                                                                                             

                                                                                                                          

www.fda.gov

FDA OrganizationFDA Overview

FDA CentersCBER CDER CDRH CFSAN CVM NCTRBlood Products

New Chemical & Biologic Drugs

In vitro Diagnostics

Domestic & Imported Food Safety

Animal Drugs

Biochemical & Molecular Markers

Vaccines Generic Drugs

Medical Devices

Seafood Medicated Animal Feeds

Quantitative Risk Assessment

Cellular & Gene Therapy

GMPs Radiological Products

Pesticides GMPs Animal Bioassay Data

Biological Establishments

Labeling & Promotion

GMPs Cosmetics Illegal Drug Use

Caloric Restriction

Tissues for Transplantation

Pharmacokin- etic Research

Device Standards

Food & Color Additives

Methods Development

Neuro-toxicology

Adverse Event Reporting

Adverse Event Reporting

Adverse Event Reporting

Nutrition Labeling

Developmental Toxicology

Risk Assessment

Methods Development

[Unfortunately no longer on the FDA web site

Non-Clinical Components of an IND

1. Best available descriptive name of the drug, including the chemical name and structure of any new drug substance (NCE)

2. Complete list of components of the drug3. Quantitative composition of the drug4. Name and address of the supplier of any new

drug substance and a description of the preparation (chemical synthesis or other method of manufacture) of any new drug substance

Definition of a New Drug“…any drug that is not generally recognized as safe and effective under the conditions

prescribed, recommended, or suggested in the labeling…”

A drug may be considered “new” because of its composition, its use, its dosage, or its dosage

form. It’s readily recognized that an NCE would be considered to be a new drug; however, a drug can be new resulting from composition of inactive ingredients, the proportion of ingredients, active

or inactive, or the combination of ingredients, active or inactive

Non-Clinical Components of an IND4. A description of the preparation (chemical

synthesis or other method of manufacture) of any new drug substance

Implications :

Is the “drug” substance pure? Analytical methodology for drug substance

and potential contaminants (intermediates)

Validation of analytical methodology

(Quality control vs. Quality assessment)

Controls on chemical process development

Selecting the “right” physico-chemical form of the drug substance

This process involves discovering, identifying and characterizing all available candidates (API

[active pharmaceutical ingredient] polymorphic forms, solvates/hydrates and related salts,

complexes/co-crystals etc), selecting the best crystal form(s) from the candidates, and

determining process boundary conditions among the selected API form and other related forms, by

thermodynamic principles.

Drug Synthesis Considerations

• Compound fully characterized• Raw materials available• Synthesis scaleable• Impurity profile understood; identification of potential

genotox impurities• Sufficient quantities available for analytical

development• Final salt form resolution/crystallization defined• pH and organic solvent solubility profile defined• Reasonable COGs (cost of goods) possible

Preliminary Testing of the Lead Compound

• Forced Degradation --Aids in the development of the analytical

methods, especially specificity• Preformulation and Excipient Compatability --Aids in the formulation approach and

formulation possibilities• “Open Dish” Stability --Aids in the selection of packaging and

selection of expiry or retest dates

Non-Clinical Components of an IND5. Methods, facilities and controls used for the

manufacture, processing, and packaging of the new drug (here new drug is the product)

Implications :

Are the non-drug (excipients) pure?

Analytical methodology for excipients and potential contaminants

Validation of analytical methodology (Quality control vs. Quality assessment) Controls on chemical process development

Non-Clinical Components of an IND

5. Methods, facilities and controls used for the manufacture, processing, and packaging of the new drug (here new drug is the product)

Implications :

Stability: effects of time (shelf life for drug, excipients and formulation), temperature, humidity

SOPs (standard operating procedures)

GMP (Good Manufacturing Practices)

Good Manufacturing Practices

The requirement that drugs, and the methods used in, or the facilities or controls used in their manufacture, processing, packing, or holding

conform with those practices that will assure that such drugs meet the requirements of the Act as to safety, and have the identity, strength, quality, and purity characteristics that they purport or are represented to possess. If they do not they are

adulterated.

“Current good manufacturing practice” is not defined in the Act or the regulations. The regulations concern themselves with specific criteria for buildings, equipment, personnel, components, master formula

and batch production records, production and control procedures, product

containers, packaging and labeling, laboratory controls, distribution records,

stability and complaint files.

FDA Statistics• ~ 10,200 employees; > 1/2 in Centers;

>1/3 in Regulatory Affairs; 1/8 in Commissioner’s Office

• Of all the money you spend 25¢ of every $1 goes to products regulated by the FDA

• Regulatory – 5 Districts responsible for > 90,000 establishments

• Budget FY 2007 $1.545 billion; $4/yr per person

Components of an IND

6. A statement covering all information available to the sponsor derived from preclinical investigations and any clinical studies and experience with the drug.

7. Copies of the labels for the drugs and informational material that will be supplied to the investigators. This material must describe the preclinical studies with the drug and describe all relevant hazards, side effects, contraindications, and other information pertinent to use of the drug by the investigator.

Historical New Chemical Entity (NCE) Success Rate

(Slide I first made about 18 years ago)

Traditional Med Chem

Rational Drug Design

Combinatorial Chemistry & High Throughput Screening

NCEs prepared

500

5,000

5,000,000

Evaluate PK/Metab/Tox

50

500

5,000

Clinical

3

3

3

Marketed Drugs

1

1

1 (an overestimate)

Preclinical Animal TestingTox & PK

Toxicity• Acute Tox, 2 weeks,

rodent/non-rodent, male/female, single dose, dose rising

• Long Term Tox, 6 months, multiple dose, dose rising

• Mutagenicity• Teratogenicity, rabbits• Carcinogenicity,

life time, rats

PK/Metabolism• Rodent/Non-rodent• Male/Female• Single dose,

dose rising• Multiple dose,

dose rising

Metabolism• Identify all the metabolites in each of the

preclinical species (rat, mouse, dog, cyno) in liver microsomes, hepatocytes, whole animals and compare with human liver microsomes and hepatocytes (use in lead compound selection and comparison with competitors compounds)

• Concern with saturable metabolism; not so much with saturable absorption

• Inducing liver enzymes (usual kills a compound)• Radiolabeled compound mass balance studies

with lead compound.

Pharmacokinetics

• Oral bioavailability

• Is clearance too high and half-life too short?

• Is clearance too low and half-life too long?

• Can animals be scaled to man?

• Time and dose nonlinearities (again increasing and decreasing dose normalized areas/exposure are worrisome)

• The extent of protein binding should have no influence on choosing a lead, except possibly for COG (cost of goods) considerations

Formal (GLP) Preclinical Safety Testing

• General Toxicity and Tolerability (repeated dose) -- Two species (rodent and non-rodent)

-- Broad and comprehensive assessment (screen) -- Duration at least as long as human exposure (min. 2 weeks)

-- Define MTD (maximum tolerated dose), NOAEL (no-observed adverse

effect level) and target organ/systems • Safety Pharmacology -- Acute effects on vital integrated organ systems

• CNS (central nervous system)• Respiratory• Cardiovascular (HR, BP, rhythm)

• Genetic Toxicology -- Gene mutation (Ames, bacteria) -- Chromosome damage (mammalian cells) -- In vitro (target cells) and in vivo (target cells)

Continued Nonclinical Safety Testing (Usually not done until after Phase 1/2 Human Studies)

• Reproductive and Developmental Toxicity Assessment -- Two species (rodent, rabbit, non-human primate)

-- Concentrate on periods of extraordinary susceptibility• Organogenisis (“teratogenicity”); roughly equivalent to second trimester• Peri- and post-natal development; roughly equivalent to neonates and infants

-- Purpose is to label for use in pregnancy and lactation

-- Disruption of early development patterns: physical and cognitive • Carcinogenicity -- Two species (rodent); generally life-time exposure paradigms

-- Multiple interpretational difficulties; threshold considerations -- Purpose is to label for extraordinary risks

• Specific Populations -- Juvenile animal studies

• Purpose driven (pharmacology, pharmacokinetics, adult effects)• Cardiovascular (HR, BP, rhythm)

Safety Risk: Prolonged QT Interval• Toursades de Pointes -- Polymorphic ventricular contraction (arrhythmia)

-- Target risk of <1:10,000 – 100,000

-- Predicted by prolongation of QT interval on EKG

-- Cause believed to be disruption of cardiac channels

• Preclinical assessment in intact, non-rodent animal model -- Dose causing a 10% or greater prolongation in corrected QT

-- Cmax comparison to upper levels of human exposure

• In vitro assessment

-- Generally focused on the IKr channel (rapid delayed potassium rectifier channel)

-- Voltage clamp studies of fresh cardiomyocytes

-- hERG: mammalian cell lines transfected with human ether-related aGOGO gene (IKr channel)

-- EC50 concentration (50% reduction in current)

< 1 μM 1-10 μM > 10 μM

Biologics (proteins, mAbs)• Consistency of therapeutic supply is problematic

-- Source, process, stability, demonstrated comparability

• Importance of species selection

-- Equivalent biological/pharmacological activity

-- Extrapolatable pharmacokinetics

-- Technical feasibility

-- Biological surrogates (BSUR)

• Immunogenic potential (antibody formation)

-- Reduced therapeutic effect

-- Abrogate effect of endogenous ligands

-- Prolong elimination

• Inflammatory reactions

-- Complex, poorly-understood, species dependent immune system

-- Potential for cytokine “storm”

Recognizing my Financial Disclosure, I want to discuss some recent

advancements by Hμrel Corporation, a company that I co-founded and for

which I serve as Chair of the SAB

PETA honored Hμrel with its “Proggy” Award for Best Scientific Achievement 2010

Liver

LungGas Exchange

Other Tissues (Non-metabolizing, non-accumulating)

Adipose

In

Out

The original vision: an “animal on a chip”(i.e., an in vitro, multi-tissue, microfluidic, cell-

based assay platform for improved pharmacological / toxicological prediction)

Working together with bioengineers and experts in liver microstructure we

developed microfluidic, cell-based biochips

Individual compartments contain cultures of living cells of different organs

Heterogeneous cell types mimic different organs or tissues of an animal (and humans)

Compartments fluidically interconnected Fluid and compounds recirculate as in a living system (See Nature, 435: 12-13, May 5, 2005;Forbes, August 15, 2005, pp. 53-54;The Observer, September 25, 2005, p.7;Newsweek, October 10, 2005, p.59)

Photo of early prototype silicon biochip

Hμrel (human relevant) CorporationA new model in private-private partnerships

www.hurelcorp.comHμRELstatic™ liver-simulative cellular co-culture; highest functionality available;

convenience of arriving ready for use “out of the box” in standard labware; robotics-compatible, established workflow-compatible (available Q3-Q4 2010)

HμRELflow™contract research service performed by Hurel.high-functioning liver-simulative cellular co-culture with additional attribute of flow; flow affords cellular functionality higher still by multifolds (available Q3-Q4 2010)

HμRELflow™customer-operable version of HμRELflow™. high-value, consumable biochips that arrive with HμRELstatic™ cells pre-cultured on them (Q1 2012)

“Allergy Test on a Chip™ skin allergenicity test to replace Local Lymph Node Assay (“LLNA”), animal-

based test widely used in cosmetics and industrial and consumer product toxicology (prototype 4Q11; production version 2013)

follow-on application areas multi-tissue; Hepatitis C and other virology; immunology; environmental

testing, biodefense testing