From Drug Discovery and Development to Clinical Trial ...• Design protocols for 2-week pilot...
Transcript of From Drug Discovery and Development to Clinical Trial ...• Design protocols for 2-week pilot...
Translational MedicineFrom Drug Discovery and
Developmentto Clinical Trial:
Small Molecule vs Protein Product
Presented by
Ada Kung, Ph.D. DABT, MBA
Apr. 24, 2017
Expedient Solutions International, a drug
development and regulatory consulting company
• Alliance management leveraging on hands-on experience and
knowledge of both Greater China and US pharmaceutical/
biotechnology companies and CRO's
• Form strategic alliance with EPL/Aclairo in 2017
• Infrastructure planning including project management/
scheduling, budgeting design and planning/study or project
costing and analysis
• All aspects (preclinical, clinical, chemistry manufacturing, and
control, investigator’s brochure) of drug development of small
molecules, biologics, proteins, peptides, genetic & protein-
based vaccines and botanical products
• Project Management
• IND/NDA/BLA submissions to US FDA and China CFDA
•
2
ESI Preclinical Development
• Toxicology, PK/Metabolism, Safety Pharmacology,
Genetic Toxicology, and efficacy modelings
• Preclinical GLP laboratory design and building per
AAALAC requirement
• Alliance with pathology, toxicology, and
pharmacology labs in China and U.S.
• Report writing in both English and Chinese
3
What is Translational Medicine
• Turning Research into Medicines and
Treatment
• From Bench to Bed
• Bridging the gap between the discoveries at
the “Bench” and interventions and therapies
at the “Bedside”
• Research becomes an reality
4
New Drug Development Process
Drug DiscoveryPreclinical
DevelopmentClinical Development
In animal
studies
Multidisciplinary
research areas
In human
begins studies
5
6
NEW DRUG
DEVELOPMENT
PROCESSDrug discovery
Multidisciplinary approaches
Pre-clinical
development
For Potential drug candidate
Cellular Biology
Pharmaceutical Organic Chemistry
Basic and Clinical pharmacology
Toxicology
Pharmaceutical Development
Analytical Research
Molecular Modeling
Regulatory sciences
Animal studies (in-vitro & in-vivo)
IND filing &
Approval
Clinical
developmentClinical trials
Human beings
Pharmacokinetics (ADME)
Pharmacodynamics (Receptors, enzymes and channels level etc)
Toxicological (Toxicokinetics and toxicodynamics)
Posological (Doses of drugs) NDA filing and
approval
New drug
continue use
Phase-I
Who
Volunteers, Terminal illness (20-80)
Why
Safety, PK, PD, Toxicology, dose
range
By Whom
Clinical Pharmacologists
Phase-II
Who
Selected patients (100-200)
Why
Efficacy, PK, PD, Dosage schedule
By Whom
Clinical Pharmacologists & clinical
investigators
Phase-III
Who
Large sample of patients
Why
Results confirmation of Phase I, II
By Whom
Clinical investigators
Phase-IV
Post-marketing
surveillance study
Who
Patients regular treatment
Why
Long term safety, efficacy under
actual conditions
By Whom
All physicians
Drug Discovery
新藥研發
Drug Value 1X
Pre-clinical Studies 臨床前試驗
Pharmacology藥理Toxicology 毒理PK/PD 藥物動力學/藥效
File IND
IND 申請
Phase I/II Clinical Trails
臨床試驗第一/二期
Process
Development
製程開發Cell Line 細胞株Upstream Process 上游製程Downstream Process下游製程
Formulation劑型
Analytical Science分析方法
Protein Characterization
蛋白質定性
Pre-clinical material supply
提供臨床前試驗藥品
Drug Value 2X
Drug Value 4X
Drug Value 5X
Drug Value 10X
Translational Medicine 轉譯醫學
7
Drug Discovery - Development
(~$1B)• Years 0-3: Drug Discovery
• Years 4-5: Preclinical in vitro, in vivo
• Years 6-9: Clinical Trials
• Registration of the drug with USFDA
• Year 10+: Drug to market
• Year 10-11:Product Surveillance
• Phase IV : Observations/monitoring the product
8
Tools in Translational Medicines
• Analytical and bioanalytical methods: Method
development and validation
• Biomarkers: The use of pharmacology and safety
biomarkers in early drug development
• Toxicology, DMPK, Pharmacology and
Biological effects: Translation of animal efficacy
and toxicity to human
• CMC
9
Drug Discovery
10
Target
Discovery
Informatics
& Functional
Genomics
Lead
Discovery
Medical
Chemistry
Cellular
& Molecular
Pharmacology
Preclinical
Development
Target
IdentificationBioinformatics
Assay
Development
Library
Development
In Vitro
Drug ActivityPK
Target
ValidationGenomks
HTP
Screening
Structure-Based
Drug Design
Cellular
Disease Model
In Vitro
Pharmacology
Assay
DevelopmentProteomks
Biochemistry
& Enzymology
Medical
ChemistryMOA
Tox/Safety
Pharmacology
Drug
Candidates
Drug Discovery Plan
11
The New Discovery Process Poses
Many Challenges
12
Biomarker and Molecular
Diagnostic Development
Building Disease KnowledgeInternal Focus on disease delivers
diagnostics which further refine disease
understanding
Building Target KnowledgeTarget validation molecule becomes
therapeutic molecule
Building Biomarker KnowledgeInternal Focus on disease delivers
molecular markers which support
clinical studies
Biologics
Based
Molecule
Delivery
1-2 years
Target Validation
Adapted from IBM Business consulting services
Define
Disease
Models
Target ID/
Molecule
Selection
Preclinical
PoC
Target/Molecule
PoC In Man
Drug Discovery Plan
• Bioavailability study in the rat (more animals with more time points)
• In Vitro Microsomal P450 inhibition and drug-drug interaction studies
• CaCO2 permeability study
• Plasma protein binding and red cell binding assay
• In vitro efficacy studies with and without the microsomal preparation
• Biomarker research
• Analytical and bioanalytical method development
• Single dose PK study (linear or non-linear PK potential)
• Tissue distribution study (may combine with the PK study)
• In vitro screening for cardio-toxicity, hepatotoxicity…..
• 7-day mammalian tox/toxicokinetics study in the rat; formulation not necessary for oral small molecule drugs
• Establish safety margin based on the efficacy and toxicity data
• Preformulation
13
CYP 450 Interaction
• Liver is the major organ for drug metabolism / elimination
• Predominate enzyme system that metabolizes drugs is the
P450 (CYP450) family of enzymes which mediate oxidative
reactions, such as hydroxylations
• Could be used for species selection for animal toxicology
studies
– Select the animal species with the closest finger-print
metabolic profiles to human
• Could be used in the drug screening program: Select the drug
candidate that has the least adverse effect on the system
• Could be an useful tool in the combined drug therapy
14
In vitro Toxicity Testings
• hERG for cardiovascular toxicity
• Hepatocyte for hepatotoxicity
• Ames tests for genotoxicity and
carcinogenicity potential
• Could be combined with Cytochrome P450
studies
15
Biomarker
• What is a biomarker: “A characteristic that is
objectively measured and evaluated as an indicator
of normal biological processes, pathogenic
processes, or pharmacologic responses to a
therapeutic intervention.”
• Guidance for Industry (August, 2011)
– E16 Biomarkers Related to Drug or Biotechnology Product
Development: Context, Structure, and Format of
Qualification Submissions .
• Could be used as a surrogate end point for clinical
studies.
16
Preformulation
• Formulation Research: explore different
vehicles and establish stability of the drug
candidate.
• Initial oral route of administration: suspension
for animal toxicology study
• Formulation components had been used in
the marketed drugs.
17
Single Dose PK
• Animal Species: same as the projected
toxicology studies: the species with the
closest metabolic profiles to human.
• Wide enough dose range to reach saturable
PK
• Dose frequency for the toxicology study
based on the length of clearance half lives
• Ready for the determination of Bioavailability
18
Bioavailability
• Definition : "Fraction of a dose of drug that is
absorbed from its site of administration and reaches,
in an unchanged form, the systemic circulation."
• Applied for mostly oral drugs, also any route of
administration other than the intravenous routes.
• In vitro CaCO2 permeability study
• In vivo single dose PK study: AUC of oral /AUC of IV
• If bioavailability is low, will need lots more drug and
thus costly
19
7-Day Mammalian Toxicology in
the Rat• This is a pre-exploratory or pre-dose range
finding study
• No need to go any higher than 2,000 mg/kg
dose level
• To establish a safety margin
• To identify potential target organ of toxicity
• Get a preliminary idea of dose levels.
20
Additional Consideration for
Proteins• Most drugs are administered intravenously
and no bioavailability study needed
(exception: Subcutaneous injection)
• CaCo2 permeability not needed
• In vitro Genotox may not needed: solubility
• Microsomal studies not needed
• Immunogenicity is a major concern
21
Drug Development
22
Drug Development
• Preclinical: Lead Optimization (Drug
Discovery) → Toxicology/Safety, Formulation,
Analytical Method Development/Validation,
PK/PD/ADME → Investigational New Drug
(IND)
• CMC (Chemistry, Manufacture, Control)
• Clinical Trials
• Regulatory Affairs
• Project Management
23
Drug
Development
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
IND filing
Stage 1 (Initiation)
• Historical data
• Preliminary PK
• Potency/efficacy
• Safety margin
• Pre-formulation
• Analytical method
1
Stage 2 (Month 1 & 2)
•
•
•
•
•
2
Stage 3 (Month 3 & 4)
•
•
•
•
•
3
Stage 5 (Month 8 & 9)
•
•
•
•
5
Stage 4 (Month 5, 6, & 7)
•
•
•
•
4IND filing (Month 10)
•
•
6
24
Stage 1 (Initiation)
• Review all background information and historical
data
• Lead selection and optimization (optional)
• Preliminary PK, potency (efficacy), safety margin
• Pre-formulation
• Analytical method development for
characterization and assay
• Open dialogue with FDA, e.g. Pre-IND meeting
25
Guidance for Industry
• M3 Nonclinical Safety Studies for
the Conduct of Human Clinical Trials for
Pharmaceuticals. July 1997 ICH
• M3(R2) Nonclinical Safety Studies for the
Conduct of Human Clinical Trials and
Marketing Authorization for Pharmaceuticals
January 2010 ICH
26
ICH Guidelines (S6): Preclinical Evaluation of
Biotechnology-Derived Pharmaceuticals
• Case-by-case, Science-based approach
• Product used in Pharm/Tox studies comparable to product for initial clinical studies: Formulated product vs API
• Biological Activity, Receptor binding, Cross- rereactivity in man & a range of animal species
• Animal Species: Pharmacologically active in vitro/in vivo: epitope or receptor expression; transgenic animals expressing human receptors or homologous proteins
• Number of animals (increases in frequency & monitoring duration)/Gender
• Administration/dose selection: Route/frequency approximates clinical use, Doses of multiples of human dose, PK, NOAEL, MTD/MFD
• Immunogenicity: Antibody titers, Antibody influence on PK/PD, complement activities and pathology
27
Stage 2 (Month 1 & 2)
• Design protocols for 2-week pilot toxicity studies
(preferably in two different species).
• Audit and inspect preclinical CRO’s
• Start the preparation and protocol design for
safety pharmacology studies
• Continue on analytical method development and
formulation work
• Establish drug stability in the formulation
selected for the duration of toxicity studies.
28
Animal Species
• Small Molecule:
– Microsomal metabolic profile comparable to man: Rat, Dog,
Monkey or Rabbit
• Protein Product:– mAb:
Cross-reactivities with the target cell and adverse effect as a result of undesirable binding to tissues
Immune complex formation (Pathology)
In vitro cell-based assay and in vivo efficacy
Immunohistochemistry
– Cytokine: Exhibit comparable pharmacologic effect as in man
29
Dosing Regimen
• Duration, Frequency and Dose Level:
– approximates clinical design
– could be affected by PK/saturable PK and
clearance of the drug
Protein:
o Duration: could be limited by the antibody
formation against the protein drug (ADA)
30
Dose Selection
• NOAEL to MTD
• Often given by oral route, soluble formulation
not necessary
• Alternate routes of intravenous administration:
Continuous vs Bolus
Protein
o Could be limited by the formulation concentration
(MFD vs MTD)
31
Parameters to be Evaluated :
Proteins• Immunogenicity and anti-drug antibody titers
• Immunotoxicity:
– Inflammatory reactions at the injection site
– Distribution of surface antigen on target cells,
eg. CD4/CD8 ratios on T cells and CD20 for B cells
• Immune Function Assays: Natural killer cell activity,
Host resistance, Macrophage/Neutrophil function
32
Parameters Potentially Affecting
the Immunogenicity• May lose efficacy
• Presence of protein aggregate potentially increases
immunogenicity
• Subcutaneous (vs iv) injection more likely induce
immunogenicity
• The presence of foreign protein (non-self)
• mAb targeted at cell bound epitope ~Immune stimulating protein
• Pegalation decreases immunogencity
• Impaired immune system in cancer patients
• Modified Fc may be less immunogenic
33
Additional Considerations for
Study Design for Proteins• Recovery group:
– Evaluate reversibility (or the trend of reversibility) of toxicities or delayed
toxicities
– Allow more time for the antibody titer generation
• Metabolism and gene tox may not be needed
• Local tolerance (can be formulation)
• Case-by-case – Reproductive: Clinical indication & intended patient population: Tysabri for
MS
– Chronic and carcinogenicity: Generally inappropriate (growth factors)
• PK/TK
• Safety Pharm in one species
• Immune complex formation
34
Other Issues with mAb &
Proteins Preclinical Development• Dose response may be threshold dose dependent
• Toxicity of excipient components
• Protein aggregates and degradation products
• Bioassay and cell-based assay for drug release, tertiary
structure, potency
• Exaggerated pharmacology vs frank toxicity
• Formulation may affect immunogenicity and bioavailability and
the selection of route of administration (sc vs iv)
35
Stage 3 (Month 3 & 4)
• Initiate pilot toxicity study (including TK) in the rat and in the
non-human primate (or dog), two weeks apart.
• Pre-IND meeting– Documentation preparation.
– Request meeting and/or discussion with FDA
– Submit the document with all preliminary data to FDA to gain consent for
the GLP toxicity study design (hopefully before the start of GLP toxicity
studies)
• Receive results from the pilot toxicity studies and prepare for
the initiation of GLP toxicity studies.
• Protocol design for GLP toxicity studies finalized.
• Continue on analytical method development with validation of
the methods.
36
Stage 4 (Month 5, 6, & 7)
• Pre-IND meeting with FDA
• Initiate the GLP toxicity studies in rodent and non-rodent (4-
week dosing + 4 week recovery or alternative study design as
agreed upon between sponsoring company and FDA); either
concurrently or one month apart.
• Continue on formulation development with stability studies
• Start genotox & safety pharmacology studies
• On-going GLP PK studies to support IND
• Start IND submission document preparation
37
Stage 5 (Month 8 & 9)
• Develop clinical plan and protocols
• Review QA’ed data from CRO with the GLP toxicity studies
• Develop clinical plan and protocols and write investigator Brochure
• Validation of analytical methods completed to be used for the release of clinical materials
• Start looking for CRO’s for clinical trials
38
IND Filing (Month 10)
• Submit IND
• Complete the one-month stability study for clinical materials and data to be included in the IND
39
Toxicology Studies Post IND
Submission• Species and Route: same as pre-IND studies: small
molecules: rat/dog; protein and vaccine: rat/NHP
• Dosing Regimen and Duration: match the clinical
• Reproduction and Teratology: in 2 species toward mid and late Phase II clinical
• Start planning and initiating tox studies to support Phase III
– Chronic: 6 month rat and 9 month non-rodent
– Carcinogenicity: Rat or transgenic mouse model
40
How to set the Clinical Starting Dose
Based upon the results from animal toxicity studies
41
FDA Guidance
• Estimating the maximum safe starting dose in initial clinical
trials for therapeutics in adult healthy volunteers, July 2005:
HED
• S9 Nonclinical evaluation for anticancer pharmaceuticals,
March 2010
• Protein drugs:
• -No fixed alogrithm, case-by-case, and risk-benefit conditions
• -MABEL: Minimum Anticipated Biological Effect Level
• -PAD: Pharmacologically Active Dose
• -MRSD: Maximum Recommended Starting Dose
42
Clinical Starting Dose for an
Anti-cancer Drug• STD: Severely Toxic Dose:
• Clinical Starting Dose:
– STD 10: At 1/10 of severely toxic dose if rodents
– HNSTD:
Highest dose level that does not produce evidence of
lethality, life-threatening toxicities or irreversible findings
1/6 HNSTD in non-rodent
• Need Safety Factor
43
Chemistry Manufacturing
and Control
(CMC)
44
CMC
Stage 3/4 (Month 3~7)
•QC release API
Extensive characterization of
reference standard
Final formulation selected
Start preparation of API and drug
product per GMP for clinical supply
Further validation of analytical
methods
Discuss preliminary data with FDA Lead Optimization Phase (Month -5~-1)
• Month -5 Start development of analytical methods Preliminary API stability Start biological screening of different analogs, if any
• Month -4 ~ -2 Initial characterization
• Month -2 ~ -1 Process transfer to GMP manufacturing Develop acceptance criteria for analytical methods Develop pre-formulation
• Month -1 Develop preclinical formulation for tox studies
1
Stage 2 (Month 1 & 2)
•Start pre-IND phase
Continue process optimization
Start tech transfer
•Pre-formulation stability study
Start analytical methods validation
Start pilot tox study and preparation
for pre-IND discussion Start preparing API per GM
2
Stage 5 (Month 8 & 9)
•Continue on analytical methods
validation
Continue API synthesis
•Start stability study of the
clinical materials (drug product)
5
3/4
IND filing (Month 10)
•All tasks completed and QC
release API and drug product
File IND
6
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
IND filing
45
Clinical Development
• Phase 1
– Usually healthy volunteers
• Phase 2
– Proof of principle
• Phase 3
– Confirmation of efficacy and safety
46
Thank You!!!
47