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Transcript of New Drug Discovery.pptx
NEW DRUG EVALUATION
Dr. Bijoy Bakal
INTRODUCTION:
• Drug development -Scientific endeavor
• Highly regulated
•Complex & time-consuming process
DRUG DISCOVERY:
Challenging & Expensive
With technology advance-
Time taken for drug discovery
Cost of drug discovery
AIM: Develop clinically efficacious & safer drug
Economically viable
Discover entirely new class of drug
Discover new use of old drugs
Explore mechanism/ pharmacodynamics property
BROADLY DIVIDED INTO 3 PHASES:
1. Drug discovery phaseCandidate molecules are chosen
2. Preclinical phaseAnimal studies are performed
3. Clinical trial phaseEvaluated for efficacy, safety and adverse effects
METHODS OF DRUG DISCOVERY:
1. Random/nontargeted screening
2. Serendipity (by chance)
3. Rational drug designing (High throughput screening)
4. Mechanism-based drug design
PRECLINICAL EVALUATION PHASE (ANIMAL STUDIES):
• Performed according to GLP
• Major areas:
Pharmacodynamic studies.
Toxicological studies -OECD-425 Guidelines.
Pharmacokinetic studies.
Assessment of safety index.
TYPES OF ANIMAL TEST: General Screening for Pharmacological effects
Hepatic & Renal Function monitoring
Blood and Urine Tests
Gross & HPE of tissues
Tests of Teratogenicity
Mutagenesis
Carcinogenecity
TRANSGENIC & KNOCKOUT ANIMAL MODELS:
Powerful tool for Drug Discovery, Gene Therapy
Knock-ins & floxP system - manipulate gene
functions in particular tissues
Extensive use in cancer, obesity (ob/ob knock out
mice), heart disease, arthritis, Substance abuse.
Eg. OncoMouse/ Harvard mouse
CLINICAL TRIAL PHASE (HUMAN TRIALS):
• Biomedical/behavioral research study in human
subjects
• Generate data for clinical claims
• Finding adverse effects
• After preclinical screening -IND application filed.
OBJECTIVES OF CLINICAL TRIALS: Identify the relationship between dose and
plasma concentration(PK)
Define the shape and location of dose/concentration/response curves for both desired and undesired effects
Identify the range of dosage/concentration producing maximum benefit with fewest undesirable effects
THE KEY PLAYERS IN A CLINICAL TRIAL:
Internal:
Sponsors
Contact research organization(CRO)
Medical writing team
Statistician
Clinical research associate
Principal investigator
Clinical research coordinator
Data management team
External:
Ethics Committee (IRB/IEC)
Regulatory/ licensing authority
Data safety monitoring boards
Central laboratories
CLINICAL TRIAL DESIGN:
i. Research design and protocol
ii. Types of control
iii. Volunteer and subject selection
iv. Number of subjects
v. Influence of the disease indication on trial design*Acute condition *Chronic condition
vi. Randomization-simple or stratified
vii. Duration of dosing
viii. Methods of clinical measurement-must be standardized.
GOOD CLINICAL PRACTICES (GCP)
Aim: i) To ensure that the studies are scientifically and
ethically soundii) To document the clinical properties of the
pharmaceutical substanceTwo cardinal principles:
i) Protection of the rights of human subjects ii) Authenticity of biomedical data generated
INVESTIGATIONAL NEW DRUG(IND) APPLICATION:
• Provides the data showing that it is reasonable to begin tests of a new drug in humans
• It is a result of successful preclinical development program
• It is a vehicle through which a sponsor advances to the stage of clinical trials
IND INCLUDES: Information on the composition of Drug. Source of Drug. Chemical & Manufacturing information. All data from animal studies. Proposed clinical plans & protocol. Names & Credentials of Physicians conducting
trial. Compilation of Key Data made available to
investigators & Institutional Review Boards.
IND APPLICATION TYPES:
1.Investigator IND
2.Emergency use IND
3.Treatment IND
ETHICS COMMITTEE AND ITS RESPONSIBILITIES:
Review and accord its approval to a clinical trial according to the protocol
Safeguard the rights, safety and well being of the trial subjects
Periodical review of the ongoing trial and to ensure SOPs are being followed
ETHICS COMMITTEE:• The ethics committee should have at least 7
members Chairperson(from outside the institute) Member secretary(from the clinical department) Medical scientists (Preferably a pharmacologist) Clinicians from various disciplines. One legal expert. One social scientist One lay person
PHASES OF
CLINICAL TRIALS
1. Is the data from Animal Studies Adequate?
2. What is the probable risk involved in giving the drug
to humans? Is it worth the risk?
3. Is there any need for a new drug in the disease under
consideration and if so does the new remedy seem
promising?
MICRODOSING [PHASE 0]:• Primary application of exploratory IND
studies.
• Permit collection of human pharmacokinetics and bioavailability data.
• MICRODOSE is 1/100th of the dose calculated to yield a pharmacological effect of a test substance and a maximum dose of 100µg.
MICRODOSING [PHASE 0]:
Can be initiated with less preclinical safety data.
Requires very less number of subjects
Requires fewer resources for selecting promising
drug
Techniques applied:
* Accelerated Mass Spectrometry
* PET
MICRODOSING [PHASE 0]:Human PK data can be used to:
Assist in the candidate selection process Determine the 1st dose in phase I Establish the likely pharmacological dose
Advantages: Select the best lead compound Save time Save money
PHASE-I HUMAN TESTING:(1ST IN HUMAN)
Phase I clinical studies sit at the interface between the end
of preclinical testing and the start of human exploration
Assess the safety of the drug in humans
Efficacy of the drug
Pharmacokinetic and pharmacodynamic parameters
Comprises of 20-80 healthy volunteers
PHASE-I HUMAN TESTING: DESIGN
Type of control- Generally placebo
Subject selection - Inclusion and exclusion criteria
Randomization- Blinding
Type of trial design- Parallel or crossover
Dosing- Estimation of the 1st dose is done using
preclinical studies
PHASE-I HUMAN TESTING: PROCEDURE
PHASE-I HUMAN TESTING: OUTCOME
Safe dose range is established
Bioavailability data depending on Cmax, Tmax, AUC,
t1/2, metabolic pathway, route and rate of
excretion
Nature of ADR
Secondary objectives like drug activity, potential
therapeutic benefits etc.
PHASE-I HUMAN TESTING: In India
Schedule Y requirements:
• Phase I trials are done to determine the maximum
tolerated dose in humans, pharmacodynamic
effects, adverse effects, if any, with their nature
and intensity as well as the pharmacokinetic
properties of the drug
• At least two subjects should be used for each dose.
Challenges:
Ethical issues arise due to the inclusion of
healthy volunteers as study subjects
Stringent monitoring of the subject is
required, as it is a first in human study.
PHASE-I HUMAN TESTING:
PHASE-II THERAPEUTIC EXPLORATION (1ST IN PATIENT)
• Comprises of 20-300 patient volunteers
• Done to assess-how well the drug works(efficacy) and continues the phase I safety assessments
• When development process fails it is usually in this phase: Failure due to toxic effects Failure due to decreased efficacy
PHASE-II THERAPEUTIC EXPLORATION:
Objectives: To explore the therapeutic efficacy and safety Identify common side effects Provide essential risk benefit assessment
Prerequisites: Preclinical safety data Early phase clinical trial data Regulatory authority and ethics committee approval
PHASE-II THERAPEUTIC EXPLORATION
Types of phase II IIa-In these studies, dosage which was safe in phase
I is used IIb- Done to establish a safe dose range in patients
Site: IIa- Single site IIb- Multiple centers
Players Investigators Patient volunteers
PHASE-II. TRIAL DESIGN:
PHASE-II THERAPEUTIC EXPLORATION
• Phase II studies are comparative studies with either placebo or gold standard treatment as the comparator
• Outcomes: Safe dosage schedule Characterization of Dose Response Curve Clinical benefit Pharmacokinetic characteristics Nature of Adverse Drug Reactions
PHASE-II THERAPEUTIC EXPLORATION: In India:
Schedule Y requirements:
• To determine possible therapeutic use, effective dose ,safety and pharmacokinetics• 10-12 patients should be studied at each
dose level. Studies limited to 3-4 centers.• In case of multinational trial number of sites,
patients and justification for undertaking such trials should be provided
PHASE-II THERAPEUTIC EXPLORATION
• Advantages: Efficacy of test drug is determined
• Challenges: If positive results are not obtained during this phase, dosage schedules for phase III cannot be determined
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
• Comprises of several hundreds to thousand patients
• Most expensive, time consuming, difficult trials to design and conduct
• Major component of New Drug Application(NDA)
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
• Additional information about effectiveness and safety to evaluate benefit-risk relationship
• Provide an adequate basis for extrapolating results
• It excludes many real world patients. Eg: those with other serious medical conditions, women of child bearing age etc
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
Objectives: Primary objective- Confirm the therapeutic benefit Confirm the preliminary evidence accumulated in
phase II• Site:
Multispecialty hospitals
• Subjects: Patient population of around 250-1000
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS: • Prerequisites:
Preclinical safety data. Early phase clinical trial data. Regulatory authority and ethics committee approval.
• Types of phase III: IIIa- Compulsory regulatory requirement for
submission of NDA IIIb- Extended trials of IIIa after NDA submission,
done before launch and are a marketing need.
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS: TRIAL DESIGN:
Control types: placebo, gold standard, different doses
of the drug
Patient population should be representative of the
general population
Influence of disease indication
Randomization and blinding (usually double blinding
is preferable)
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
• Types of trial design: Either parallel, crossover or factorial
• Outcomes: Efficacy confirmed in a Realistic Population Efficacy assessed in Special Population Tolerability And Safety Advantages and Disadvantages over standard
treatment
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS: In INDIA
Schedule Y requirement:
• Data on at least 500 patients over 10-15 centers and
post marketing surveillance for ADR must.
• For new drug approved outside India there should
be data on 100 patients over 3-4 centers.
• PK studies to be undertaken to verify that the data
generated on Indian population is in conformity
with that generated abroad.
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS:
Advantages:
Therapeutic confirmation
Less stringent inclusion/exclusion criteria
Simultaneous generation of large data
Results are generalizable
PHASE-III THERAPEUTIC CONFIRMATORY TRIALS: CHALLENGES
Approval from IEC/IRB.
Patient recruitment should be large and heterogenous
Training of staff and monitoring the trial
Central laboratory & Clinical trial supplies
Central data management and analysis
Different study outcomes, difficult to interpret
Drafting of a common final report and public issues
NEW DRUG APPLICATION(NDA)
• NDA - Formally propose that the FDA approve a new drug for sale & marketing
• Data gathered during animal studies and human clinical trials of an IND becomes part of the NDA
• Can be filed on completion of phase IIIa in the form of a dossier
NEW DRUG APPLICATION: GOALSTo provide FDA enough information to permit the reviewer to reach the key decisions:
•Whether the drug is safe and effective
•Whether the drug’s proposed labeling is appropriate and
what it should contain
•Whether the methods used in manufacturing the drug and
the controls used to maintain the drug’s quality are adequate
NEW DRUG APPLICATION:• After review of NDA, 3 possible action to the
sponsor:
Not approvable letter- Lists the deficiencies Approvable letter - Signals that, ultimately, the
drug can be approved after minor deficiencies corrected
Approval letter - States that the drug is approved
ABBREVIATED NEW DRUG APPLICATION (ANDA):
• Provides for the review & approval of a generic drug product
• Once approved, the applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the public
• “Abbreviated” because they are generally not required to include preclinical and clinical data to establish safety and efficacy.
POST MARKETING SURVEILLANCE
• Systematic detection and evaluation of adverse reactions
• Periodic Safety Update Reports (PSUR) to be submitted
every 6 monthly for 1st two years and thereafter, yearly
for two years to DCGI
• Ascertain whether further investigation needs to be
carried out
• Changes to the marketing authorization and product
information
PHASE-IV MARKETING STUDIES/EXPERIENCE STUDIES
Purpose: To extend knowledge about drug efficacy To confirm safety in a wider patient population
Involves comparison with available treatment:Example:
Compare different chemical entities eg: methyldopa versus propranolol for hypertension
PHASE-IV MARKETING STUDIES/EXPERIENCE STUDIES:
• These can also explore:
New indication for a product.
New dosage regimen.
New formulations.
• These mark the introduction of the drug into clinical practice.
• Randomization: Crucial aspect of phase IV trials is that they
should be based on a sound statistical design.
PHASE V:
Phase V is a growing term used in the literature
of translational research to refer to comparative
effectiveness research and community-based
research; it is used to signify the integration of a
new clinical treatment into widespread public
health practice.
SPECIAL CONSIDERATIONS
TRIALS FOR VACCINES: Given to healthy individuals mostly children & infants
Given to prevent disease
Biological products i.e., Highly complex substances
derived from living materials/ living organisms.
Require specialized assays & testing to assure their
quality and safety.
CANCER DRUG DEVELOPMENT-PHASE 0 TRIALS:
• Patients with the disease participate in Phase I studies
• Types of phase 0 trials: Imaging studies or measurement of agent
pharmacokinetic parameters Comparison of analogs to select a lead agent for
further evaluation Assessment for modulation of a molecular target in
a tumor
ORPHAN DRUGS:• To treat a rare medical condition, the condition itself
being referred to as “Orphan disease.”
• Developing of Orphan drugs is not only challenging but involves many disincentives, which include career disincentives, lack of funding, and the multiple areas of expertise that are required.
Advantages of developing an Orphan Drug: The time from Phase II to market is often shorter. Once a compound has been granted orphan
designation, the odds for approval are high (82%).
BIOLOGICS: Biologicals or “biologics” can be defined as products of
which the active substance is produced by or extracted from a biological source.
Eg: Vaccines, Blood or components, Somatic cells, Gene therapies etc.
Challenges in Development: The production and purification process is complex. Huge risks with regards to the safety profile. The predictability data of animals to humans is limited.
ROLE OF REGULATORY BODIES:
• In order to license or register a new chemical entity a pharmaceutical company should develop a dossier that describes the pharmaceutical quality, safety and efficacy of the product for a specified indication.
• Eg: USFDA, Drugs Controller General of India (DCGI)
DRUGS CONTROLLER GENERAL OF INDIA (DCGI):
The pharmaceutical industry in India is governed by
Drugs and Cosmetics Act 1940.
The legislation is enforced by the Central Govt
2 drug organizations exercise control over drugs:
CDSCO.
State Drug Control Organizations
FUTURE TRENDS IN NEW DRUG DISCOVERY:
High-throughput screening has undoubtedly emerged as a powerful lead-finding technology.
A new trend is the growing of biopharmaceuticals, particularly monoclonal antibodies e.g. Development of Secukinumab .
Genotyping to individualize drug treatments.
CONCLUSION:• Drug discovery revolutionized due to changes in
technology.
• Careful decision making during drug development is
essential to avoid costly failures.
• Novel initiatives include partnering between
governmental organizations and industry.
• In 2004, the FDA created the “Critical Path Initiative”
(CPI) project to guide the new drug development process
REFERENCE:
1. Goodman & Gilman’s : The Pharmaceutical
Basis of Therapeutics. 12th Edition.
2. Kulkarni SK. Handbook of Experimental
Pharmacology. 4th Edition.
3. Satoskar RS, Bhandarkar SD, Rege NN.
Pharmacology and Pharmacotherapeutics.
4. Various Internet Sources.