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.