Drug Development Process

Drug Discovery Process

Drugs - & the improved quality of health they bring to the people are truly miracles of modern science.

(1)

What is Clinical Research?

Multidisciplinary, multibillion, multinational, industry governed by many complex & interrelated regulations and guidelines.

Historical Overview
Pharmaceutical industry came into being at the start of 19th century Earlier products were based on ancient art of pharmacy Proper clinical testing of new medicines was established as late as 1950s

Historical Overview
Thalidomide disaster of the 1960s led to pharmaceutical legislation for testing of drugs for efficacy and safety Process of clinical testing of drugs has continuously evolved, till its present global harmonization Emergence of CROs since 1990s has resulted in a shift away from permanent in-house CR staff to out-sourcing studies or whole development projects.

Economical Environment
Governments, the world over, are concerned about healthcare costs Growing geriatric population Introduction of modern pharmaceuticals & high technology procedures has an impact on clinical practice, from hospital-based to outpatient management e.g. peptic ulcers Shortening hospital stay time, e.g. treatment for myocardial infarction

Economical Environment
Role of Pharmacoeconomics (PE) & improvements in Quality of Life (QoL) Introduction of complex surgical techniques & diagnostic procedures e.g. MRI have increased healthcare costs Continuing AIDS epidemic, introduction of new expensive medicines have increased strain on limited financial resources

Economical Environment
Government reaction is to explore ways to either increase revenue or minimize costs, or both Modern pharmaceutical industry operates within this environment of cost control

Drug Discovery Process

The process for discovering , developing and testing new drugs encompasses some of the most exciting areas of scientific discovery today.

(2)

Drug Discovery Process

The research process is a complicated,timeconsuming,and costly one whose end result is never known at the outset. Discovering a new drug has been likened to searching for the proverbial needle in a haystack.

(3)

PRE-CLINICAL RESEARCH

CLINICAL STUDIES

NDA REVIEW

E
SYNTHESIS AND PURIFICATION

PHASE 1
E PHASE 2 PHASE 3
ACCELERATED DEVELOPMENT/REVIEW

ANIMAL TESTING

TREATMENT IND PARALLEL TRACK

SHORT-TERM LONG -TERM

INSTITUTIONAL REVIEW BOARDS
INDUSTRY TIME IND SUBMITTED FDA TIME
NDA SUBMITTED
REVIEW DECISION

SPONSER/FDA MEETINGS ENCOURAGED EARLY ACCESS

ADVISORY COMMITTEES

SUBPART E

SPONSER ANSWERS ANY QUESTIONS FROM REVIEW

(3) Literally hundreds, and sometimes thousands, of chemical compounds must be made and tested to find one that can achieve that desirable result without too serious side effects. The complexity of the process can be gauged, in part, by the diversity if scientific disciplines engaged in finding new drugs. Traditional organic and statisticians have been joined in recent years by new kinds of specialists. Biochemists study the chemistry of life processes. Molecular biologists study the molecules that make up living matter. Toxicologists investigate chemicals potential for harm. Pharmacologists look at how drugs work. And computer scientists apply the power of their sophisticated machines to analyze and assess new chemicals. Each provides a different way of looking for that needle.

Drug Discovery
The Process

Drug development is a lengthy and expensive process It is highly regulated It is fraught with risks It brings together people from many disparate backgrounds & disciplines, all working towards the same goal

Drug Discovery
The Goal To develop a drug that will benefit patients, satisfy prescribers & earn profits for the company Drug development is not always successful, but when it does lead to a new drug available to patients and doctors, it is a very satisfying endeavor.

A pyramid of uncertainty

Drug Discovery

For over 10000 chemicals screened only 1000 have biological activity Of these 1000, only 10 will/may advance so far as to be administered to humans Only 1 will/may reach the market place

A pyramid of uncertainty

Drug Discovery

Approximate cost to develop a new drug from concept to market is US$ 350 million Therefore process of drug discovery is fraught with great uncertainty & financial burden

Risk & Reward

The patent life for any new compound begins to tick as soon as it is registered Patent is available fro 20 years from date of registration By the time, the drug is launched only 5 to 10 years of patent life remains to maximize the return on investment

Risk & Reward

Therefore the need to complete all activities within the shortest possible time, without compromising on quality, rules and regulations

Legal Environment
Rules & Regulations
Pharmaceutical industry is highly regulated by local country laws, Declaration of Helsinki (DoH), ICH GCP guidelines & regulatory authorities DoH defines biomedical research in human subjects European Agency for Evaluation of Medicinal Products (EMEA) provides for pan-European registration

Legal Environment
Rules & Regulations

US FDA controls licensing of new medicines in the US Schedule Y of the Drug and Cosmetic Act of India is applicable in India ICH began as an attempt to harmonize requirements between the US, Europe and Japan

Legal Environment
Guidelines & SOPs
ICH-GCP guideline sets out the obligations of sponsors, investigators and monitors All pharma companies and CROs have their own SOPs based on GCP guidelines GCP has brought great improvement to the CR process, resulted in greater acceptance and credibility of data generated GCP is a vital factor contributing to successful drug registration

Evolution of a Drug
Rational drug design (exception sildenafil) Generation of lead compounds In-vitro tests Pre-clinical studies Pharmaceutics (dosage forms)

Evolution of a Drug
Analytical method development Clinical Studies/Development Registration for Marketing Authorization Post-launch studies and activities

Pre-Clinical Testing
Carried out to assess safety and biological activity so as to understand therapeutic ratio of the compound Various types of studies exist: in-vitro models to in-vivo animal studies For registration purposes a battery of tests is specified, covering genotoxicity, acute, subacute and chronic toxicity, oncogenecity, & fertility and reproduction

Pre-Clinical Testing
Genotoxicity
Potentially harmful effects of the compound upon genetic material occurring in the DNA within cells Mutagenic properties may represent a potential hazard in terms of carcinogenic potential of the compound Drugs for topical use are tested for irritation & sensitization potential to the skin

Pre-Clinical Testing
Toxicity
Performed to assess the possible risks of exposing humans to the compound Toxic effects caused by drugs in animals are often predictive of adverse reactions in humans Pre-clinical safety aims to establish whether potential drugs have side effects that might preclude or limit their therapeutic use Provides an indication of potential safety margins

Pre-Clinical Testing
Oncogenecity
To detect whether or not a compound has the potential to cause neoplastic changes in tissue/s. These studies are required when the drug is intended to be used continuously for long periods Meticulous records are essential as a vast data is generated & detailed autopsy is required on every animal

Pre-Clinical Testing
Reproductive Toxicology

These studies assess new compounds for their effect on the complex process of reproduction including fertilization, implantation, embryogenesis, foetal growth Studies for general reproductive effects examine whether male or female fertility is affected

Pre-Clinical Testing
Reproductive Toxicology

Developmental effects are investigated to detect abnormalities in the developing offspring Reproductive toxicology examines
Fertility & general reproductive performance Teratogenecity study Perinatal and postnatal study

Clinical Development
Phase I
First administration in humans occurs in young healthy volunteers
Specialist clinical pharmacology units with panels of volunteers are available Volunteers are carefully screened to avoid exposing them to any major risk Volunteers are paid a reasonable sum for their participation

Other populations may be involved later e.g. patients with hepatic or renal impairment, or elderly

Clinical Development
Phase I

Such studies provide information on tolerability of a range of doses, PK, & early dose-response relationship findings Data will also be generated on plasma concentrations & on PD activity, BA of the drug, its clearance mechanisms, metabolites

Clinical Development
Phase II

It is the first time that patients are exposed to the drug Such studies are conducted in units with specialist investigators Require prior regulatory & ethics approval

Clinical Development
Phase II
Identification of the optimum dose is crucial These studies attempt to identify the dose that produces efficacy with minimal sideeffects Short term exposure of the drug, usually include a placebo control, specialist investigators will measure surrogate endpoints (disease markers) by blood tests, scans or other means rather than conduct studies for long period of time

Clinical Development
Phase III

To assess the real outcome in a variety of patients who will receive the drug once launched Regulatory & ethics committee approval is mandatory Safety and efficacy determined

Clinical Development
Phase IIIb

Conducted for marketing purposes Studies start pre-launch but are not intended to form part of regulatory dossier Typically use market leader as comparator, hoping to achieve a benefit over the existing drug in order to maximize performance after launch

Pharmacoeconomics
QoL scales are included in pivotal studies to quantify other benefits of the drug, apart from simple efficacy E.g. Does lowering of BP matter per se, or should one measure effect of lowering BP on mortality due to stroke and heart disease?

Post-launch studies
Drug development program does not cease after the drug has been launched Pharma companies must have a strategy to develop new formulations, expand patient population, to seek new indications & to work with prescribers optimum patient profile. Case control studies or classical PMS studies