Pakistan Pharma Career DoorOnline Course on

Introduction to Pharmaceutical Dosage Form

Lecture # 03

New Drug Development and Approval Process

Facilitator

Naila Kanwal had done her B.Sc inBiochemistry and M.Sc inNeuropharmacology from Federal UrduUniversity. She completed her M.B.A inHuman Resource Management. She iscurrently affiliated with Searle Company Ltd.As Senior Officer Regulatory Affairs. We arethankful to her for her support.

PREPARED BY : NAILA KANWAL

Sr. Officer Regulatory Affairs

THE SEARLE COMPANY LIMITED

DEFFINATION :

Drug development is the process of bringing a

new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes pre-clinical research on microorganisms and animals, clinical trials on humans, and may include the step of obtaining regulatory approval to market the drug.

How it is absorbed, distributed, metabolized,

and excreted ?

Its potential benefits and mechanisms of action

The best dosage

The best way to give the drug (such as by

mouth or injection)

Side effects (often referred to as toxicity)

How it affects different groups of people (such as by gender, race, or ethnicity) different

How it interacts with other drugs and treatments

Its effectiveness as compared with similar drugs

• Drug development can generally be divided into phases. The first is the preclinical phase, which usually takes 3 to 4 years to complete. If successful, this phase is followed by an application to the FDA as an investigational new drug (IND).

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• Drug Development Tools are methods, materials, or measures that have the potential to facilitate drug development.

The Federal Food, Drug, and Cosmetic Act does not give the agency responsibility to develop new drugs. So, FDA physicians, scientists, and other staff review test results submitted by drug developers. The FDA determines whether the drug is safe enough to test in humans and, if so--after all human testing is completed--decides whether the drug can be sold to the public and what its label should say about directions for use, side effects, warnings, and the like.

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Step 1: Properly classify your healthcare productStep 2: Identify the claim of your healthcare productStep 3: Determine your healthcare marketStep 4: Develop your regulatory strategyStep 5: Establish a healthcare product development

planStep 6: Execute the product development planStep 7: Execute the clinical planStep 8: Collect your data for regulatory submission.Step 9: Collate your regulatory submissionStep 10: Ensure post-marketing compliance.

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Before testing a drug in people, researchers must find out whether

it has the potential to cause serious harm, also called toxicity.

The two types of preclinical research are:

In Vitro

In Vivo

Process1- Synthesis and Purification

2- Animal Testing

3-Short-Term Testing

4- Long Term Testing

5-Institutional Review Boards

FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for

preclinical laboratory studies. The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical

Laboratory Studies. These regulations set the minimum basic requirements for:

study conduct

personnel

facilities

equipment

written protocols

operating procedures

study reports

and a system of quality assurance oversight for each study to help assure the safety of FDA-regulated product

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds which

emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease; however,

little will be known about the safety, toxicity, pharmacokinetic and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to make a recommendation of the dose and schedule to

be used the first time an NCE is used in a human clinical trial ("first-in-man" [FIM] or First Human Dose

[FHD]).

Drug development is required to establish the physicochemical properties of the NCE: its chemical

makeup, stability, solubility. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a medicinal chemist, it can be manufactured on the kilogram and then on the ton scale. It will be further examined for

its suitability to be made into capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together

these processes are known in preclinical development as Chemistry, Manufacturing and Control (CMC).

Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. These generally constitute a number of tests designed to

determine the major toxicities of a novel compound prior to first use in man. It is a legal requirement that an

assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive

system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug

is to be delivered through the skin). While, increasingly, these tests can be made using in vitro methods (e.g. with

isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism

that the complex interplay of metabolism and drug exposure on toxicity can be examined.

The information is gathered from this pre-clinical testing, as well as information on CMC, and

submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug application or IND. If the IND is approved, development moves to the clinical phase.

Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies.

Phase I trials, usually in healthy volunteers, determine safety and dosing.

Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients.

Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients.

“Clinical research” refers to studies, or trials, that are done in people. As the developers design the

clinical study, they will consider what they want to accomplish for each of the different Clinical

Research Phases and begin the Investigational New Drug Process (IND), a process they must go

through before clinical research begins.

Clinical Trials consist of:• Designing Clinical Trials

• Clinical Research Phase Studies

• The Investigational New Drug Process

• Asking for FDA Assistance

• FDA IND Review Team

• Approval

The process of drug development doesn't stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to

ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility,

reproduction, immune system, etc.). The compound will also be tested for its capability to cause cancer (carcinogenicity testing).

If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the

desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application or NDA.

Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do

not work in clinical trials.

• Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.

In the IND application, developers must include:

• Animal study data and toxicity (side effects that cause great harm) data Manufacturing information

• Clinical protocols (study plans) for studies to be conducted

• Data from any prior human research Information about the investigator

• Asking for FDA Assistance

• Review Team

• The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities.

• Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor.

• Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete.

• Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data.

• Pharmacologist: Reviews preclinical studies.

• Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes. Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules.

• Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc.

• Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes.

Subject-Related CDER Guidance of Interest

• Single Dose Acute Toxicity Testing for Pharmaceuticals • Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs

• Safety Review

• Biopharmaceutical Review

• Chemistry Review

• Clinical Hold Decision

• Notify Sponsor

• Sponsor Notified of Deficiencies

• Study Ongoing

• The mission of FDA's Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in this country are safe and effective. CDER does not test drugs, although the Center's Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness.

Generally, this includes data and information in three broad areas:

• Animal Pharmacology and Toxicology Studies

• Manufacturing Information

• Clinical Protocols and Investigator Information

Types of INDs:Commercial INDs" are applications that are

submitted primarily by companies whose ultimate goal is to obtain marketing approval for a new product. However, there is another class of filings broadly known as "noncommercial" INDs. The vast majority of INDs are, in fact, filed for noncommercial research. These types of INDs include "Investigator INDs," "Emergency Use INDs," and "Treatment INDs."

CDER is the largest of FDA's six centers. It has responsibility for both prescription and nonprescription or over-the-counter (OTC)

drugs. For more information on CDER activities, including performance of drug reviews, post-marketing risk assessment, The other five FDA centers have responsibility for medical and radiological devices, food and cosmetics, biologics, veterinary

drugs, and tobacco products.Some companies submit a new drug application (NDA) to introduce

a new drug product into the U.S. Market. It is the responsibility of the company seeking to market a drug to test it and submit

evidence that it is safe and effective. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists

reviews the sponsor's NDA containing the data and proposed labeling.

The CDER's best-known job is to evaluate new drugs before they can be sold. CDER's evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. The center ensures that drugs, both brand-name and generic, work correctly and that their health benefits outweigh their known risks.