Summary 145

NON-CLINICAL DRUG DEVELOPMENT

A targeted drug has to go through from various studies such as non-clinical and clinical

studies. Non-clinical studies are also known as pre-clinical studies. It is a stage of

research that happens before clinical studies. During non-clinical studies important

drug safety data is collected. These studies are necessary before filing Investigational

New Drug (IND) application.

Objectives of Non-clinical Drug Development

The main objective of non-clinical study is to confirm that either the target drug is safe

for use in human or not. This is done by studying animal pharmacology and toxicology

testing.

The need for non-clinical studies:

Non-clinical studies are essential:

• To determine the lethal dose, toxic dose (like LD50, ED50, etc.).

• To determine the pharmacological action of the target drug.

• It is necessary to submit the animal testing report during the IND application.

• To determine the pharmacokinetic properties of a drug.

• To determine the route of administration.

Types of non-clinical study

There are two types of non-clinical study. These are:

1. Pharmacodynamics (What drug does to the body or how the drug makes the body

to react?)

2. Pharmacokinetics (What the body does to the drug?)

TOXICOLOGY

This study helps in determine the toxicity of the compound.

DRUG METABOLISM

It is defined as the chemical alteration of a drug in the body. This chemical alteration

converts nonpolar compounds to polar and lipid-soluble compounds to lipid-insoluble

compounds. The products of drug metabolism are called metabolites. Drug metabolism

includes conversion of:

• Active drug to inactive or less active metabolite (pharmacological inactivation). For

example, phenobarbitone to p-hydroxyphenobarbitone.

• Active to a more active metabolite (bioactivation or toxicological activation). For

example, codeine to morphine.

• Inactive to more active toxic metabolite (lethal synthesis)

• Inactive drug (pro-drug) to an active metabolite (pharmacological activation). For

example, phenacetin to paracetamol.

• Active drug to an equally active metabolite (no change in pharmacological activity).

For example, digitoxin to digoxin.

• Active drug to an active metabolite which is having different pharmacological

activity (change in pharmacological activity). For example, iproniazid to isoniazid.

146 Industrial Pharmacy

The main and major site of drug metabolism is liver. Other sites of biotransformation

because a variety of metabolising enzymes are present in liver.

GENERAL CONSIDERATIONS OF INVESTIGATIONAL NEW DRUG (IND)

APPLICATION

INDA filed before conducting clinical trials. It is a submission to the regulatory

authority requesting permission to initiate a clinical study on the new drug product

by sponsor.

IND is required

At the time of the clinical trial of an unapproved drug.

 

INTRODUCTION

Medicines have their existence in parallel with the existence of mankind. It is perhaps

as old as a human being. The current pharmaceutical industry is more systematic,

well organised and in compliance with respective guidelines. This is because of effective

pre- and post-approval regulation of new drugs and the existing drugs. Regulatory

affairs play this role for pharmaceutical manufacturing companies and the government

of the country. It is a new profession which emerges after government and

manufacturing companies felt the need for a bridge in them which promotes

coordination and communication. The regulatory affairs act as an interface between

government and manufacturing companies.

Regulatory affairs is actively involved in every stage of drug development in case

of new drug and post-approval surveillance in case of an existing drug. All the

applications for getting a pharmaceutical product approved for entering into the market

has been prepared by the regulatory department of companies. The regulatory

professionals act as liaison with government regulatory agencies. These applications

are reviewed by government regulatory agencies to check the compliance with issued

guidelines. The regulatory department of the company internally also liaison with

QC, marketing, production, administration and other departments of company to keep

them updated with changes in guidelines and to ensure their compliance with the

guidelines.

HISTORICAL OVERVIEW OF REGULATORY AFFAIRS

The quality assurance and regulation of medicines evolved gradually over time. Many

unfortunate incidents have catalysed the development of regulations and guidelines

of assuring quality, safety and efficacy of medicines. In 1947, in United States over

100 died due to sulphanilamide elixir. This event led to the introduction of Federal

Food and Cosmetics Act for new drugs in 1948. In 1956, the introduction of Thalidomide

(a drug prescribed to pregnant women for morning sickness) in 46 different countries

resulted in an estimated 10000 babies born with phocomelia (Deformities related to

limbs). This event results in reshaping of the whole regulatory system. Due to these

types of incidents at different stage regulatory bodies introduce new laws and

guidelines which make norms related to drug approval or site approval stricter than

before. Due to more guidelines and laws, the need for regulatory affairs has been felt.

It led to the emergence of regulatory affairs as a profession.

 

REGULATORY AUTHORITIES

For every country, the health of its people is of utmost importance. To maintain the

health of the people country has to ensure the quality of medicines and other

142

Summary

Summary 143

pharmaceutical products as well as devices. So, every country has its regulatory

authority which regulates the following:

1. Import of drugs from another country

2. Export of drugs to another country

3. Manufacturing of drugs in the country

4. Establishment of manufacturing companies in the country

5. Dispensing of medicines

6. Approval of new drugs

7. Approval for clinical trials

8. Testing of drugs in the certified laboratories

9. The compliance with international guidelines

10. Regular inspections

11. Issuing various types of licence related to drugs

ROLE OF REGULATORY AFFAIRS DEPARTMENT

Drug regulatory affairs is a dynamic and challenging field in the pharmaceutical

industry. It has to deal with government authority on one hand and applicant/company

on another hand. Because of the crucial nature of the job regulatory affairs professionals

should be experts in managing the product life cycle. They should have the capability

to solve technical as well as administrative problems within the limits of laws and

regulations. Regulatory affairs department is a bridge between government regulatory

authority and pharmaceutical company. It also has a connection with all the

departments of the company internally.

Regulatory affairs department plays many important roles. These are as follows:

• Role in drug development

• Role in drug approval

• Keep other departments updated

• Acts as interface

• Acts as an adviser

• Maintenance of licences

• Preparation of documents

• Helps in the execution of clinical plan

• Data collection and storing

RESPONSIBILITY OF REGULATORY AFFAIRS PROFESSIONALS

There are some qualities which make efficient regulatory professionals. These are:

• Good communication skills

• Good computer knowledge

• Work independently

• Active listeners

• Good presenter

• Good data management skills

• Patient worker

• Effective negotiator

• Punctual

• Have sound knowledge

144 Industrial Pharmacy

Because of the critical nature of this job, there are several important responsibilities

of regulatory affairs professionals. These are as 

 

c. Conducting plant studies d. None of the above

3. IND is required:

a. In case the drug is not intended for human subjects.

b. In case the drug is intended for in vivo testing.

c. When the drug is already approved and study is conducted within the approved

indication for use.

d. At the time of the clinical trial of an unapproved drug

4. Which CTD module is not required while filing INDA?

a. Module 4 b. Module 2

c. Module 3 d. Module 5

5. How many types of INDA are there?

a. 2 b. 4

c. 6 d. 3

6. The FDA will review and issue an approval, approvable, or non-approvable letter

within 180 days of receipt of application. This time period is known as:

a. Filing time frame b. Patent time frame

c. Review time frame d. None of the above

7. The term that denotes that a drug substance in two or more identical dosage forms

reaches the systemic circulation at the same relative rate and to the same relative

extent is known as:

a. Bioequivalence b. Bioavailability

c. Therapeutic value d. Absorption

8. It is a measure of the extent of absorption:

a. Cmax b. Tmax

c. AUC d. None of the above

9. The exemptions that are granted by USFDA from conducting human

bioequivalence studies are known as:

a. Clinical trial waivers b. Clinical waivers

c. Geowaivers d. Biowavers

INDA and NDA 141

10. Bioequivalence studies are not required in case of:

a. Drugs are parenterally administered b. Drugs in solution form

c. Drugs in gaseous form d. All of the above

11. Biowavers are given in case of:

a. Drugs are highly soluble and highly permeable.

b. Highest dose strength of the drug is soluble in 250 ml aqueous solution over a

pH 1–7.5 at 37°C.

c. 90% of the drug is absorbed if administered orally.

d. All of the above

12. Match the following

Form no Required for filing

a. Form FDA-356h i. INDA

b. Form FDA-3397 ii. Application to market a new drug, biologic, or an

antibiotic drug for human use

c. Form FDA-3331 iii. User fee cover sheet

d. 21 CFR, Sec. 312.23 vi. New drug application field report

or Sec. 312.20

13. Fill in the blanks

a. _________ IND is submitted primarily by companies whose main goal is to obtain

the approval for new drug marketing.

b. _________ IND is for the experimental drugs which show promising results in clinical

testing of life-threatening conditions.

c. After _______ days of receiving the application, the FDA will decide whether the

application may be filed or not. It is known as _________.

d. The main and major site of drug metabolism is ______.

e. ______is the observed maximum concentration of a drug.

f. _______ is a measure of the rate of absorption.

g. Bioequivalence studies are of two types such as __________ and ________.

ANSWERS

1. b 2. a 3. d 4. d 5. b 6. c 7. a 8. c

9. d 10. d 11. d 12. a (ii), b(iii), c(iv), d(i)

13. (a) Commercial, (b) Treatment, (c) 60, Filing time frame, (d) Liver, (e) Cmax,

(f) Tmax, (g) In vivo and In vitro.

142 Industrial Pharmacy

 

i. To play a lead role in initiating, planning, executing, monitoring and controlling,

analysis and reporting a project

ii. To communicate and present trial effectively whenever needed

iii. To organise and motivate others

iv. To manage the trial budget.

Effective trial management includes the following:

i. Proper planning of the project

ii. Time management

iii. Timely approval of the trial

iv. Proper designing of the clinical trial protocol

v. Good collaboration between the trial staff and participants

vi. Good communication between each section of the trial pyramid

vii. Proper management of the budget

viii. Proper training to the staff

ix. Appropriate credit will be given to the responsible persons

x. Effective recruitment of staff and trial participants

xi. Efficient evidence and study in the support of the trial

xii. Genuine reporting to the competent authority

xiii. Compliance with the regulatory guidelines for clinical trials

xiv. Efficient management of the resources

xv. Good record keeping

Effective management of clinical studies will only be possible if all the stakeholders

come together and ‘own’ the project.

PRACTICE QUESTIONS

Long Answer Type Questions

1. Explain the general considerations of INDA.

2. Explain the procedure for NDA filing in detail.

140 Industrial Pharmacy II

Short Answer Type Questions

1. What are bioequivalence studies? Describe in detail.

2. Explain the importance of biostatistics in drug development process.

3. What are the contents of IB?

4. What are the general considerations for data submission in FDA?

5. Explain the following:

a. Biowavers

b. Management of clinical studies

Objective Type Questions

1. _____filed before conducting clinical trials

a. ANDA b. INDA

c. NDA d. All of the above

2. INDA filing is done for:

a. Conducting animal studies b. Conducting human studies

 

INDA and NDA 135

Fig. 9.7: Bioequivalence study is the process of estimation of closeness of the effects innovator drug

and its generic version.

Important pharmacokinetic parameters are:

AUC: Area under the concentration–time curve. It is a measure of the extent of

absorption.

Cmax: It is the observed maximum concentration of a drug. It is a measure of rate and

extent of absorption.

t

max: It is the time at which Cmax is observed. It is a measure of the rate of absorption.

Types of bioequivalence studies (Figs 9.8 and 9.9)

Fig. 9.8: Types of bioequivalence studies

Fig. 9.9: Types of in vivo bioequivalence studies

136 Industrial Pharmacy II

Biowavers

Biowavers are the exemptions that are granted by USFDA from conducting human

bioequivalence studies. Biowavers reduce the need for bioequivalence studies. They

are given when in vitro studies data provides sufficient estimate of a relative in vivo

performance of two products. These are given when API meets certain solubility and

permeability criteria. Biowavers are given in case if:

i. Drugs are highly soluble and highly permeable.

ii. Highest dose strength of the drug is soluble in 250 ml aqueous solution over a

pH 1–7.5 at 37°C.

iii. 90% of the drug is absorbed if administered orally.

iv. 80% of the drug is absorbed within 15 min of administration at 37°C.

v. Clinical research protocols

Bioequivalence studies are not required in case of:

i. Drugs are parenterally administered

ii. Drugs in solution form

iii. Drugs in gaseous form

iv. The new drug has a high therapeutic window.

v. Drugs with rapid and similar dissolution.

9.5 BIOSTATISTICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT

Statistics is the science which deals with collection, tabulation and classification of

numerical facts as the basis for explanation, description and comparison of the

phenomenon.

Biostatistics is the branch of statistics concerned with mathematical facts and data

related to biological events. Sir Francis Galton is the Father of biostatistics.

There are two types of biostatistics

1. Inferential biostatistics: It is the methods of generalising a larger group. The

generalization is based on information about a sample. The sample is considered to

be similar to the population.

2. Descriptive biostatistics: These are used to explain the basic features of the data.

They also provide simple summary of the data (Fig. 9.10)

 

Fig. 9.10: Types of biostatistics

INDA and NDA 137

Biostatistics is the most appropriate methods for the collection, presentation, analysis,

and interpretation of data. Based on the analysis of statistical methods, decisions are

made.

Application of Biostatistics

After the Kefauver Harris Drug Amendments, it is compulsory for the firms to prove

the safety of the drug with suitable statistical evidence. Statistics is involved in all

stages of drug development, i.e. from drug discovery to post-marketing processes

(Fig. 9.11).

Application of biostatistics at the clinical stage: Stage 3

Clinical testing includes step by step process. At the initial stage, the pharmacokinetics

and pharmacodynamics of the drug is studied. At the next stage, the efficiency of the

drug is studied. The efficiency studies are done with the help of statistics. Next stage

is the confirmatory stage, at which most of the studies are based on statistical analysis.

The trial design is also prepared by using statistics. The risk–benefit analysis and

cost-effectiveness of drug are also calculated with the help of statistics.

Application of biostatistics at non-clinical stage: Stages 1, 2, 4, 5

At stage 1 and stage 2 biostatistics has application in the following processes:

i. Screening of drug product

ii. Chemical development

iii. Drug delivery process designing

iv. Assay development

v. Formulation development

vi. Prediction of rare disease

vii. Identification of biomarkers

viii. Quantification of gene expression

ix. In physiology and anatomy

x. Data presentation for FDA submissions

xi. Management of clinical studies

Fig. 9.11: Different stages at which statistics is involved

138 Industrial Pharmacy II

At stage 4 and stage 5 biostatistics has application in the following processes:

i. Rate of market expansion

ii. Calculate brand impact

iii. Create value of the drug

iv. Calculate optimized resources

v. Maximize the value of the launch

vi. Improve work efficiency

vii. Improve customer service

viii. Determine key factors influencing the target population

ix. Determine competitors efficiency

x. Designing successful strategies to overcome challenges

9.6 DATA PRESENTATION FOR FDA SUBMISSIONS

The FDA accepts electronic submissions. The electronic submission's regulatory process

is divided into four steps:

1. Early planning and management of the project

2. Document preparation

3. Dossier publishing

4. Dossier submission

During the planning stage applicants are recommended to use the following tools:

i. Checklist: This includes the name of each document that is needed to be submitted

with all information.

ii. Glossary: Applicants should create a list of a general glossary.

iii. Template: It is a standard file format document which contains pre-defined layout,

text, style and graphics.

iv. Timeline table: Timeline management is one of the most important tasks in the

submission planning phase. Applicant must update a timeline table or a Gantt

chart that also includes the role and responsibility of each person involved in the

process.

File formats used for electronic documents are:

i. Version: One should be able to read all the PDF files with the Acrobat Reader

version 3.0 with the search plug in.

ii. Fonts: Used only True Type or Adobe Type 1 font of black color for text and blue

color for hypertext link. Avoid using light colors for text.

 

Review time frame: The FDA will review and issue an approval, approvable, or

non-approvable letter within 180 days of receipt of application. This period is known

as review-clock. In this period the application is reviewed by the FDA thoroughly.

During this period applicant may withdraw the application and resubmit it later.

Filing time frame: After 60 days of receiving the application, the FDA will decide

whether the application may be filed or not. If the FDA filed the application, then

applicants will be notified, otherwise the applicant will be allowed to discuss the reason

for non-filing of application with FDA (Fig. 9.5).

Guidance documents to help prepare NDAs (Source: FDA)

i. Bioavailability and bioequivalence studies submitted in NDAs or INDs and

general considerations

ii. Changes to an approved NDA or ANDA

Fig. 9.4: General requirements for filing an NDA

Fig. 9.5: Classifications of drugs in NDA

134 Industrial Pharmacy II

iii. Changes to an approved NDA or ANDA: Questions and Answers

iv. Container closure systems for packaging human drugs and biologics

v. Format and content of the microbiology section of an application

vi. Format and content of the clinical and statistical sections of an application

vii. Summary for new drug and antibiotic applications—format and content of the

summary for new drug and antibiotic applications

viii. Formatting, assembling and submitting new drug and antibiotic applications

ix. Guideline for submitting supporting documentation in drug applications for the

manufacture of drug products

x. NDAs: Impurities in drug substances

xi. Format and content of the human pharmacokinetics and bioavailability section

of an application

xii. Format and content of the nonclinical pharmacology/toxicology section of an

application

xiii. Providing clinical evidence of effectiveness for human drug and biological

products

xiv. Drug master files: Guidelines

xv. FDA IND, NDA, ANDA, or drug master file binders

xvi. PET drug applications—content and format for NDAs and ANDAs—2011

NDA forms and electronic submissions (Source: FDA)

i. Form FDA-356h. Application to market a new drug, biologic, or an antibiotic

drug for human use

ii. Form FDA-3397. User fee cover sheet

iii. Form FDA-3331. New drug application field report

iv. Guidance documents for electronic submissions

9.4 CLINICAL RESEARCH / BE (BIOEQUIVALENCE) STUDIES

BE stands for bioequivalence. It is a relative term. It denotes that a drug substance in

two or more identical dosage forms reaches the systemic circulation at the same relative

rate and to the same relative extent (Figs 9.6 and 9.7).

Fig. 9.6: Concentration–time graph of bioequivalence study of two drugs (innovator drug and sample

drug)

 

ix. Signature of sponsor

b. Table of contents

c. Investigators brochure

d. Study protocol

e. Investigator facilities and IRB data

f. Chemistry manufacturing and control data

g. Previous human experience

9.2 INVESTIGATOR'S BROCHURE (IB)

It is a compilation of the clinical and non-clinical data on the investigational product

that is relevant to the study of the product in human subjects. The main purpose of an

investigator's brochure is to provide information to the investigator. It also enables

the investigator to understand the trial and make benefit/risk assessment of the

investigational product by own. The investigator’s brochure is edited by a medically

qualified person. The information included in the investigational brochure contains

(Fig. 9.3).

i. Dose

ii. Dose frequency

iii. Method of administration

iv. Safety monitoring procedure

A typical investigator’s brochure consists of:

• Contents of IB

• Title page

Fig. 9.2: Information attached with IND application

132 Industrial Pharmacy II

• Sponsor’s name

• The identity of each investigational product

• The release date

• Confidentiality statement

• Table of contents

• Summary

• Physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic,

metabolic and clinical information available of investigational product

• Introduction

• Chemical name

• Active ingredients

• Therapeutic/diagnostic indications

• Pharmacological class

• Description of investigational product

• Physical, chemical, pharmaceutical properties of investigational product

• Storage and handling of investigational product

• Any structural similarity with another compound

• Non-clinical study data

• Non-clinical pharmacology

• Pharmacokinetics and product metabolism in animals

• Toxicology

• Known effects in humans

• Summary of data and guidance for the investigator

9.3 NEW DRUG APPLICATION (NDA)

The application through which drug sponsors propose the approval of a new drug

product; for marketing in front of regulatory authority. It includes all clinical and

non-clinical data (Fig. 9.4).

According to FDA “The documentation required in an NDA is supposed to tell the

drug's whole story, including what happened during the clinical tests, what the

ingredients of the drug are, the results of the animal studies, how the drug behaves in

the body, and how it is manufactured, processed and packaged”.

The NDA provides enough information to FDA by which they can be easily established:

i. Safety of drug ii. Effectiveness of drug iii. Benefit–risk ratio

iv. Appropriateness of package insert v. Compliance with GMP

Fig. 9.3: Describing the importance of investigator's brochure

INDA and NDA 133

 

The phase I reactions are oxidation, reduction, hydrolysis, cyclization, decyclization.

Phase II: Synthetic/conjugation

In this phase, the metabolite is generally inactive.

The phase II reactions are glucuronide conjugation, acetylation, methylation, sulphate

conjugation, glycine conjugation, glutathione conjugation, ribonucleotide synthesis.

Inhibition of Drug Metabolism (Fig 8.5)

Fig. 8.5: Methods of inhibition of drug metabolism

128 Industrial Pharmacy II

PRACTICE QUESTIONS

Long Answer Type Questions

1. Explain the function of drug development team.

2. Explain in detail about non-clinical drug development. How is it different from

clinical drug development?

Short Answer Type Questions

1. Describe the types of non-clinical studies.

2. Explain drug development process with diagram.

3. What is toxicology? Explain the types of toxicological studies.

4. Explain drug metabolism in detail.

Objective Type Questions

1. Which of the following is one of the stages of drug development process?

a. Drug discovery and target validation

b. Pre-clinical testing

c. Investigational new drug application filing

d. Clinical studies (phase 1, phase 2, phase 3)

e. All of the above

2. INDA filing is done for:

a. Conducting animal studies b. Conducting human studies

c. Conducting plant studies d. None of the above

3. LD 50 stands for:

a. Legal dose 50 b. Lethal dose 50

c. Legitimate dose 50 d. None of the above

4. Who is responsible for filing INDA?

a. Sponsor b. Investigator

c. Monitor d. None of the above

5. The study helps in determine toxicity of the compound is known as:

a. Toxicology b. Pharmacodynamics

c. Drug metabolism d. None of the above

6. To detect possible interactions with chromosomes and DNA is known as:

a. Genotoxicity b. Carcinogenicity

c. Drug metabolism d. None of the above

7. Match the following

Name of stage of drug development process Order in the process

a. Drug discovery and target validation i. 4th

b. Pre-clinical testing ii. 1st

c. INDA iii. 2nd

d. Clinical studies iv. 3rd

e. NDA v. 6th

f. FDA review and decision vi. 7th

g. Phase 4 clinical studies vii. 5th

Drug Development and Non-Clinical Studies 129

8. Fill in the blanks

a. _________ is a process of bringing a new pharmaceutical drug to the market after

a lead compound has been identified by process of drug discovery

b. LD 50 is a parameter for determining _________.

c. Chemical alteration of drug in the body is defined as __________.

d. The main and major site of drug metabolism is ______.

e. There are _________ phases of drug metabolism.

ANSWERS

1. e 2. a 3. b 4. a 5. a 6. a

7. a(ii), b(iii), c(iv), d(i), e(vii), f(v), g(vi)

8. (a) Drug development, (b) Toxic dose, (c) Drug metabolism, (d) Liver, (e) 2

130 Industrial Pharmacy II

9.1 GENERAL CONSIDERATIONS OF INVESTIGATIONAL NEW DRUG (IND)

 

8.4 DRUG METABOLISM

It is defined as the chemical alteration of a drug in the body. This chemical alteration

converts nonpolar compounds to polar and lipid-soluble compounds to lipid-insoluble

compounds. The products of drug metabolism are called metabolites. Drug metabolism

includes conversion of:

i. Active drug to inactive or less active metabolite (pharmacological inactivation).

For example, phenobarbitone to p-hydroxyphenobarbitone.

ii. Active to a more active metabolite (bio-activation or toxicological activation).

For example, codeine to morphine.

iii. Inactive to more active toxic metabolite (lethal synthesis)

Drug Development and Non-Clinical Studies 127

iv. Inactive drug (pro-drug) to an active metabolite (pharmacological activation).

For example, phenacetin to paracetamol.

v. Active drug to an equally active metabolite (no change in pharmacological

activity). For example, digitoxin to digoxin.

vi. Active drug to an active metabolite which is having different pharmacological

activity (change in pharmacological activity). For example, iproniazid to

isoniazid.

Sites of Drug Metabolism

The main and major site of drug metabolism is liver. Other sites of biotransformation

because a variety of metabolising enzymes are present in Liver. If metabolism

occurs outside the liver or in organs other than the liver, then it is known as extrahepatic metabolism. Secondary organs are kidney, lungs, testes, skin, intestines.

Some drugs also metabolised without enzymes. It is known as non-enzymatic

metabolism.

Advantages of Drug Metabolism

i. It is necessary for the termination of drug action. Therefore, decrease toxicity.

ii. It also reduced lipophilicity.

iii. It increases renal excretion.

There are two phases of drug metabolism:

Phase I: Non-synthetic/functionalization

In this phase, the metabolite may be active or inactive.