drug development process and regulatory submissions

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1. INTRODUCTION 2. DEFINITIONS 3. FDA, CFR 4. IND 5. NDA 6. ANDA 7. Conclusion & 8.REFERENCES

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Page 1: Drug development process and regulatory submissions
Page 2: Drug development process and regulatory submissions

By

Suyog Pratap SulakeM.Pharm (Sem-I)

Under the Guidance of

Dr. N.H. Aloorkar(M.Pharm Ph.D)

(Head of Department of Pharmaceutics)Satara College of Pharmacy, Satara.

“DRUG DEVELOPMENT PROCESS AND REGULATORY SUBMISSIONS”

A SEMINAR ON

Page 3: Drug development process and regulatory submissions

CONTENTS

1. INTRODUCTION 2. DEFINITIONS 3. FDA, CFR 4. IND 5. NDA 6. ANDA 7. CONCLUSION & 7.REFERENCES

Page 4: Drug development process and regulatory submissions

1. INTRODUCTION

Drug Development Process:

• The process of bringing a new drug to the

market.

• Takes about 10-15 years

• Out of 5,000 – 10,000 compounds that

enters (R&D) pipeline, ultimately only one

receives approval.

• Average cost – $800 million – $1 billion

Page 5: Drug development process and regulatory submissions

Steps involved in Drug development Process:

A) Pre- Drug discovery

• Understanding the disease : to discover underlying cause

• Target identification : e.g Protein, genes

• Target validation : to confirm its role.

B)Drug discovery

• Finding a lead : Nature, Denovo, Highthroughput Screening

• Early safety tests : ADME/Tox properties

• Lead optimization : to optimze lead properties viz. toxicity, potency,etc

C) Post- drug discovery

• Pre- Clinical testing : To assess the safety of drug (animals)

• IND (Investigational New Drug Application)

• Clinical trials : conducted in 3 Phases, Safety and efficay.

• NDA (New Drug application)• Post marketing Surveillance: Expanded

safety, PV, Rare side effects.

Page 6: Drug development process and regulatory submissions

2. DEFINITIONS

i) Sponsor: individual, company, institution or an

organization, responsible for initiation,

management and financing of clinical trials.

ii) Innovator Drug: drugs with patents on their

chemical formulations or production process.

Page 7: Drug development process and regulatory submissions

3. FOOD AND DRUG ADMINISTRATION (FDA)

The Federal Food, Drug, and Cosmetic Act is the

basic food and drug law of the U.S.

It assures consumers about safety and

effectiveness of

• foods

• drugs and devices

• Cosmetics

And all labeling and packaging is truthful, and

not deceptive.

Page 8: Drug development process and regulatory submissions

Code of Federal Regulation (CFR):

• The final regulations published in the Federal

Register are collected in the CFR.

• Divided into 50 titles

• The FDA's portion of the CFR interprets the

Federal Food,

Drug and Cosmetic Act related statutes.

• Section 21 of the CFR contains: all regulations

pertaining to food and drugs.

Page 9: Drug development process and regulatory submissions

4. INVESTIGATIONAL NEW DRUG APPLICATION

The IND application is the result of a successful

preclinical development program. After its

approval sponsor advances to the next stage of

drug development known as clinical trials

(human trials).

Types of INDs:

There are two IND categories:

i) Commercial : submitted by companies

ii) Research (non-commercial) : e.g.

"Investigator INDs," "Emergency Use INDs,”

Page 10: Drug development process and regulatory submissions

Criteria for application:

• New indication

• Change in route of administration or

dosage level

• Change in the approved patient

population (e.g. pediatric)

Page 11: Drug development process and regulatory submissions

Laws, Regulations, Policies and Procedures

21CFR Part 312

Investigational New Drug Application

21CFR Part 314

INDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval)

21CFR Part 50 Protection of Human Subjects

Page 12: Drug development process and regulatory submissions

Fundamentals of an IND:The IND application must contain information in three broad areas:

i) Animal Pharmacology and Toxicology

Studies:

whether the product is reasonably safe for initial

testing in humans.

ii) Manufacturing Information:

composition, manufacturer, stability, and

controls.

iii) Clinical Protocols and Investigator

Information:

Detailed protocols for proposed clinical studies to

assess unnecessary risks.

Investigator's Brochure : Educates the trial

investigators to conduct the clinical trial with the

least hazard to the subjects.

Page 13: Drug development process and regulatory submissions

 

Review Timeline:

Once the IND is submitted, the sponsor must

wait 30 calendar days before initiating any

clinical trials. During this time, FDA has an

opportunity to review the IND.

Page 14: Drug development process and regulatory submissions

IND Review

Process

Page 15: Drug development process and regulatory submissions

5. NEW DRUG APPLICATION

Submitted when:

• clinical testing has been completed

• final manufacturing processes and procedures

are in place

• and the company has ready other required

information

The Drug and/or the formulation cannot be

marketed until the FDA has approved an NDA.

Page 16: Drug development process and regulatory submissions

Goals of the NDA

To assess whether:

• the drug is safe and effective (benefits of the

drug outweigh the risks)

• the drug’s proposed labeling (package insert)

are appropriate

• the methods used in manufacturing (&

controls) the drug are adequate to preserve

the drug’s identity, strength, quality, and purity

Page 17: Drug development process and regulatory submissions

Classification of drugs in NDA

1) New Molecular Entity

2) New Salt of Previously Approved Drug (not a

new molecular entity)

3) New Formulation of Previously Approved

Drug (not a new salt OR a new molecular entity)

4) New Combination of Two or More Drugs

5) Already Marketed Drug Product - Duplication

(i.e., new manufacturer)

6) New Indication (claim) for Already Marketed

Drug

7) Already Marketed Drug Product - No Previously

Approved NDA

Page 18: Drug development process and regulatory submissions

Laws, Regulations, Policies and Procedures:

21 CFR Part

314

Applications for FDA Approval

to Market a New Drug or an

Antibiotic Drug.

Page 19: Drug development process and regulatory submissions

NDA Content and Format:

A) SUMMARY

B) THE SAFETY UPDATE REPORTS

C) CHEMISTRY, MANUFACTURING AND

CONTROL

An overview of the drug substance and drug

product.

• Drug substance: Description including physical

and chemical characteristics and stability

• Drug product: Composition and type of dosage

form, manufacture, specifications and analytical

methods, container/closure system, stability,

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D) NON CLINICAL PHARMACOLOGY AND

TOXICOLOGY

Toxicological effects of drugs on reproduction and

the developing fetus, ADME animal experiments of

the drugs

E) HUMAN PHARMACOKINETICS AND

BIOAVAILABILTY

F) MICROBIOLOGY

Applicable to anti-infective and to antiviral drugs.

G) CLINICAL DATA

Page 21: Drug development process and regulatory submissions

H) STATISTICS

I) LABELING

• Critical part of the NDA ,

• Sponsors often "push the envelope”—by

wording the indications for the drug as

widely as possible, and by downplaying the

importance of the drug’s side effects—in their

proposed labeling, and negotiations to finalize the

labeling often occur when the NDA has been

reviewed and deemed "approvable” by the Agency

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J) CASE REPORT FORMS AND TABULATIONS

The sponsor must submit case study report form

for every clinical trial patient who died or

withdrew from the study because of an adverse

event.

K) PATENT INFORMATION

Patent related information that covers the drug

substance, formulation, or method of use.

Upon approval of the NDA, this information is

published in the FDA’s Orange Book serves as

a guide to firms wishing to develop generic copies

of the innovator’s product.

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L) DRUG SAMPLES

Submitted upon the FDA’s request to the District

Laboratory assigned to test them.

GENERAL REQUIREMENTS FOR FILING AN NDA:

Submitted in two copies :

i)An Archival copy (permanent record )

ii)A Review copy

Both are submitted in hard copy, the regulations

permit an applicant to submit the archival copy as

microfiche.

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i) Archival copy is bound in a BLUE cover jacket.

 

ii) The Review copy is divided into six technical

sections ("review sections”) and submitted

separately bound in a specific color:

1. Chemistry, Manufacturing and Controls (CMC) -

RED;

2. Nonclinical Pharmacology and Toxicology -

YELLOW;

3. Human Pharmacokinetics and Bioavailability -

ORANGE;

4. Microbiology (if required) - WHITE;

5. Clinical Data - LIGHT BROWN;

6. Statistical - GREEN.

Page 25: Drug development process and regulatory submissions

NDA REGULATIONS

Review Time Frames (21 CFR 314.100):

• 180-day period is called the ‘review-clock’

• The FDA will review and issue an approval,

approvable, or not approvable letter.

• The time period may be extended by mutual

agreement between the FDA and the applicant.

Page 26: Drug development process and regulatory submissions

Filing Time Frames (21 CFR 314.101):

• Within 60 days after the receipt of an

application, FDA decides whether the application

may be filed or not.

• If FDA files the application, the applicant will be

notified in written.

If FDA refuses to file the application, the sponsor

will be given the opportunity to meet with FDA to

discuss the reasons why the application is not file

able.

Page 27: Drug development process and regulatory submissions

Computer assisted NDA:

Concept:

It is designed to shorten FDA review time by

submitting data to FDA in a form ready for

manipulation by a computer.

Importance is given on the clinical sections of

the NDA, as they require the maximum time to

review by FDA.

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NDA REVIEW PROCESS

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6 ABBREVIATED NEW DRUG APPLLICATION (ANDA)

Submitted to FDA's Center for Drug Evaluation

and Research, Office of Generic Drugs, for

review and ultimate approval of a generic drug

product.

Generic Drug product : comparable to an

innovator drug

• in dosage form,

• strength,

• route of administration,

• quality,

• performance characteristics and

• intended use.

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Why Abbreviated ?

because it is not necessary to include

preclinical (animal) and clinical (human)

data to establish safety and effectiveness.

Instead, applicant must demonstrate that

their product is bioequivalent .

E.g. time taken by the generic drug to reach the

bloodstream

healthy volunteers is measured and compared

with the Innovator drug

.

Page 31: Drug development process and regulatory submissions

Laws, Regulations, Policies and Procedures

21 CFR Part 314 Applications for FDA Approval to Market a New Drug or and Antibiotic Drug.

21CFR Part 320 Bioavailability and Bioequivalence Requirements.

Page 32: Drug development process and regulatory submissions

THE HATCH-WAXMAN ACT

Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and `Patent Term Restoration Act of 1984,"

also known as the HATCH -WAXMAN ACT.

Page 33: Drug development process and regulatory submissions

Concept of PARAGRAPH I TO IV

For filing ANDA, generic company must include a

patent certification as per section 505(j) (2) (A)

(vii) of the Hatch Waxman Act.

I. No patent information on the drug product

that is the subject of the ANDA has been

submitted to FDA

II. That such patent has expired

III.The date on which such patent expires

IV.That such patent is invalid or will not be

infringed by the manufacture, use, or sale of

the drug product which the ANDA is submitted.

Page 34: Drug development process and regulatory submissions

The first three paragraphs (I, II, III) results in no

generic drug being sold during the term of the

innovator’s patent protection.

In case paragraph IV certification generic drugs

can be sold during the term of the

innovator’s patent protection.

Substantially complete ANDA:

Only the applicant submitting the first

"Substantially complete ANDA” with a paragraph IV

certification would be eligible for exclusivity.

Page 35: Drug development process and regulatory submissions

According to FDA all ANDA applications containing :

Paragraph IV certifications

for a particular drug product

received by the FDA on the same day

will be eligible for exclusivity if no other ANDA with a

paragraph IV certification for the drug product had been

filed on an earlier day. All such same day applicants

would be considered first applicants.

Page 36: Drug development process and regulatory submissions

Trigger Period

Sometime there is unnecessary delay in entry of

generic drug into the market due to:

i) delay in approval of ANDA by FDA or

ii) some kind of settlement between first

generic (first ANDA approver) and

innovator.

Page 37: Drug development process and regulatory submissions

e.g. first generic tells to innovator that it will not

start its 180 days until “x” number of days in

return to “Y” number of dollars from innovator.

Thus as per rule until first generic finishes 180 day

exclusivity period no other generic manufacturer

can be granted 180 exclusivity period. As a result

innovator and first generic enjoys undue

advantage.

Page 38: Drug development process and regulatory submissions

To overcome this FDA has introduced "Triggering

period”

Under this concept the commencement of the

180-day exclusivity period for the first applicant

is either the first commercial marketing of the

first applicant’s product, or a decision of a

court holding the patent invalid, not

infringed, or unenforceable, whichever is

earlier.

If neither of these events occurs in the

triggering period then the first generic would lose

its eligibility for exclusivity and subsequent

generic filers for ANDA would be eligible for

immediate approval.

Page 39: Drug development process and regulatory submissions

ANDA Review Process

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CONCLUSION

Regulatory submissions forms a very important part of Drug development process.

The extensive review process done by the regulatory bodies, ensures that not only effective but also a safe Drug product reaches the market.

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REFERENCES 1. Guarino, “New Drug Approval Process”, Third edition, The Global Challenge, Marcel Dekker Inc., Pg. no. 93-102, 103-256, 289-217.2. Berry, Martin, “The Pharmaceutical Regulatory Process”, Seond edition, Marcel Dekkker Inc., Pg. no. 45-60, 61-102, 269-282.3. www.fda.gov4. www.drugs.com/new-drug-applications.html5. gateway.nlm.nih.gov6. en.wikipedia.org/wiki/New_Drug_Application7. www.news-medical.net8. www.genengnews.com9. oig.hhs.gov/oei/reports/oei-01 -01 -00590.pdf10. en.wikipedia.org/wiki/Investigational_New_Drug11. www.mdci.com12. www.accessdata.fda.gov

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13. www.domain-b.com14. www.pointcrosslifesciences.com15. www.researchgate.net16. www.law.washington.edu/casrip/symposium17. pharmtech.findpharma.com18. www.ftc.gov/be/v990016.shtm19. www.activery.com20. www.access.gpo.gov

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