Generic Drugs Review

8/11/2019 Generic Drugs Review

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Generic Drug Review

Hanan KakishMedical Research Scientist, M.Sc. Pharm.

Middle East and North Africa Post

Office of International Programs

U.S. Food and Drug Administration

[email protected]

[email protected]

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mailto:[email protected]






Disclaimer

This presentation constitutes an informal communication

that represents the best judgment of the speaker at this

time but does not constitute an advisory opinion, does not

necessarily represent the formal position of U.S. FDA,and does not bind or otherwise obligate or commit the

U.S. FDA to the views expressed

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FDA Product RegulationFDA is organized around the products it regulates.

• CDER: Center for Drug Evaluation and Research (also

responsible for therapeutic proteins/antibodies)

• CBER: Center for Biologics Evaluation and Research

including vaccine and blood products• CDRH: Center for Devices and Radiological Health

• CVM: Center for Veterinary Medicine

• CFSAN: Center for Food Safety and Applied Nutrition

• CTP: Center for Tobacco Products

In addition:

• ORA: Office of Regulatory Affairs (The field)

•

NCTR: National Center for Toxicological Research 3



CDER Mission: to ensure that SAFE and EFFECTIVE prescription, non-prescription, and generic drugs are available to

the American public. CDER evaluates applications through

review teams:

• To assure that the data submitted are adequate and scientifically

sound

• Assess the submitted data, make recommendations, and

document the decision rationale

• Provide feedback to sponsor’s proposal for the next stage of

development and approval

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CDER Offices

Most relevant offices to generic review are:1. Office of Compliance is the lead within CDER for the

management of establishment evaluation and the inspection process for supplemental applications to approved NDAs/ANDAs.

• Drug Manufacturing Inspections Compliance PolicyGuidance Manual (2/1/2002, 7356.002)

• Pre-Approval Inspections Compliance Policy GuidanceManual (5/10/2010, 7346.832)

• Post-Approval Audit Inspections Compliance Policy

Guidance Manual (7346.832)

2. Office of Pharmaceutical Science (OPS) is the lead withinCDER for the review of the Product Quality informationsubmitted in supplemental applications to approved

NDAs/ANDAs. 5



FDA Marketing Authorization Applications

• Investigational New Drug (IND) Application

Allows initiation of clinical studies in humans

Allows inter-state shipping of drug candidate to clinical trial

sites

• New Drug Application (NDA)/Biologics License

Application (BLA)

Submission of information needed for marketing approval

• Abbreviated New Drug Application (ANDA)

Application for approval of a generic drug.

Reviewed by the Office of Generic Drugs (OGD)

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Generic Drugs• A generic drug is therapeutically equivalent to the brand name

drug.

• Therapeutic Equivalence “have the same clinical effect and

safety profile when administered to patients under the conditions

specified in the labeling”

• FDA Practice

Pharmaceutical Equivalence + Bioequivalence = Therapeutic Equivalence

• Generic drug products provide the public with safe, effective,and low cost alternatives to innovator drugs.

• ANDAs are generally not required to include preclinical and

clinical data to establish safety and effectiveness. (i.e.,it

performs in the same manner as the innovator drug). 7



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Generic Drug Availability in the US

With generics now covering ~80% of total prescriptions filled

with a tremendous cost savings to the US market, it is important

that drug product quality is assured.

In August 2012, the Generic

Pharmaceutical Association

released an independently

conducted analysis showing that

the savings to consumers and the

U.S. health care system from the

use of generic prescription

drugs has risen to a current rate of

$1 billion every other day —

totaling $193 billion in 2011 and

more than $1 trillion over the last10 years (2002-2011).

2011 spending

increase $5.6 BN



Generic Drug

The following regulations apply to the ANDA process:• Applications for FDA Approval to Market a New Drug or an

Antibiotic Drug

• Bioavailability and Bioequivalence Requirements

• Bioequivalence Study Retention Samples

• Bioavailability and Bioequivalence Requirements; Abbreviated

Applications; Final Rule

A complete list of drug guidance documents, including ones forANDA approval is available at:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInforma

tion/Guidances/default.htm

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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm






Generic Drug Requirements

For a generic drug to be approved, it must, when compared to

the reference drug, have:

1. Same active ingredient(s)

2. Same dosage form

3. Same route of administration

4. Same labeled strength

5. Same conditions of use

6. Meet compendial or other applicable standards of strength,

quality, purity, and identity

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Generic Drug Requirements - Cont.

1. Fully documented chemistry, manufacturing steps, and

quality control measures. Detailed manufacturing process,

step-by-step

2. The raw materials and the finished product must meet USPspecifications (if applicable)

3. The generic drug must maintain stability as labeled and

continue to monitor drug’s stability

4. The generic drug’s labeling must be basically the same as that

of the approved brand-name drug

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Generic Drug Requirements - Cont.

5. The drug company must show the generic drug is“bioequivalent” to the brand-name drug.

6. The drug company must:

• comply with federal regulations for current good

manufacturing practices

• give a full identification of the facilities it uses to

manufacture, process, test, package, label, and control the

drug

7. Inspection at the proposed manufacturing site ensures that the

firm:

• is capable of meeting commitments of the application

• can manufacture the product consistently12



NDA vs. ANDA Review Process

Brand Name Drug Generic DrugNDA Requirements ANDA Requirements

1. Chemistry /Micro 1. Chemistry/Micro

2. Manufacturing 2. Manufacturing

3. Controls 3. Controls4. Labeling 4. Labeling

5. Testing 5. Testing

6. Animal Studies

7. Clinical Studies 6. Bioequivalence8. Bioavailability

Number of annual generic drug approvals > new drug

approvals

CMC

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Generic Drugs: Assurance of Quality• First 5 steps (Chemistry, manufacture, control, label,

testing) of review process are identical to NDA process.

• Bioequivalence is reviewed by OGD, in case of complicated

products might be reviewed by other offices.

• FDA has extensive experience with the innovator drug

product.

• Scientific literature published about the innovator drug

• Product is known to be safe.

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Generic Drug

Review Process

Bioequivalence ReviewLabeling ReviewChemistry & MicroReview

Request for PlantInspection

APPLICANT

ANDA

Acceptable

& Complete

Application Review

NChem/Micro

OK?

Labeling

OK?

Bioequivalence

OK?

Pre-Approval

Inspection Results

OK?

Complete Response

Letter

Approval Withheld

until Results

SatisfactoryAPPROVED

ANDA

NNN

N

Y Y Y

Y

Y

Refuse to Receive

Letter

http://www.fda.gov/cder/ob/15



FDA RequirementsBrand Name

Drug

Generic

Drug

FDA evaluates the manufacturer's adherence to good

manufacturing practices before the drug is marketed.

FDA reviews the active and inactive ingredients used in the

formulation before the drug is marketed.

FDA reviews the actual drug product.

FDA reviews the drug's labeling.

Manufacturer must seek FDA approval before making major

manufacturing changes or reformulating the drug.

For reformulations of a brand-name drug or generic versions

of a drug, FDA reviews data showing the drug is bioequivalent

to the one used in the original safety and efficacy testing.

Manufacturer must report adverse reactions and serious

adverse health effects to the FDA.

FDA periodically inspects manufacturing plants.

FDA monitors drug quality after approval. 16



• Components and Composition: make sure that the formulation isstable and in compliance with FDA regulations and standards.

• Manufacturing and Controls

• Batch Formulation and Records

• Description of Facilities (for sterilized or aseptic processes)

• Specifications and Tests: make sure that impurities are within FDA

acceptable limits and the tests are appropriate for that product.

• Packaging: to make sure it assures the stability of the product (withthe proper product design, manufacturing quality control and

storage conditions)

• Stability: to assure that the shelf life of the product is appropriate.

CMC Review

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• Office of New Drug Quality Assessment has adopted ICH Q1A.

• OGD has adopted ICH Q1A for Drug Substances but does not

have a formal published stability guidance for drug products and

generally relies on same ICH Guidance documents which CDERrelies on for brand drugs.

• A draft guidance is posted on FDA web site on September 2012

(will become official by January 2014). Available at:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform

ation/Guidances/UCM320590.pdf

So, industry will have to revise their scheduling to accommodatenew filing requirements.

Current Status & Emerging Stability Expectations at OGD

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320590.pdf








Current/New Expected ANDA Stability Data Submission Requirements

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Requirements Current Draft Guidance

Accelerated

Stability Data

3 months at 40°C ± 2°C/75%

RH ± 5% RH

6 months at 40°C ± 2°C/75% RH ± 5% RH

(at time of submission)

Intermediate _____________6 months at 30°C ± 2°C/65% RH ± 5%

RH, if 6 months accelerated fails

Long Term

Stability Data

(at time of

submission)

3 months long term stability

data at 25°C ± 2°C/60% RH ±

5% RH

6 months at 25°C ± 2°C/60% RH ± 5%

RH, or

6 months at 30°C ± 2°C/65% RH ± 5% RH

Batch

Requirements

One lot of drug product

which is at least 10% of theintended market batch size or

100,000 dosage units,

whichever is greater (size of

the exhibit lot may vary upon

consultation with the Office)

At least 3 primary batches of drug product

(2 of the 3 batches should be at least pilot scale)

•Same formulation, manufacturing process

& specifications as those for market.

•Same container/closure system as proposed

for market.

•Different lots of API where possible.



Labeling Review• “Same” as brand name labeling

• May delete portions of labeling protected by patents or

exclusivity

• May differ in excipients, PK data, and how supplied

BE Review: Review BE and waiver requests.

To assure that the two products perform in an equivalent manner.

Showing that the active ingredient is absorbed at the same rateand extent as the reference product allows the generic to rely on

the findings of safety and efficacy of that innovator product.

Generic Drug Review

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Clinical Review

• Reviews BE studies with clinical endpoints

• Evaluates safety issues (inactive ingredients, adverse

events, etc.)• Assesses clinical issues in ANDAs (effect of different

vehicles, inactive ingredients)

• Assesses equivalence challenges

Generic Drug Review

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Manufacturing Compliance Programs

• Purpose - To assure quality of marketed drug products

• Product Testing

• Surveillance

Manufacturing/Testing Site Inspections (Establishment

Evaluation Requests [EERs])

Assess firm’s compliance with good manufacturing/

laboratory processes

Generic Drug Review

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QbD is a systematic approach for designing and developing

formulations and for manufacturing processes to ensure

predefined product quality.

Design of experiments and risk assessment are tools to

facilitate the implementation of QbD

Implementing Quality by Design

(QbD)

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QbR is a general framework that provides a science and risk-

based assessment of drug product quality.

• Contains 37 important scientific and regulatory review questions.

• ANDA applicants answer the questions.

• Chemistry reviewers evaluate the responses to the questions

along with the body of data.

The questions incorporate QbD principles and require the applicant

to demonstrate their level of process and product understanding.

Question-based Review (QbR)

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What are the Advantages of QbR?

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• In January, 2012, OGD began to include a recommendation ineach letter to an applicant strongly recommending that QbD

principles be used in the development of future submissions.

• OGD will continue to work with the industry to implement

QbD for generic drugs as quickly and smoothly as possible.

• OGD has developed hypothetical examples (not templates) for

Immediate and Modified Release drug products to demonstrate

the process of using the revised QbR/QbD format. Theseexamples can be found online at FDA's Generic Drugs:

Information for Industry webpage at:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDev

elopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicatio

nANDAGenerics/ucm142112.htm

QbD at the Office of Generic Drugs

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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm142112.htm










ANDA FormatCommon Technical Document (CTD)

• Module 1: Administrative information (region specific) and

labeling

• Module 2: Summaries of the information that is provided (in

full) in the remaining modules & includes a Quality-related

subsection called the Quality Overall Summary (QOS)

• Module 3: Quality

• Module 4: Preclinical

• Module 5: ClinicalOGD’s ANDA Checklist contains detailed information regardingwhere documents are to be placed. ANDA Checklist forCompleteness and Acceptability is available on the FDA website

eCTD format is preferred. 28



eCTD• eCTD, accepted since 2003, became FDA’s standard in 2008.

Receive 400-600 e-submissions daily

• FDA has published draft eCTD guidance in Jan 2013 and

the applications subject to agency's actions (ANDA, NDA,

BLA) are required to be in eCTD format in two years once theguidance is finalize and in three years for certain IND.

• DMF is highly encouraged to be in eCTD format.

• All eCTD submissions are validated for compliance with FDAstandards

• Validations errors are assigned a severity level: High, Medium,

Low, & Ignore. (High errors cause rejection of submission)29



The e-Submission Process

Sponsor obtains pre-assigned applicationnumber from FDA

Sponsor sends submission

Document Room (EDR) and automated processes validate and load the submission

Review teams are notified

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The e-Submission Process

e-Submissions are sent by:

• Electronic Secure Gateway

• USB Portable Hard Drive

• CD-ROM/DVD

(Tape is no longer an option; phased out by 12/31/2012)

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What Gets Rejected (eCTD)?

How Many are Rejected?

~1% of submissions are rejected

(current averages are 10,000 submissions per month, 100

rejected)

Reasons for Rejection:

• Invalid submission number or type

• Single file submissions• High-level validation errors

• Duplicate submissions

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For Questions

Contact:

1. MENA Post at:

[email protected]

[email protected]

[email protected]

2. Office of Generic Drugs at

[email protected]

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References

1. The Office of Generic Drugs home pagehttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrug

sareDevelopedandApproved/ApprovalApplications/AbbreviatedNe

wDrugApplicationANDAGenerics/ucm142112.htm

2. Abbreviated New Drug Application (ANDA): Generics

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNew

DrugApplicationANDAGenerics/default.htm

3. ANDA Filling Checklist

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess

/HowDrugsareDevelopedandApproved/ApprovalApplications/Abbre

viatedNewDrugApplicationANDAGenerics/UCM151259.pdf

4. CDER’s Training and Continuing Education Page

http://www.fda.gov/Training/ForHealthProfessionals/default.htm

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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/default.htm



http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM151259.pdf
























References

5. CDER’s Consumer Education page www.fda.gov/usemedicinesafely

6. FDA eCTD web page:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSub

missionRequirements/ElectronicSubmissions/ucm153574.htm

7. Guidance Documents

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformati

on/Guidances/ucm121568.htm

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http://www.fda.gov/usemedicinesafely

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm


http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm121568.htm










http://www.fda.gov/usemedicinesafely



Office of Generic Drug StaffCDER

Acknowledgements

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Generic Drugs Review

Documents

Transcript of Generic Drugs Review