Generic Drug Review

Hanan Kakish
Medical Research Scientist, M.Sc. Pharm.
Middle East and North Africa Post
Office of International Programs
U.S. Food and Drug Administration

Hanan.kakish@fda.hhs.gov
Kakishh@state.gov


1
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 Regulation

FDA 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


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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 sponsors 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 Policy
Guidance Manual (2/1/2002, 7356.002)
Pre-Approval Inspections Compliance Policy Guidance
Manual (5/10/2010, 7346.832)
Post-Approval Audit Inspections Compliance Policy
Guidance Manual (7346.832)

2. Office of Pharmaceutical Science (OPS) is the lead within
CDER for the review of the Product Quality information
submitted in supplemental applications to approved
NDAs/ANDAs.
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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).


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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 last
10 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 for
ANDA approval is available at:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInforma
tion/Guidances/default.htm
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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 USP
specifications (if applicable)

3. The generic drug must maintain stability as labeled and
continue to monitor drugs stability

4. The generic drugs 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 consistently




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NDA vs. ANDA Review Process
Brand Name Drug Generic Drug
NDA Requirements ANDA Requirements
1. Chemistry /Micro 1. Chemistry/Micro
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies
7. Clinical Studies 6. Bioequivalence
8. 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 Review

Labeling Review

Chemistry & Micro
Review
Request for Plant
Inspection
APPLICANT
ANDA
Acceptable
& Complete
Application Review
N
Chem/Micro
OK?
Labeling
OK?

Bioequivalence
OK?
Pre-Approval
Inspection Results
OK?
Complete Response
Letter
Approval Withheld
until Results
Satisfactory

APPROVED
ANDA

N
N
N
N
Y Y Y
Y
Y
Refuse to Receive
Letter
http://www.fda.gov/cder/ob/
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FDA Requirements
Brand 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.
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Components and Composition: make sure that the formulation is
stable 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 (with
the 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 CDER
relies 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 accommodate
new filing requirements.
Current Status & Emerging Stability Expectations at OGD
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Current/New Expected ANDA Stability Data Submission Requirements
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Requirements Current Draft Guidance
Accelerated
Stability Data
3 months at 40C 2C/75%
RH 5% RH
6 months at 40C 2C/75% RH 5% RH
(at time of submission)

Intermediate

_____________
6 months at 30C 2C/65% RH 5%
RH, if 6 months accelerated fails
Long Term
Stability Data
(at time of
submission)
3 months long term stability
data at 25C 2C/60% RH
5% RH
6 months at 25C 2C/60% RH 5%
RH, or
6 months at 30C 2C/65% RH 5% RH
Batch
Requirements

One lot of drug product
which is at least 10% of the
intended 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.
Current Advances in CMC Review Process at OGD
Currently OGD has 15 dedicated staff to review DMFs for the
drug substance separately from review of the drug product
allowing for greater consistency and improved efficiency in the
reviews.
Review of the DMF Critical information from the DMF will be
shared with the CMC reviewer of the drug product.
The new review process for DMF will require developing and
revision of a Question-based Review (QbR) format for drug
products.
This staff also work as centralized support for proposed new
DMF requirements under GDUFA.

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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 rate
and 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 firms 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 in
each 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. These
examples 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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ANDA Format
Common 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: Clinical

OGDs ANDA Checklist contains detailed information regarding
where documents are to be placed. ANDA Checklist for
Completeness and Acceptability is available on the FDA website

eCTD format is preferred.
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eCTD
eCTD, accepted since 2003, became FDAs 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 the
guidance 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 FDA
standards

Validations errors are assigned a severity level: High, Medium,
Low, & Ignore. (High errors cause rejection of submission)
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The e-Submission Process
Sponsor obtains pre-assigned application
number 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:
US-FDA-MENA@fda.hhs.gov
BatarsehLI@state.gov
Kakishh@state.gov
2. Office of Generic Drugs at
genericdrugs@fda.hhs.gov

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References
1. The Office of Generic Drugs home page
http://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/HowDrug
sareDevelopedandApproved/ApprovalApplications/AbbreviatedNew
DrugApplicationANDAGenerics/default.htm
3. ANDA Filling Checklist
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess
/HowDrugsareDevelopedandApproved/ApprovalApplications/Abbre
viatedNewDrugApplicationANDAGenerics/UCM151259.pdf
4. CDERs Training and Continuing Education Page
http://www.fda.gov/Training/ForHealthProfessionals/default.htm
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References
5. CDERs 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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Office of Generic Drug Staff
CDER




Acknowledgements
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