The BLA Review Process

The
BLA Review Process
Week 10
RGA6200 Biologics Development: A QA/Regulatory Overview
Stephen F. Amato, PhD, MBA, RAC
Biologics License Applica6on (BLA)
Interna6onal Harmoniza6on
Using the CTD (Common Technical Document)

An agreed upon common format for the modular presenta4on
of summaries, reports and data
Content is harmonized to the extent of relevant ICH guidelines
Guidance for Industry: SubmiBng Marke4ng Applica4ons

According to the ICH-CTD Format - General Considera4ons
hIp://www.fda.gov/RegulatoryInforma4on/Guidances/ucm129703.htm

2
Electronic Submissions
Submission of BLAs may be made on paper or electronically
Submissions should be made in accordance with published

guidance:
hIp://www.fda.gov/RegulatoryInforma4on/Guidances/
ucm126959.htm

3
Managed Review Process
CBER focuses on reviewing BLAs for:
Vaccines
Blood Products
Cellular Therapies
Gene Therapies
From Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 60-62 (2007).
4
Pre-Review Mee6ngs
Made available by CBER due to complexi4es involved in assembling
and submiBng BLAs
Represents the beginning of the license review process since they

trigger a series of ac4ons within CBER administra4on
Goals:
To describe for CBER reviewers the general informa4on that will be submiIed in the
marke4ng applica4on
To discuss preliminary ecacy results
To discuss appropriate methods for sta4s4cal analysis
To discuss proposed format for data in the marke4ng applica4on
To iden4ty the studies that the sponsor will rely on as adequate and well-controlled
To discuss the submission of an incomplete applica4on under the fast track program
5
Pre-Review Mee6ngs
Addi4onal items include an overview of the facility to be licensed
The manufacturing valida4on program
Manufacturing business/contractual rela4onships
Poten4al refusal to le issues
Under PDUFA IV, CBER must:

Schedule the pre-BLA mee4ng within 14 calendar days of receiving a
formal mee4ng request
Should no4fy the sponsor by leIer or fax of the date, 4me and place
for the mee4ng as well as CBER par4cipants

6
Pre-Review Mee6ngs
Sponsors Pre-Review mee4ng request must include the following:
Product name and IND number
Statement of the purpose of the mee6ng
A lis6ng of the specic objec6ves or outcomes that the sponsor expects
A list of external a?endees
A list of requested CBER par6cipants
Approximate 6me that a background package for the mee6ng will be
distributed
Suggested dates for the mee6ng

7
Pre-Review Mee6ngs
Under PDUFA IV
Companies that manufacture products that have par4cular safety
concerns can ini4ate discussions of preliminary risk management
programs and post-approval risk management studies
Pre-BLA Mee4ngs should be scheduled within 60 calendar days of CBERs

receipt of mee4ng request
If the sponsor requests a later date then Mee4ng should be scheduled

within 14 days of the requested date
FDA is required to draa minutes of the pre-BLA Mee4ng and send them to
the sponsor within 30 calendar days of the Mee4ng
8
Pre-Review Mee6ngs
Administra4ve ac4ons:
CBER begins to evaluate the need for, and forecast the scheduling of key
ac4vi4es during the review process
Assess whether a bioresearch monitoring (BIMO) inspec4on will be
necessary to verify data/informa4on included in the license applica4on
Review the mee4ng schedule of the FDA advisory commiIee relevant to
the applica4on
Director for the oce responsible for reviewing the BLA will designate the
applica4on as either a priority or standard submission
Triggers the forma4on of the BLA review team generally the same
members who were on the IND review team
9
Ini6al Processing
Early stage processes for handling BLA submissions are detailed in the
following SOPs:
Administra6ve Processing of Biologics License Applica6ons (May

2003)
Inves6ga6onal and Marke6ng Applica6ons Submission of Regulatory

Documents in CBER (February 2003)

10
Ini6al Processing
License review process begins in CBERs Document Control Center (DCC)

Key informa4on about BLA is logged
Oce to which the applica4on should be forwarded is determined
BLA receives a date of receipt stamp
User fee review clock starts

11
Ini6al Processing
Once the BLA is forwarded to the appropriate reviewing division, the
regulatory project manager (RPM) performs various administra4ve
processing ad screening ac4vi4es:
Screens the license applica4on to determine whether the ling has any
major deciencies
Verify that the applicant has paid the required user fees associated with
the submission
Assign a unique submission tracking number (STN)
The appropriate division then prepares and acknowledgment leIer,

which informs the sponsor of the applica4ons tracking number, the
agency contact person and other cri4cal informa4on
12
Licensing CommiHees
For each submission, CBER forms a BLA licensing commiIee that
includes a reviewer from the Division of Manufacturing and
Product Quality (DMPQ) to evaluate the GMP and facility related
aspects of the BLA
Original BLA submission is forwarded to the chairperson/lead of

the BLA licensing commiIee

13
Licensing CommiHees
Chairpersons responsibili4es include the following:
Cons4tu4ng the review commiIee
Assigning sec4ons of the applica4on for review
Scheduling and conduc4ng mee4ngs
Developing ac4on leIers regarding a BLA
AIending advisory commiIee mee4ngs
Reques4ng pre-license inspec4ons
Preparing a summary basis for approval document

14
Typical Licensing CommiHees
Chairperson
At least one clinical reviewer
A product reviewer
A sta4s4cian
A pharmacologist/toxicologist
A manufacturing facility reviewer
BIMO coordinator (if necessary)
Lead scien4st from IND review (if applicable)
Members from other FDA Centers (if necessary)
15
Refusal to File (RTF) Decisions
If BLA applica4on does not meet basic standards of completeness and

quality to jus4fy a formal review then ini4al commiIee mee4ng(s)
may involve deciding whether to issue a Refusal to File (RTF)
RTF decisions primarily based on:

1) Administra4ve incompleteness of applica4on
2) Scien4c incompleteness of applica4on
3) Inadequacies of content, presenta4on or organiza4on

16
Refusal to File (RTF) Decisions
Issued within 60 days aaer the BLA is received
RTF decisions must be supported by documenta4on that clearly

outlines the deciencies that form the basis for the decision
Issuing an RTF decision:

Discon4nues the CBER BLA review process
Eliminates 4me consuming review eorts
Enables the review center to focus resources on quality applica4ons

17
Review Process Principles
The RPM is the FDA point of contact
FDA will convey readily correctable issues as they are iden4ed, which should
be addressed quickly
Filing review issues are conveyed to applicant
Communica4on through secure e-mail is encouraged
Informa4on Request (IR) LeIers iden4fy the need for addi4onal data or
request clarica4on to facilitate the review
The decision to present to an Advisory CommiIee (AC) is made by the review
division.
The AC becomes an integral part of the review process
18
Advisory CommiHees
Advisory CommiHee (AC): A group of individuals with recognized exper4se and
judgment in a specic eld who can provide independent (unbiased) expert
advice to the FDA on complex scien4c, technical, and policy issues
Objec6ve: To obtain outside advice and opinions from expert advisors
Composed of a Chair and several core members - Core members
Appointed by the Commissioner (or his designee) and serve for the
dura4on of the commiIee or un4l their terms of appointment expire, they
resign, or they are removed
- Include: Physician-scien4sts, sta4s4cians, epidemiologists, nutri4onists,
toxicologists, consumer representa4ve, pa4ent representa4ve (can be
vo4ng or non-vo4ng), industry representa4ve (non-vo4ng)
Advisory CommiIee recommenda4ons are not binding on CBER, but carefully
considered when deciding biologic issues
Review Process Principles
End of the rst-cycle review:
Within the PDUFA review goal 4meline
FDA provides ac4on leIers : product approved or complete response leIers
(approvable/non-approvable) with list of deciencies
Approvable applica4on: deciencies range from labeling comments to
comple4on of addi4onal clinical trials
Non-approvable applica4on more serious deciencies with need of signicant
addi4onal work
Review of BLA resubmissions (Class 1 or 2) within 2 to 6 months

20
Pilot Program
Expansion of rolling BLA reviews
Limited to Fast Track drugs and biologics
FDA/sponsor agreement to pre-submission of reviewable units of NDA/BLA
6-month review clock for each RU with phased-in performance goals
FDA feedback to sponsor in the form of a discipline review leIer
Guidance in development

21
Biogenerics Debate
The debate between the innovator companies and generic companies on
whether or not a biosimilar developed would have the same result as the
innovator drug, has been going on for more than a decade.
Un4l 2010 there was no legisla4on or established regulatory pathway for

the approval of generic biologics
Thus, even aaer biologics patents expire, there was liIle prospect for
compe44on from lower-cost alterna4ves
There also is no mechanism for challenging biologics patents in advance

of marke4ng a poten4ally infringing product

Biogenerics Debate
The generic drug approval statute (Hatch- Waxman) specically
applies only to versions of innova4ve drugs approved under Sec4on 505
(b) of the FDCA
Biologics are approved under the PHSA, a separate statute from the
FDCA
However, there are some biologics approved under FDCA for which
generic approval may be possible
Highly complex molecules are dicult to characterize and produce

Biogenerics Debate
Bio (Biotechnology Industry Organiza4on), the leading lobby organiza4on
of innovator companies posi4on:
Safety: Biologics much more complex in structure than small molecule
drugs and therefore it isnt possible to have a generic of the branded drug
Immunogenicity: Occurs when our bodies treat a protein as if it is a foreign
substance and produces an4bodies to aIack it. All biologics have the
poten4al to s4mulate an4body produc4on in pa4ents. Switching back and
forth between products could trigger an immunogenic reac4on
Science not available to review biogenerics without clinical studies
Even if it were possible to establish the sameness of a follow-on biologic
without clinical trials, agency reviewers would be unable to perform the
rigorous scien4c assessment necessary to reach legi4mate conclusions
about sameness without rst examining trade secret data concerning the
manufacturing processes of the innovator, which is prohibited by law
www.bio.org
Biogenerics Debate
www.genentech.com RGA6200 Biologics Development: A QA/Regulatory Overview

FDAs Historical Perspec6ve Ar6cle
J. Woodcock, et al., The FDAs Assessment of Follow-On Protein
Products: a Historical Perspec6ve, Nature Reviews Drug Discovery
(June 2007)
Basic technical overview of protein products
Discussion of FDA history of reviews and approvals of follow-on protein

products
1st indica4on from FDA regarding their thinking on regula4on of

biogeneric products
FDAs Historical Perspec6ve Ar6cle
1st deni4ons of similarity and interchangeability:
To establish that two protein products would be subs6tutable, the sponsor of a

follow-on product would need to demonstrate through addi6onal clinical data
that repeated switches from the follow-on product to the referenced product
(and vice versa) would have no nega6ve eect on the safety and/or
eec6veness of the products as a result of immunogenicity. For many follow-on
protein products and in par6cular, the more complex proteins there is a
signicant poten6al for repeated switches between products to have a nega6ve
impact on the safety and/or eec6veness. Therefore, the ability to make
determina6ons of subs6tutability for follow-on protein products may be
limited.
Biogenerics Recent Legisla6on
The Pa4ent Protec4on and Aordable Care Act (PPAC Act) was signed
into law by President Obama on March 23, 2010 these statutory
provisions also referred to as the Biologics Price Compe44on and
Innova4on Act of 2009 (BPCI Act)
PPAC Act amends the Public Health Service Act (PHS Act) to create an
abbreviated approval pathway for biologic products that demonstrate the
following with respect to already FDA-approved biologic products:
High Similarity
Interchangeability
FDA hearings regarding the enactment of this legisla4on held in
November 2010 & guidance on biosimilars issued in February 2012
Biogenerics Debate Implica6ons
Under any approach, biogenerics
Will not be easy to manufacure or get approved
In most cases are s4ll a long way o, even with a pathway
Will rarely be interchangeable
Will be dicult to market without a branded-type approach
Will have less cost-savings than tradi4onal generics

The BLA Review Process

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The BLA Review Process

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The

BLA Review Process

Using the CTD (Common Technical Document)

Content is harmonized to the extent of relevant ICH guidelines

Guidance for Industry: SubmiBng Marke4ng Applica4ons

RGA6200 Biologics Development: A QA/Regulatory Overview

Submission of BLAs may be made on paper or electronically

Submissions should be made in accordance with published

RGA6200 Biologics Development: A QA/Regulatory Overview

CBER focuses on reviewing BLAs for:

Represents the beginning of the license review process since they

Poten4al refusal to le issues

Under PDUFA IV, CBER must:

RGA6200 Biologics Development: A QA/Regulatory Overview

RGA6200 Biologics Development: A QA/Regulatory Overview

Pre-BLA Mee4ngs should be scheduled within 60 calendar days of CBERs

If the sponsor requests a later date then Mee4ng should be scheduled

Administra6ve Processing of Biologics License Applica6ons (May

Inves6ga6onal and Marke6ng Applica6ons Submission of Regulatory

RGA6200 Biologics Development: A QA/Regulatory Overview

License review process begins in CBERs Document Control Center (DCC)

Oce to which the applica4on should be forwarded is determined

BLA receives a date of receipt stamp

User fee review clock starts

RGA6200 Biologics Development: A QA/Regulatory Overview

The appropriate division then prepares and acknowledgment leIer,

Original BLA submission is forwarded to the chairperson/lead of

RGA6200 Biologics Development: A QA/Regulatory Overview

Assigning sec4ons of the applica4on for review

Scheduling and conduc4ng mee4ngs

Developing ac4on leIers regarding a BLA

AIending advisory commiIee mee4ngs

Reques4ng pre-license inspec4ons

Preparing a summary basis for approval document

If BLA applica4on does not meet basic standards of completeness and

RTF decisions primarily based on:

RGA6200 Biologics Development: A QA/Regulatory Overview

Issued within 60 days aaer the BLA is received

RTF decisions must be supported by documenta4on that clearly

Issuing an RTF decision:

RGA6200 Biologics Development: A QA/Regulatory Overview

RGA6200 Biologics Development: A QA/Regulatory Overview

FDA/sponsor agreement to pre-submission of reviewable units of NDA/BLA

6-month review clock for each RU with phased-in performance goals

FDA feedback to sponsor in the form of a discipline review leIer

RGA6200 Biologics Development: A QA/Regulatory Overview

Un4l 2010 there was no legisla4on or established regulatory pathway for

There also is no mechanism for challenging biologics patents in advance

RGA6200 Biologics Development: A QA/Regulatory Overview

Highly complex molecules are dicult to characterize and produce

RGA6200 Biologics Development: A QA/Regulatory Overview

www.genentech.com RGA6200 Biologics Development: A QA/Regulatory Overview

Discussion of FDA history of reviews and approvals of follow-on protein

1st indica4on from FDA regarding their thinking on regula4on of

To establish that two protein products would be subs6tutable, the sponsor of a

RGA6200 Biologics Development: A QA/Regulatory Overview

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