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7 April 2017 S3931-MAR-032 v1.1
Commercially Confidential
Welcome
New FDA Human Factors Guidelines on
Generics and Interchangeable
Biosimilars
Thursday 6 April, 2pm (London)
Matthew Allen PhD and Suresh Gupta PhD
Live Webinar
Suresh Gupta
Matthew Allen
Coordinator
Presenter
7 April 2017 S3931-MAR-032 v1.1 2 Commercially Confidential
Cambridge Consultants
We are an end-to-end product development company with a
strong emphasis on human factors engineering (HFE).
For over 55 years we have led the way in the Cambridge hi-
tech cluster for innovative design & development.
Our team of ~700 human factors engineers, designers,
engineers and scientists have an enviable track record of
world firsts and breakthrough developments.
We have a global presence with our offices in Cambridge,
Boston, Seattle, San Francisco, New Delhi, Singapore and
Tokyo.
We have a world-class facilities to cater for a diverse range of
sectors including drug delivery, surgical, and diagnostics.
We have delivered many successful projects for big
pharmaceutical companies and start-ups, including both
innovative and generic companies.
Our work has been recognised by numerous awards.
7 April 2017 S3931-MAR-032 v1.1 3 Commercially Confidential
Suresh Gupta, PhD (Cantab)
Presenter
Head of Human Factors and Usability Engineering, UK
Suresh is the Head of Human Factors and Usability Engineering at Cambridge
Consultants, UK. He leads a group of highly professional human factors engineers.
He has over fifteen years’ experience working within the medical device domain
which includes ten years’ of providing human factors expertise to the design and
development of medical devices and combination products within a design
consultancy environment.
He has been responsible for managing, planning and implementing of a wide range
of human factors activities ranging from front-end user requirements capture
through to preliminary analyses, formative and validation studies, and risk
management. Suresh has a track record of delivering successful human factors
and usability projects to pharmaceutical and medtech companies worldwide.
He is also responsible for promoting human factors within medical product
development, and growing the human factors capabilities and service offerings at
Cambridge Consultants. Suresh has a PhD degree in engineering design,
specialising in human factors, from Cambridge University.
7 April 2017 S3931-MAR-032 v1.1 4 Commercially Confidential
Housekeeping
Please switch on your speakers.
Today’s webinar including the Q&A session will take about 45 minutes.
This webinar is being recorded – we will share the link with you afterwards.
If you have any questions during the webinar, please submit them via the Q&A.
We will cover as many questions as possible at the end of the presentation.
If you have any further questions, please email me directly (details at the end).
Q&A
Q
7 April 2017 S3931-MAR-032 v1.1
Commercially Confidential
New FDA Human Factors Guidelines
Generics and Interchangeable
Biosimilars
What do they mean and how do they impact
current human factors practice?
Suresh Gupta (PhD), Head of Human Factors and Usability Engineering, UK
Live Webinar
7 April 2017 S3931-MAR-032 v1.1 6 Commercially Confidential
Agenda
Introduction to FDA new guidance
Background and context
Human factors requirements and process
Discussion and conclusion
Q & A
7 April 2017 S3931-MAR-032 v1.1 7 Commercially Confidential
Generics and biosimilars market
The analysts forecast global
generic drugs market to grow at
a CAGR of 10.53% during the
period 2016-2020.
http://www.prnewswire.com/news-releases/global-generic-drugs-market-
growing-at-1053-cagr-to-2020-583076381.html
The global biosimilar market is
estimated grow to $10.90 billion
by 2021 from $3.39 billion in
2016, at a CAGR of 26.3%. http://www.marketsandmarkets.com/PressReleases/global-biosimilars-
product-market-worth-19.4-billion-by-2014.asp
By 2016, it is expected that the
value of the total global generics
sector will have risen to $358
billion, representing more than
18% of all pharmaceuticals https://www.bccresearch.com/market-research/pharmaceuticals/generic-drugs-
global-market-phm009f.html
As per RNCOS report "Global
Biosimilar Market Outlook 2022",
the global biosimilars market is
anticipated to witness a high
double digit growth during 2016-
2022 http://www.pharmaceuticaldaily.com/global-biosimilars-market-could-see-
high-double-digit-growth-by-2022/
Generic and Biosimilar product market is expected to grow significantly in the
coming years and this should create a lot of opportunities
7 April 2017 S3931-MAR-032 v1.1 8 Commercially Confidential
Some examples
Refe
rence L
iste
d D
rug
(RLD
)
https://www.gskdirect.com/gsk/en/USD/RootCategory/Vaccines(non-
flu)/IMITREX-STATDOSE-SYSTEM-6M
Refe
rence P
roduct
http://www.neupogen.com/about/
Bio
sim
ilar
http://www.mims.com/malaysia/drug/info/zarzio
Ge
neric (
AN
DA
)
http://www.sumainject.com/
http://www.antarespharma.com/portfolio-and-products/drugs/sumatriptan-autoinjector
7 April 2017 S3931-MAR-032 v1.1 9 Commercially Confidential
FDA guidance
7 April 2017 S3931-MAR-032 v1.1 10 Commercially Confidential
Background and
context
7 April 2017 S3931-MAR-032 v1.1 11 Commercially Confidential
Generics
A generic drug is identical – or bioequivalent – to an FDA-approved drug, known as Reference Listed Drug
(RLD), in dosage form, safety, strength, route of administration, quality, performance characteristics and
intended use – FDA
Reference Listed
Drug (RLD)
Generics Same active ingredients
(inactive ingredients may vary)
Same strength, dosage form,
and route of administration
Bioequivalent
Same quality standard
7 April 2017 S3931-MAR-032 v1.1 12 Commercially Confidential
Biosimilars and Interchangeable Biological Products
Biosimilar
A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an
FDA-approved biological product, known as a reference product, and has no clinically meaningful differences
in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive
components are allowable in biosimilar products - FDA
Substitutable (without HCP intervention or additional training)
Interchangeable Biological Product
An interchangeable biological product, in addition to meeting the biosimilarity requirement, may be substituted
for the reference product without the intervention of the healthcare provider or additional training - FDA
Reference Product Biosimilar Biological product
Highly similar
Safety and effectiveness http://www.mims.com/malaysia/drug/info/zarzio
http://www.neupogen.com/about/
7 April 2017 S3931-MAR-032 v1.1 13 Commercially Confidential
Types of FDA applications
IND Investigational New Drug (IND) Application
NDA New Drug Application (NDA)
ANDA Abbreviated New Drug Application (ANDA): Generics
OTC Drug Applications for Over-the-Counter (OTC) Drugs
BLA Therapeutic Biologics Application (BLA)
7 April 2017 S3931-MAR-032 v1.1 14 Commercially Confidential
Types of FDA applications
IND Investigational New Drug (IND) Application
NDA New Drug Application (NDA)
ANDA Abbreviated New Drug Application (ANDA): Generics
OTC Drug Applications for Over-the-Counter (OTC) Drugs
BLA Therapeutic Biologics Application (BLA)
Generics
ANDA / 505(j)
Biosimilars: 531(k)
Interchangeable
Biological Products
Abbreviated Licensure Pathway
351(K)(4)
IBP
7 April 2017 S3931-MAR-032 v1.1 15 Commercially Confidential
If the proposed Generic or Interchangeable Biological
Product has a device constituent part, then the
application of human factors engineering is required
by the FDA
Application of human factors
Generics Abbreviated New Drug Application (ANDA): Generics Generics
ANDA / 505(j)
Interchangeable
Biological Products
Abbreviated Licensure Pathway
351(K)(4)
IBP Interchangeable Biological Product
HF HF
7 April 2017 S3931-MAR-032 v1.1 16 Commercially Confidential
Application of human factors
Interchangeable
Biological
Products
Generics
7 April 2017 S3931-MAR-032 v1.1 17 Commercially Confidential
Human factors
requirements and
process
7 April 2017 S3931-MAR-032 v1.1 18 Commercially Confidential
Human factors requirements
Safety and effectiveness
Fundamentally FDA
(CDER) requires that
any product that goes
on to the market
is SAFE and
EFFECTIVE
We used to follow traditional human
factors approach of:
risk assessment
preliminary analyses
formative studies
validation study
Generic or Interchangeable
Biological Product
7 April 2017 S3931-MAR-032 v1.1 19 Commercially Confidential
Human factors requirements
Combination products
Fundamentally FDA
(CDER) requires that
any product that goes
on to the market
is SAFE and
EFFECTIVE
Follow traditional
Human Factors
approach
Generic or Interchangeable
Biological Product
7 April 2017 S3931-MAR-032 v1.1 20 Commercially Confidential
Human factors requirements
Confusions
Fundamentally FDA
(CDER) requires that
any product that goes
on to the market
is SAFE and
EFFECTIVE
There was a lot of confusion and
questions regarding HF requirements,
e.g.
Does our product need to be identical to the
reference product?
Do we need to test our product with the IFU of
the reference product?
What if our product turns out to be superior?
Generic or Interchangeable
Biological Product
7 April 2017 S3931-MAR-032 v1.1 21 Commercially Confidential
Human factors requirements
New guidance
Fundamentally FDA
(CDER) requires that
any product that goes
on to the market
is SAFE and
EFFECTIVE
New draft guidance tries to provide
“some clarity” and a new approach,
presumably a “least burdensome
approach” in FDA’s view
Generic or Interchangeable
Biological Product
7 April 2017 S3931-MAR-032 v1.1 22 Commercially Confidential
Human factors requirements
New approach
Fundamentally FDA
(CDER) requires that
any product that goes
on to the market
is SAFE and
EFFECTIVE
Compare with Reference Product
Demonstrate that the proposed product’s
user interface is ‘similar’ to that of the
reference product
It does not have to be identical – some
differences can exist
If there are any differences, the
proposed product’s user interface must
not be inferior to that of the reference
product
It is assumed that the
FDA-approved
reference product is
SAFE and
EFFECTIVE
Generic or Interchangeable
Biological Product
FDA-approved Reference
Product
The proposed generic or interchangeable biological product can be substituted for the
reference product without the intervention of a healthcare provider and/or without
additional training prior to use of the proposed product.
7 April 2017 S3931-MAR-032 v1.1 23 Commercially Confidential
Human factors requirements
Process
Make the user interface as
Similar as possible to reference product
Some
Differences are permissible
If the differences are non-minor,
prove that the users interface is
Non-inferior to the reference product
Determine proposed product’s presentation
(as close/similar as possible to reference product)
Labeling
comparison
Comparative task
analysis
Perform Threshold Analyses
Physical
comparison of
delivery device
constituent part
Identify any non-minor differences and determine
whether a comparative use HF study is needed
Develop study protocol
(discuss protocol and results of threshold analyses with FDA)
If there are non-minor
differences
Conduct Comparative Use Human Factors Study
(Observed error rates for both products and prove
statistically that proposed product is non-inferior)
If FDA agrees with the
study design and protocol
7 April 2017 S3931-MAR-032 v1.1 24 Commercially Confidential
Determine proposed product’s presentation (1/2)
Make or choose your product as similar as possible to reference product
A sponsor developing an interchangeable product generally should not seek licensure for a presentation for
which the reference product is not licensed. For example, if the reference product is only marketed in a vial and a
syringe, a sponsor should not seek licensure for the proposed interchangeable product for a different
presentation, such as an auto-injector. – FDA
FDA-approved Reference
Product
Not a
good Idea
Generic or Interchangeable
Biological Product
Good Idea
7 April 2017 S3931-MAR-032 v1.1 25 Commercially Confidential
Determine proposed product’s presentation (2/2)
Challenges
The FDA would like you to design your proposed product as similar as possible to the reference product
Too similar Infringement Issues
Too dissimilar No amount of data would
potentially prove interchangeability
It is a tricky balance!
7 April 2017 S3931-MAR-032 v1.1 26 Commercially Confidential
Threshold analyses – labelling comparison
Make your labeling as similar as possible to reference product
FDA recommends a side-by-side, line-by-line comparison of the full prescribing information, instructions for use,
and descriptions of the delivery device constituent parts of the generic or interchangeable combination product
and its proposed product.
FDA-approved Reference
Product
Generic or Interchangeable
Biological Product
Prescribing Information
Instructions for use (IFU)
Device description
Side-by-side and line-by-line
comparison
“Same” with permissible differences
7 April 2017 S3931-MAR-032 v1.1 27 Commercially Confidential
Threshold analyses – comparative task analysis
Make your device’s user interface as similar as possible to reference product
To conduct a comparative task analysis, sponsors should systematically dissect the use process for each
product, i.e., both the proposed generic product and the reference product, and analyze and compare the
sequential and simultaneous manual and intellectual activities for end-users interacting with both the products.
FDA recommends that sponsors analyze the differences with the goal to characterize the potential for use error.
FDA-approved Reference
Product
Generic or Interchangeable
Biological Product
Decomposition of use process
Task Analyses
Identification of use errors Identification of critical tasks Identification of external
critical design attribute
Determination of differences
7 April 2017 S3931-MAR-032 v1.1 28 Commercially Confidential
Threshold analyses – physical comparison of delivery device constituent part
Make your device’s external features as similar as possible to reference product
FDA recommends that the potential applicant of the proposed generic or interchangeable combination product
acquire the reference product to examine (e.g., visual and tactile examination) the physical features of the
reference product and compare them to those of the delivery device constituent part for the proposed product
FDA-approved Reference
Product
Generic or Interchangeable
Biological Product
Physical features
Visual and tactile
examination
External critical design
attributes
7 April 2017 S3931-MAR-032 v1.1 29 Commercially Confidential
You may want to
discuss the results of
the Threshold
Analyses with the FDA
before the design
modification or study
design
Identifying differences
“Minor” differences are acceptable, non-minor differences require further data
Minor differences in design are likely to be viewed by FDA as acceptable. If there are non-minor differences the
potential applicant should first strongly consider modifying the design of the user interface. Alternatively, if such
differences are present in the final design of the user interface of the proposed product, FDA may request that
applicants provide additional information, such as data from a comparative use human factors study - FDA
Labeling
comparison
Comparative task
analysis
Threshold Analyses
Physical
comparison of
delivery device
constituent part
Any design
differences? No or “minor” design
differences
Differences not related to external
critical design attributes
Discuss results of
Threshold Analyses
with FDA
“Non-minor” design
differences Differences related to external
critical design attributes
Develop study protocol for a
comparative use human factors
study and discuss with FDA
Consider modifying
the design
OR
7 April 2017 S3931-MAR-032 v1.1 30 Commercially Confidential
Develop comparative use HF study protocol
Non-inferiority (NI) study design
Potential applicants are strongly encouraged to discuss their proposed design of a comparative use human
factors study, including determining the value of d for the specific proposed test product, prior to conducting a
comparative use human factors study. - FDA
Non-inferiority (NI) statistical study design
Comparative Use HF Study Design
Study designed to capture use errors Discuss study protocol with FDA
Paired design vs parallel design Sample size and other parameters
7 April 2017 S3931-MAR-032 v1.1 31 Commercially Confidential
Conduct comparative use human factors study (1/2)
Non-inferiority (NI) study
A comparative use human factors study should be designed to provide sufficient data to confirm that the use
error rate, for the critical task(s) as impacted by the differing external critical design attribute of the delivery
device constituent part for the proposed product, is not worse than the corresponding use error rate for the
Proposed Product when used by patients and caregivers in representative use scenarios and use environments
consistent with the labeled conditions of use. - FDA
FDA-approved Reference
Product
Generic or Interchangeable
Biological Product Comparative Use Human
Factors Study
Conduct study with both
products
Statistically analyse use
error rates
Determine inferiority/non-
inferiority
Record use error rates
7 April 2017 S3931-MAR-032 v1.1 32 Commercially Confidential
Conduct comparative use human factors study (2/2)
Demonstrate statistically that proposed product is not inferior to Reference Product
Develop study protocol
for a comparative use human factors study
and discuss with FDA
ANDA / Abbreviated
BLA Submission
Proposed product
not inferior to
Reference Product
Results?
Conduct
Comparative Use Human Factors Study
If FDA agrees with study protocol
Consider modifying
the design
Proposed product
inferior to
Reference Product
You may want to discuss the results
of the study with the FDA before
making any design modification
7 April 2017 S3931-MAR-032 v1.1 33 Commercially Confidential
Summary
Any design
differences? “Non-minor” design
differences Differences related
to external critical
design attribute
Develop study protocol for a
comparative use human factors
study and discuss with FDA
Consider modifying
the design
(Discuss with FDA)
OR
Proposed product not inferior to Reference Product
No or “minor” design
differences Differences not
related to
external critical
design attribute
Discuss results of
Threshold Analyses
with FDA
Proposed product inferior to
Reference Product
Results?
Determine proposed product’s presentation
(as close/similar as possible to reference product)
Labeling
comparison
Comparative task
analysis
Threshold Analyses
Physical
comparison of
delivery device
constituent part
FDA
agrees?
FDA not
satisfied with
the approach
of Threshold
Analyses FDA not
satisfied with
the results of
Threshold
Analyses
ANDA / Abbreviated
BLA Submission
Yes
Comparative Use Human
Factors Study
If FDA is happy with the study protocol
7 April 2017 S3931-MAR-032 v1.1 34 Commercially Confidential
Discussion and
conclusion
7 April 2017 S3931-MAR-032 v1.1 35 Commercially Confidential
Discussion and conclusion (1/4)
The generic and biosimilar market is expected grow significantly in the
near future which is likely to create huge opportunities.
– It has already attracted the interest of several major and smaller
pharmaceutical companies, as well as the interest of payers and
regulators. And this trend is likely to increase significantly in the future.
In the last few years alone the FDA has approved four biosimilars and a
number of generic products.
– The FDA is supportive of affordable drug products.
The introduction of the two draft guidance documents has changed the rules
of the game.
– Many of the approved generic and biosimilar combination products may
to fall short of meeting the new requirements, especially the
requirements of Interchangeability.
– According to the FDA website, none of the four approved biosimilars
have the interchangeable status.
– It is also not clear whether any of the approved generic products have
interchangeability status.
To
da
y, n
ea
rly 8
in
10
pre
scription
s fill
ed
in the U
.S. are
for
generic d
rugs -
FD
A
7 April 2017 S3931-MAR-032 v1.1 36 Commercially Confidential
Discussion and conclusion (2/4)
Achieving interchangeability status is an attractive proposition but more
data will be required to claim this on top of the therapeutic equivalence or
biosimilarity status.
The new guidance documents suggest an approach to achieving and
demonstrating interchangeability for generic and interchangeable biological
combination products
– Choose or design the proposed product as similar as possible to the
reference product
– Conduct threshold analyses to determine if there are non-minor
differences
– If there are non-minor differences, conduct a comparative HF study to
demonstrate that your product’s user interface is not inferior compared
to the reference product.
The human factors process described in the new draft guidance is a break
away from the conventional human factors requirements: risk
assessment, preliminary analyses, formative evaluations and validation
testing, etc.
AMJEVITA™
(adalimumab-atto)
7 April 2017 S3931-MAR-032 v1.1 37 Commercially Confidential
Discussion and conclusion (3/4)
The approach is in fact a ‘least burdensome approach’ if the proposed
product’s user interface design is ‘identical’ or ‘similar’ to the reference
product.
– But one has to be mindful of the infringement issues
However, if there are significant differences, it may be difficult to
demonstrate non-inferiority, therefore substitutability.
– Manufacturer may have to consider other application routes, e.g. NDA
or BLA (biosimilar)
Although the new guidance documents have provided some direction, there
are many open questions and areas open to interpretation, e.g.
– Subjectivity around identifying differences following the threshold
analyses
– Determinations of study design parameters (sample size, d-value,
predicted use-error probabilities, within subject correlation, etc.)
– A number of people are wondering if they could still use the
conventional HF approach to demonstrate safety and effectiveness
7 April 2017 S3931-MAR-032 v1.1 38 Commercially Confidential
Discussion and conclusion (4/4)
The FDA/CDER is perhaps aware that the draft guidance may not be
sufficient and/or accurate enough and the industry will have open questions
and interpretation.
Therefore, they “strongly encourage” potential applicants of ANDA or
Abbreviated BLA to engage with the FDA/CDER at various stages of the
process, e.g.:
– Proposed product selection design
– Results of threshold analyses
– Proposed comparative HF study design
The FDA/CDER is gathering questions and comments from the industry and
the draft guidance documents are likely to undergo substantial changes
before the final version comes out, but until that happens, the requirements in
the draft guidance are the Agency’s current thinking and there is perhaps no
alternative than to follow them.
7 April 2017 S3931-MAR-032 v1.1 39 Commercially Confidential
Q & A
7 April 2017 S3931-MAR-032 v1.1 40 Commercially Confidential
Thank you
If you have any further questions or would like to
connect with Cambridge Consultants, please reach out
directly using the contact details below.
Tel: +44 (0)1223 420024
Email: [email protected]
www.cambridgeconsultants.com
Cambridge Consultants
Science Park, Milton Road
Cambridge CB4 0DW, UK
7 April 2017 S3931-MAR-032 v1.1
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