GCP in BioEquivalence Studies

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Regulatory Background
 FDA enacted laws and formulated regulations to cover generic
drug approvals
 Rationale for legislation was to allow easier and earlier access to
products that would benefit the public health
 These regulations are found in 21 CFR 320

 Other regulations and guidances apply to BA/BE studies

 Specific areas of the FDA are involved in the reviews of BA/BE

studies
– Office of Generic Drugs
– Therapeutic area experts
– Office of Regulatory Affairs – inspections and compliance

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FDA Statistics – FY2018

1st Quarter 2nd Quarter 3rd Quarter 4th Quarter

Oct - Dec Jan- Mar Apr- Jun Jul - Sept

ANDAs Awaiting FDA Action +, * 2055 1930 2026 2001

ANDA TAs Awaiting Applicant+, ** 379 391 403 416

ANDAs Awaiting Applicant Action 1701 1873 1777 1744

+, ***
Mean AP Approval Time – Per 41.70 32.24 35.3 39.58
Quarter ++
Median AP Approval Time – Per 41.88 22.78 26.68 29.23
Quarter ++
Mean TA Approval Time – Per 32.92 20.93 30.64 34.43
Quarter ++
Median TA Approval Time – Per 29.85 15.37 28.41 27.16
Quarter ++

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 NDA vs. ANDA Review Process
Brand Name Drug Generic Drug
NDA Requirements ANDA Requirements

1. Chemistry 1. Chemistry
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

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 APPLICANT

Generic Application
Drug
Refuse to
Receive Letter

Review
Application Review

Process Acceptable
&
Complete
N

Request for Plant & Chemistry & Micro Labeling Bioequivalence

Biostudy Inspection Review Review Review

PreApproval
N Inspection Results Chem/Micro N N Labeling N
Bioequivalence
OK? OK? OK? OK?

Y Y Y Y

Approval Not
Withheld Approvable Bio Deficiency
until Results Letter Letter
APPROVED
Satisfactory
ANDA

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Patent Issues

 Off patent

 Non-infringements
– method of use
– route of synthesis
 Patent challenges

 License Agreements

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Bioequivalence Requirements

 Information to show that the drug is bioequivalent to RLD

 If petition application, information demonstrating comparable

bioavailability

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What is Bioequivalent?

 Must be pharmaceutical equivalents

 Must display comparable bioavailable and meet criteria for

bioequivalence
– rate and extent of absorption is the same
– statistical criteria for equivalence

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 Model of Oral Dosage Form Performance

Clinical/PD
Pharmacokinetic
Dosage Measuremen
Measurement
Form t
Performanc
e

Dosage Drug in Site of Therapeutic

Gut Wall Blood
Form Solution Activity Effect

Dose ln Dose

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Bioequivalence Requirements

 Product is considered to be bioequivalent in rate (Cmax and Tmax)

and extent of absorption (AUC)
 Comparison with the Reference Listed Drug (RLD)

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Statistical Analysis

 Bioequivalence criteria
– Two one-sided tests procedure
• Test (T) is not significantly less than reference
• Reference (R) is not significantly less than test
• Significant difference is 20% ( = 0.05 significance level)
– T/R = 80/100 = 80%
– R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)

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Bioequivalence Testing:
Immediate Release Products
 Single dose crossover Trial

 Normal healthy subjects

 Usually 24-30 subjects

 Blood sampling for 3-5 half-lives
– Cover >88% of AUCinf
 Sensitive, accurate analytical methods

 Statistical comparisons and ANOVA

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Bioequivalence Testing
Controlled Release Products

 Normal healthy subjects (30-36)

 Statistical comparisons and ANOVA

 Single and multiple dose studies

– SD and SS kinetics as well as peak and trough levels
 Also compare 1xCR to same interval of IR product
 Look at possible food/fasting effects

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Factors that May Affect Bioequivalence

 Potency
 Content uniformity
 Dissolution characteristics

 Excipients (?)

 Food

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 Approaches to Determining Bioequivalence

 In vivo measurement of
active moiety or moieties in
biologic fluid
FeV1
 In vivo pharmacodynamic Blanching Study
comparison Topical Corticosteroid

Topicals
 In vivo limited clinical
Nasal Suspensions
comparison
Binding Studies
 In vitro comparison
Nasal Solutions-Sprayer
 Any other approach deemed Evaluation
appropriate by Agency Droplet Size

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Generics in EU

 Data protection laws

– 8 + 2 years
 Must harmonize label to match SmPC

 Cost – no more that 25% of innovator cost

 Choice of name important

– Language issues and translations

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 BA/BE Requirements

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BE Guidance

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Current/Recent Guidance

 Bioanalytical Method Validation – May 2001

 Bioanalytical Method Validation – Revised – May 2018

 Bioavailability and Bioequivalence Studies for Nasal Aerosols and

Nasal Sprays for Local Action – April 2003
 Bioavailability and Bioequivalence Studies for Orally Administered
Drug Products — General Considerations – March 2003
 Food-Effect Bioavailability and Fed Bioequivalence Studies – Dec
2002
 Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs
Submitted Under an ANDA – December 2013
 Bioavailability and Bioequivalence Studies Submitted in NDAs or
INDs— General Considerations – March 2014
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New BE Guidance

 Population – Adults over 18 yrs

 Male & female unless not appropriate

 Single dose design preferred

 Validated bioanalytical methodology

 Fasted trial preferred

 Measure active moiety

– Active metabolite only if relevant to activity
 Use standard parameters (AUC, Cmax, Tmax, t1/2,)

 Different rules for ER dosage forms

 Blood sample testing preferred

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Sample Retention

 Need to retain reserve samples of test and reference products

used in BE trial
– Sufficient quantity for FDA to conduct 5x all release tests for the product(s)
– Stored under proper conditions
 Must be retained for at least 5 years after approval of subject
application
– If not approved, 5 years after trial completion
– If CRO/facility storing samples goes out of business, samples can be
transferred to an independent third party for storage

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Other New Items

 Update to Declaration of Helsinki (DoH) – Brazil 2013

 FDA reference to GCP (ICH) and not DoH for clinical studies
conducted outside of US and not under an IND (312.120)
 SAE reporting for BA/BE studies

 FDA regional offices to facilitate inspections and interactions

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New - BE Study Reports

 The person conducting the study, including any contract research

organization, must notify FDA and all participating investigators of
any serious adverse event, as defined in §312.32(a), observed
during the conduct of the study as soon as possible but in no case
later than 15 calendar days after becoming aware of its
occurrence…any fatal or life-threatening adverse event from the
study as soon as possible but in no case later than 7 calendar days
after becoming aware of its occurrence

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Exercise
 A sponsor organization has agreed to conduct a study for which
your company will be the overall responsible group. This will be a
multisite study involving the collection of similar samples and data
from different geographical areas. All the data generated by the
sites will be sent to your company for scientific interpretation and
inclusion in a final report. The sites have adopted different methods
for collecting data – notebooks, loose-leaf files or data collected
directly on computers (electronic data).

– How will you ensure that all the data from the various sources are
sent to you without problems and that the data you receive are
reliable?
– How will you organize the data so that you can compile your report
easily ?
– How will you deal with the archiving of raw data and other
documents at the end of the study ?
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