Bio-studies and Generic Drug Development Process Training given to professionals of public sector engaged in bio and clinical studies

1. Obaid Ali, R. Ph. Ph.D.
Expectations from Good Clinical Practices
Clarity & Flexibility
22 – 24 August 2019
at CBSBR, ICCBS, University of Karachi

3. It reflects the views & understanding of presenter
& may not be construed to represent the views
or policies of organization or association
to which presenter has ties
Applicable Regulations
ICH E6 (R2) EWG Feb 2017
Disclaimer
Reference

4. Submissions & GCP Fundamentals;
Principles of Safety & Data Reliability
Clinical Relevance for Surrogate;
Development of Generics
Biopharmaceutical Evaluation Affairs;
From Fiction to Reality
When data delivers challenges;
How to think critically
Cont’d
1
Presentation Focus
2
3
4

5. Presentation Focus
Biopharmaceutical Classification;
Science
Bioavailability/ Bioequivalence Studies;
Common Regulatory Concerns
Addendum - ICH – GCP E6 (R2);
An Overview
5
6
7

6. Submissions & GCP Fundamentals
Principles of Safety & Data Reliability

7. FDA Denies Approval
Sliver Spring/Rockville, MD
20 Aug 2019
Elegance Placebo Effect

8. Duchenne Muscular Dystrophy
Risk for
• I/V Inf. - port Infections
• Renal Toxicity

9. A previous strength
may be turning into weakness

10. Suckerpunch Challenge
Use of API in Bio-batch that was imported from a company
which later on found GMP non-compliant in the period product
was manufactured

11. Priority Fast Track
Accelerated Breakthrough
Review

12. Priority Fast Track
Accelerated Breakthrough
Review
Significant improvement
in safety or effectiveness
of the treatment when
compared to prevailing
situation

13. Priority Fast Track
Accelerated Breakthrough
Review
If no therapy exists

14. Priority Fast Track
Accelerated Breakthrough
Review
Use of surrogate endpoint
for survival of cancer
patients

15. Priority Fast Track
Accelerated Breakthrough
Review
Clinically significant
endpoint observed on
irreversible morbidity or
mortality

16. Good Clinical Practices
(GCP)

17. GCP is defined as a standard
for the design, conduct,
performance, monitoring, auditing,
recording, analysis and reporting of
clinical trials or studies
Good Clinical Practices
(GCP)

18. Nuremberg Code (1947)
• Voluntary participation
• Informed Consent
• Minimization of risk
Before GCP

19. Declaration of Helsinki (1964)
• Well-being of subject takes precedence
• Respect for persons
• Protection of subjects health & rights
• Special protection for vulnerable
population
• Scientific Principle
• Independent Ethics Committee etc.
Before GCP

20. Belmont Report Ethical Principles (1979)
Respect for Persons
• Informed consent
• Protection of vulnerable populations
Beneficence
• Non-malfeasance
Justice
• FairnessBefore GCP

21. ICH

22. GCP is defined as a standard
for the design, conduct,
performance, monitoring, auditing,
recording, analysis and reporting of
clinical trials or studies
Good Clinical Practices
(GCP)

23. GCP is an international quality
standard that is provided by the
International Conference on
Harmonisation (ICH)
ICH

24. Harmonize technical procedures and
standards; improve quality; speed
time to market
ICH Goal

25. From 1997, the FDA, EMA, Japan
started endorsing the GCP
Guidelines developed by ICH
ICH

26. ICH guidelines have been adopted
into law in several countries, but
used as guidance for the Pakistan,
US in the form of GCP
ICH

27. GCP is intended for ….
Public safety & well being
Ethical & Scientific
Credible Data
Consistent with Helsinki etc.
Good Clinical Practices
(GCP)

28. GCP revolves ….
• Clinical Investigation
• Clinical Investigator
• Human Subject
• Institutional Review Board
Good Clinical Practices
(GCP)

29. GCP somehow guarantee ….
that the rights, safety & well-being
of human subjects involved in
research are protected
Good Clinical Practices
(GCP)

30. To protect the rights, safety and
welfare of humans participating in
research
GCP Goals

31. To assure the quality, reliability and
integrity of data collected
GCP Goals

32. To provide standards and guidelines
for the conduct of clinical research
GCP Goals

33. Ethics & Quality Data
are the focus
GCP Goals

34. Principles of ICH-GCP
13

35. Ethical Conduct of
Clinical Trials
01

36. Benefits justify Risks
02

37. Rights, Safety, & Well-
being of Subjects prevail
03

38. Nonclinical & Clinical
information supports the
trial
04

39. Compliance with a
scientifically sound,
detailed protocol
05

40. IRB/IEC approval prior to
initiation
06

41. Medical care/decisions by
qualified physician
07

42. Each individual is qualified
(education, training,
experience) to perform
his/her tasks
08

43. Informed Consent freely
given from every subject
prior to participation
09

44. Accurate reporting,
interpretation, and
verification of data
10

45. Protects confidentiality
of records
11

46. Conform to GMP’s and
used per protocol
12

47. Systems with procedures to
ensure quality of every
aspect of the trial
13

48. Clinical Relevance for Surrogate
Development of Generics

49. Generic
Substance
Product
Process
Facilities
Microbiology
Biopharmaceutics

50. Generic
Substance
Product
Process
FacilitiesMicrobiology
Biopharmaceutics
Label claim
CMC
Bio-studies
GMP
Promise

51. Bioequivalence
Pharmaceutical
Equivalency
Chemistry
Clinical Relevance

52. Bioequivalence
Pharmaceutical
Equivalency
Chemistry
Clinical Relevance
Expectations of
clinical promise

53. Pharmaceutical Equivalence
Active Ingredient
Dosage Form
Route of Administration
Strength & Quality
Purity & Identity
Same

54. Allowable Difference
Shape
Scoring
Release mechanism
Excipients & Packaging
Shelf Life

55. Clinical Relevance
A generic drug that is both bio &
pharmaceutical equivalent must also act
in the same clinically relevant way
That includes duration of use,
indications, target populations

56. PK, PD, End Point, Markers etc. to establish suitability for
Clinical Relevance

57. Biopharmaceutical Evaluation Affairs
From Fiction to Reality

58. Performance
should be the
same way

59. No Worse
Performance
should be the
same way

60. No Worse
No Better
Performance
should be the
same way

61. Please make it clear
They are not
clinical studies
Nothing to do
with Safety &
Efficacy of
molecule
Evaluating the
Similarity of
Trends
&
Kinetics

62. Bioequivalence & Generic Drugs
Pharmaceutical Equivalent & Bioequivalent
Pharmaceutical Equivalence
Does not mean equivalent performance

63. HS … HP
LS … HP
HS … LP
LS … LP
BCS

64. Injectable
• Same Qualitatively & Quantitatively
• Evidence of in vitro studies, formulation &
manufacturing process available

65. Injectable
• Same Qualitatively & Quantitatively
• Evidence of in vitro studies, formulation &
manufacturing process available
• Bio-studies required ?

66. Injectable
• Same Qualitatively & Quantitatively
• Evidence of in vitro studies, formulation &
manufacturing process available
• Bio-studies required ?
•WAIVER

67. Oral Solution
• Same Qualitatively & Quantitatively
• With different excipients

68. Oral Solution
• Same Qualitatively & Quantitatively
• With different excipients
• Bio-studies required ?

69. Oral Solution
• Same Qualitatively & Quantitatively
• With different excipients
• Bio-studies required ?
•WAIVER

70. Oral Solution
• Same Qualitatively & Quantitatively
• With different excipients
• Bio-studies required ?
•WAIVER

71. Oral Solution
• Not Same Qualitatively & Quantitatively
• With different excipients

72. Oral Solution
• Not Same Qualitatively & Quantitatively
• With different excipients
• Bio-studies required ?

73. Oral Solution
• Not Same Qualitatively & Quantitatively
• With different excipients
• Bio-studies required ?
• Impact on absorption or safety
needs to be demonstrated

74. When data delivers challenges;
How to think critically
Data
Sciences

75. New Drug
New molecule entity
New formulation of previously
approved drug
New combination of two or more
approved drugs
New indication for already
marketed drugs

76. New Drug
Innovative, non-clinical data,
clinical data, product development
Screening, Assessment, Review &
Evaluation to understand safety,
efficacy & quality of drug

77. New Drug
Innovative, non-clinical data,
clinical data, product development
Screening, Assessment, Review &
Evaluation to understand safety,
efficacy & quality of drug

78. New Drug
Innovative, non-clinical data,
clinical data, product development
Screening, Assessment, Review &
Evaluation to understand safety,
efficacy & quality of drug
Protection of Promise and Label
Claim as a shared responsibility

79. Bioequivalence
Generics
No need for animal studies
No need for clinical studies
No need for bioavailability

80. Generic
Required
Chemistry
Manufacturing
Testing
Labeling
Inspections

81. Generic Drug
Product Development
& Bio-studies only

82. Relation between New & Generic Drug
New Generic
Bio-studies of generic are surrogate for all
clinical studies done by innovator

83. Cardiovascular Affairs
A B C D M*
ACE
Inhibitors
Beta
Blockers
Calcium
Blockers
Diuretics
CNS
Drugs

84. ACE inhibitors
I Captopril, Enalpril, Lisinopril etc.
II Losartan, Candesartan, Valsartan …
Angiotensin II Receptor Blockers

85. Angiotensin II Receptor Blockers
Losartan Valsartan Candesartan
Innovator / New Drugs

86. Angiotensin II Receptor Blockers
Losartan Valsartan Candesartan
Merck
Innovator / New Drugs

87. Angiotensin II Receptor Blockers
Losartan Valsartan Candesartan
Merck Novartis
Innovator / New Drugs

88. Angiotensin II Receptor Blockers
Losartan Valsartan Candesartan
Merck Novartis Astra Zeneca
Innovator / New Drugs

89. Generic
Several generics
entered in market
after expiry of patent
Meta-analysis
reported ….

90. When data speaks

91. Data
24
Months data

92. Data
Before entry
of generic in
market
24
Months data

93. Data
Before entry
of generic in
market
24
Months data
10% visited emergency
or hospitalized/month

94. Data
Before entry
of generic in
market
24
Months data
10% visited emergency
or hospitalized/month
136177 patients
66 & above age
60% women &
40% men

95. 10 use drug
9 live healthy
1 visits hospital

96. Data extended
36
Months data

97. Data extended
After 12
months entry
of generic in
market
36
Months data

98. Data extended
After 12
months entry
of generic in
market
36
Months data
Visited emergency or
hospitalized/month

99. Data extended
After 12
months entry
of generic in
market
36
Months data
Visited emergency or
hospitalized/month
18% for
Losratan
22% for
Valsartan
24% for
Candesartan

100. 10 use drug
8 live healthy
2 visit hospital

101. Data Screamed
10%
18%
22%
24% ?R
R
+
G

102. Innovator
10%
Innovator Generic
21%
24 month 36 month
Hospitalization

103. Lets think
What went wrong?
What may go wrong?

105. Concentration Levels in blood

107. Regulatory Standards

108. 80% to 125%
Cmax
AUC

109. If The test drug is compared with innovator & its profile falls on the
innovator scale in between 80 to 125%
It is Generic
We expect same therapeutic effect as established by the innovator
in their clinical studies done earlier

110. Lets have a Critical Review

111. 90 - 10080 - 90 100 - 110 110 - 125

112. 90 - 10080 - 90 100 - 110 110 - 125

113. 90 - 10080 - 90 100 - 110 110 - 125
Reference

114. 90 - 10080 - 90 100 - 110 110 - 125
Reference

115. 90 - 10080 - 90 100 - 110 110 - 125
Reference
Generic

116. 90 - 10080 - 90 100 - 110 110 - 125
Reference
Qualifying Zone
Generic

117. 90 - 10080 - 90 100 - 110 110 - 125
Reference
Qualifying Zone
Generic Generic

118. 90 - 10080 - 90 100 - 110 110 - 125
Reference
Qualifying Zone
Generic Generic
Qualifying Zone

119. 90 - 10080 - 90 100 - 110 110 - 125
Reference
Qualifying Zone
Generic Generic
Qualifying Zone

120. Information to Knowledge
Take an example
of a Tablet 1 mg

121. Information to Knowledge
Shelf life limit is
90 – 110%
Take an example
of a Tablet 1 mg

122. Information to Knowledge
Shelf life limit is
90 – 110%
0.9 mg – 1.1 mg is
acceptable
Take an example
of a Tablet 1 mg

123. Information to Knowledge
If a generic is
80% BA
&
90% of Potency

124. Information to Knowledge
It will be expected max. 72%
If a generic is
80% BA
&
90% of Potency

125. 72% instead of 100%
Remember !!!
clinical studies done
on 100%

126. Information to Knowledge
If a generic is
125% BA
&
110% of Potency

127. Information to Knowledge
It will be expected max. 137.5%
If a generic is
125% BA
&
110% of Potency

128. 137.5% instead of 100%
Remember !!!
clinical studies done
on 100%

129. 72% to 137.5% instead of 100%

130. 72% to 137.5% instead of 100%
May be Under Dose

131. 72% to 137.5% instead of 100%
May be Under Dose May be Over Dose

132. 72% to 137.5% instead of 100%
May be Under Dose May be Over Dose
May not be in every case but …

133. 72% to 137.5% instead of 100%
Drug in Blood
Minimum effective concentration
Over maximum concentration
Every breath deserve quality

134. Innovator
10%
Innovator Generic
21%
24 month 36 month
Hospitalization
We are here again

136. Move forward
Recognize capacity and its expansion
Walk with science and promote creativity
Appear on International radar with grace

137. Biopharmaceutical Classification
Science

138. Biopharmaceutical Classification System
Solubility PermeabilityDissolution

139. Biopharmaceutical Classification System
Solubility PermeabilityDissolution
Foundation of
the waiver for
bio-studies

140. High soluble high
permeable
High soluble low
permeable
Low soluble high
permeable
Low soluble low
permeable

141. Solubility
DissolutionPermeability
Determine the absorption of a
drug from a formulation

142. If a drug substance has high
solubility it is unlikely that
formulation difference between
test and reference product
would affect the rate of extent
of absorption of the API

143. If a drug substance has high
solubility it is unlikely that
formulation difference between
test and reference product
would affect the rate of extent
of absorption of the API
Provided in vivo
dissolution of both is
rapid to GI emptying
time

144. If a drug substance has high
solubility it is unlikely that
formulation difference between
test and reference product
would affect the rate of extent
of absorption of the API
Provided in vivo
dissolution of both is
rapid to GI emptying
time
Provided there are no
excipients that would
affect absorption

145. Eligible Products
IR solid dosage forms of Class I
with rapid dissolution
IR solid dosage forms of Class III
that exhibit very rapid dissolution

146. Rapid 85% in 30 minutes
85% in 15 minutesVery Rapid

147. Ineligible Products
Modified release products
Narrow Therapeutic Range drugs
Class II & IV drugs

148. High Solubility
When the highest strength is soluble
in 250 ml of aqueous media within the
pH range of 1 to 6.8
Highest strength does not mean the
highest dose

149. High Permeability
Not for Class I
1. Mass balance studies
2. Intestinal permeability method
3. Expression of efflux transporters
in cell culture system

150. High Permeability
Not for Class I
4. Validated cell culture method
5. High & low permeability
standard in pivotal study
6. In case of intestinal permeability
method, drug stability in GI tract
must be documented.

151. Excipients
BCS Class I
Product does not contain excipient
quantity that can affect rate of
absorption.

152. Excipients
BCS Class III
Qualitatively the test product
formulation should be same
& quantitatively very similar
to the reference drug

153. The highest strength is soluble
in 250 ml or less of aqueous
media within the pH range of 1
to 6.8 at temperature 37 + 1C.
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
1

154. 85% or more of labeled amount
of API dissolved within 15
minutes using USP apparatus 1
at 100 RPM or apparatus 2 at
50 RPM in
500 ml or less in 0.1 N HCl or
simulated gastric fluid USP
without enzyme.
and ...
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
2

155. 85% or more of labeled amount
of API dissolved within 15
minutes using USP apparatus 1
at 100 RPM or apparatus 2 at
50 RPM in
A pH 4.5 buffer
as well as...Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
2

156. 85% or more of labeled amount
of API dissolved within 15
minutes using USP apparatus 1
at 100 RPM or apparatus 2 at
50 RPM in
A pH 6.8 buffer or simulated
intestinal fluid USP without
enzyme
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
2

157. The test product formulation is
qualitatively the same and
quantitatively very similar to
Reference
Highly Soluble
Less Permeable
Rapid Dissolving
BCS Class III
3

158. Change in excipients expressed
as % (w/w) o total formulation
less than or equal to the:
Filler (+ 10%)
Disintegrant, starch (+ 6%)
Disintegrant, other (+ 2%)
Binder (+ 1%)
Lubricant, Ca or Mg Stearate
(+ 0.5%)
Very
Similar

159. Change in excipients expressed
as % (w/w) o total formulation
less than or equal to the:
Lubricant, other (+ 2%)
Glidant, talc (+ 2%)
Glidant, other (+ 0.2%)
Binder (+ 1%)
Film coat (+ 2%)
Very
Similar

160. Change is acceptable within
limit but the total additive
effect of all excipients changes
should not be more than 10%
Very
Similar

161. Common Concerns
In vitro BE Studies
Statistical Analysis:
Incorrect method used, missing
justification for method used.
Analytical Method: Quality
Controls not included, method
validation incomplete

162. If excipients in the formulation are
not suspected to affect on drug
absorption &
Excipients qualitatively the same and
quantitatively similar, then
Bio-waiver may be possible upon
demonstration of similarity in
comparative dissolution with
reference productRecap

163. If excipients and formulations are
suspected to have an effect on drug
absorption but excipients may affect
absorption within +10% comparative
to reference drug and
Excipients qualitatively the same and
quantitatively similar, then
Bio-waiver may be possible upon
demonstration of similarity in
comparative dissolution with
reference product
Recap

164. If not in any case whether it is
similarity of excipient or
suspect to have an effect on drug
absorption of any excipient or
More than 10% potential to change
absorption of drug ….
It is not for Biowaiver
Recap

165. If someone come and claims
that he or she has discovered a
drug for Nausea ....
What would you like to see ..

170. Review and
Evaluation
Regulatory Authorities

171. Label Review and alerts

172. Generic Drugs

173. If it is claimed that someone
used same materials and
developed generic version ...
What would you like to see ..

174. Pre Clinical
Clinical Phase 1
Clinical Phase 2
Clinical Phase 3

175. Absorption
A Distribution
D Metabolism
M Elimination
E
Absorption is a real challenge

176. Absorption is a real challenge
Solubility Permeability

177. Absorption is a real challenge
Solubility Permeability
Will formulation be able to deliver similar
amount of drugs with similar rate?
Bioavailability

178. Absorption is a real challenge
Solubility Permeability
Will formulation be able to demonstrate
similar pattern of both?
Bioequivalence

179. Reaching in Blood
Site of Action
Excreting from Body

180. Reaching in Blood
Site of Action
Excreting from Body
Disintegrate Dissolution Absorption

181. Reaching in Blood
Site of Action
Excreting from Body
Disintegrate Dissolution Absorption
Solubility Permeability

182. Reaching in Blood
Site of Action
Excreting from Body
Disintegrate Dissolution Absorption
Solubility Permeability
GIT

183. Reaching in Blood
Site of Action
Excreting from Body
Disintegrate Dissolution Absorption
Solubility Permeability
GIT pH

184. Reaching in Blood
Site of Action
Excreting from Body
Disintegrate Dissolution Absorption
Solubility Permeability
6.84.61.2GIT pH

185. Scenario A
If innovator changes the
formulation
of its new drug, what do you think it
requires clinical studies or bio-studies
or comparative dissolution studies or
none of them

186. Scenario B
If innovator changes the
manufacturing site
of its new drug, what do you think it
requires clinical studies or bio-studies
or comparative dissolution studies or
none of them

187. Scenario C
If innovator changes the
manufacturing process
of its new drug, what do you think it
requires clinical studies or bio-studies
or comparative dissolution studies or
none of them

188. Scenario D
If innovator changes the
manufacturing equipment
of its new drug, what do you think it
requires clinical studies or bio-studies
or comparative dissolution studies or
none of them

189. Product
Process
Understand
Built into
entire process
For Installation of
Appropriate Controls
The only way
to have Quality

190. Warm up exercise
Fundamental Scenarios and Bio-studies or Dissolution Studies

191. Drug must be available in the blood stream in the same pattern
on which clinical studies have been performed
Similarity & Equivalency?

192. If a tablet is disintegrated, in which
situations, it will not reach to the blood

193. If a tablet is dissolved, in which
situations, it will not reach to the blood

194. Have you ever imagined a situation
where a tablet can come out from the
body as it is?
If so, can it produce effect

197. Drug Performance
Dosage
Form
Drug in
solution
Gut wall Blood
Site of
Activity
Therapeutic
Effect
Dosage Form
Performance
Pharmacokinetic
Measurement
Clinical/PD
Measurement

198. Science of Bioequivalence
Developed over the last few decades
Continues to evolve
Specific approaches depend on a number of
factors
Can be simple or highly complex

199. Generic Drug
….. equivalent drug products
that can be substituted at the
pharmacy level for the
reference /innovator drug, and
each other, without any
adjustment in dose or other
additional therapeutic
monitoring

200. Pharmaceutical Equivalence
Same active ingredient
Same dosage form
Same route of administration
Identical in strength or concentration

201. What is Substitutability?
Pharmaceutically
equivalent
1
Bioequivalent
2
Generic Drugs must be

202. Generics not necessarily identical
Excipients Difference
Manufacturing Differences
Formulation Difference
Shape, color difference

203. Bioequivalence & Generic Drugs
Pharmaceutical Equivalent & Bioequivalent
Pharmaceutical Equivalence
Does not mean equivalent performance

204. Label
1 CMC
2 Bio-
studies
3 Plant
GMP
4

205. Brand Name Drug Generic Drug
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

206. Bio-
studies
Dissolution
BioavailabilityBioequivalence

207. PK PD

208. 208
Clinical/PD Dose-
Response
Clinical/PDResponse
Log Dose

209. 209
Plasma
Concentration-Dose
Dose
PlasmaConc.

210. What is Reference/Innovator Drug
Innovator
Brand
Authorized
Brand

211. 211
AUC and Cmax 90% Confidence Intervals (CI) must
fit between 80%-125%

212. To determine rate and extent of absorption of
generic, innovator
From 2009

213. On healthy human volunteers but use patients if
there is a safety concern (Etoposide, Clozapine)
Male, Female both

214. Bio-analytical method must be validated

215. 215
• In vivo measurement of
active moiety or moieties
in biologic fluid
• In vivo pharmacodynamic
comparison
• In vivo limited clinical
comparison
• In vitro comparison

216. Single-dose,
two-way
crossover,
fasted
Single-dose,
two-
waycrossover,
fed
Alternatives

217. 1
• Single-dose,
parallel, fasted
• Long Half-Life
(wash-out)
Amiodarone,
Etidronate
2
• Single-dose,
replicate design
• Highly
Variable Drugs
3
• Multiple-dose,
two-way
crossover,
fasted
• Less Sensitive
Clozapine
(Patient Trials)
Chemotherapy
Trials
4
• Clinical
endpoint study
• Topicals Nasal
Suspensions

218. Urine may be used for measurement when drug cannot
be measured in plasma e.g. Potassium Chloride
Baseline in blood is too high to permit accurate
measurement

219. Special Case: Alendronate Sodium (5 to 70 mg)
Problem with plasma detection because of low
concentration & re-distribution from bone

220. Pharmacodynamics Approach
Generic topical corticosteroid, ability to produce
vasoconstriction

221. Special Case: Tretinoin Acne Gel
Problem with plasma detection, endpoint related to
healing region is considered

222. Special Case:
Highly Variable Drugs
3 period bio-studies TRR, RTR, RRT

223. BioWaivers
IV solutions, Oral solutions, BCS class 1, old drugs
with no bio-equivalency problem

224. Oral Solution
Must not contain an excipient that may significantly
affect absorption of API
e.g. Prednisolone sodium phosphate oral solution
Inactive must not have safety issue

225. Solid Oral Dosage
Dissolution testing on all strengths
Strength proportionality must be similar to the biostrength
In-vivo BE must be established for higher strength
But for safety lower strength
E.g. Terazosin HCl 1, 2, 5 & 10 mg strength, 2 is acceptable

226. Highly Soluble, Highly Permeable, Rapidly Dissolving
e.g. Ofloxacin

227. Dissolution e.g. Omeprazole
Use of dissolution data for biowaiver of non-bio strength
Two stage dissolution testing
(acid medium & buffered medium)

228. Bioavailability/ Bioequivalence Studies
Common Regulatory Concerns

229. Pharmacokinetics
Repeats
The criteria for selection of
samples for re-analysis are
considered not objective,
unscientifically sound or
potentially biased toward
favorable bioequivalence
outcome

230. Standard Operating
Procedure (SOP)
The bio-analytical SOPs
used in the application were
not submitted.

231. Long term
Storage Stability
The long-term frozen
storage stability data were
not submitted or not enough
to cover the whole
biological sample storage
time period

232. Potency, Content
Uniformity &Formulation
The potency or content
uniformity data for the test
product was not submitted
Cont’d

233. Potency, Content
Uniformity &Formulation
Color & Flavor
The information on colorant
or flavor used in the test
formulation submitted was
……..
Cont’d

234. Potency, Content
Uniformity &Formulation
Excipient over Limit
One or more excipients are
over the limit in the inactive
ingredient guide
Cont’d

235. Potency, Content
Uniformity &Formulation
Exceeded Iron Intake
Based on the maximum
daily dose of the drug and
formulation, the intake of
iron from the drug may
exceed the limit of 5 mg per
day

236. Dissolution Specification
The in vitro dissolution
testing specifications were
not proposed or not as
recommended by DBE

237. Dissolution Method
The dissolution method
used in the application is
not optimal or not
consistent as that suggested
by DBE

238. Unclassified Dissolution
Issues
Failure to submit individual
dissolution data for each of the 12
units of test and reference
products.
Incomplete dissolution
testing (e.g, lacking dissolution
data in multimedia for extended
release products and alcohol dose
dumping data for certain
products).
Dissolution deficiencies that
cannot be categorized into
specification or method

239. Unclassified Dissolution
Issues
Failure to provide information
on dissolution testing date and
site address
High variability in dissolution
data.
Dissolution deficiencies that
cannot be categorized into
specification or method

240. Bio-summary Tables
The summary tables for BE
studies are not submitted or
incomplete

241. Unjustified Exclusion
of Subjects
Subjects are excluded from
statistical analysis without
proper justification

242. Analytical Issues
Insufficient submission of
analytical raw data from the study
runs of all the subjects.
Incomplete bio-analytical report
(for example, missing dilution
integrity data, stock stability data,
absolute recovery data).
Lacking chromatograms for 20%
of study subjects.
Analytical Method Validation /
Analytical Report Deficiencies

243. General Issues
Dropping subjects who are
assumed outliers from statistical
analysis without adequate
justification.
Improper submission or missing
of electronic data files which are
required for statistical analysis.
Inadequate information on the
failed bioequivalence
study.
Deficiencies that do not fall
into any of the
categories above

244. Relative Dissolution
Specifications
Proposed dissolution
specifications followed by
bioavailability study are not
included in release and
stability testing

245. Relative Dissolution
Specifications
Increase testing frequency
to exhibit compliance of
DP with proposed
specifications in release
and stability testing or
justify the waiver

246. Addendum - ICH - GCP E6 (R2)
An Overview

247. Background
Why Addendum?

248. Evaluation of Clinical Trials
after 1996
Background
Why Addendum?

249. Background
Why Addendum?
Globalization
Study Complexity
Tech. Capabilities

250. Approach to GCP
Modernization in complexity of CT
its scale up & appropriate use of
technology
Background
Why Addendum?

251. Flexibility to implement
Innovative approach ... misinterpreted
Background
Why Addendum?

252. Emphasizing less important aspects of trials
At the expense of critical aspects

253. Focusing on the completeness & accuracy
of every piece of data
Carefully managing risk to the integrity
of key outcome data

254. ICH E6 (R2)
Objective
E2A
E3
E7
E8
E9
E11
Guidance Doc

255. Thank You