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paperMay2011TRANSCRIPT
The true story behind bioequivalence and equivalence trial
� Affordable price in era of constrain health budgets.
� Increasing numbers of population who need drug.
� Aging Societies
� Advance in medical sciences
� Need by payers, including government, and formularies to reduce healthcare costs
� In USA, Congressional Budget Office estimates
generics save consumers $8 to $10 billion a year
at retail pharmacies.
� Expense of brand name drugs for patients, such
as National Healthcare Policy group, can be
substantial.
� USFDA’s commitment to generic medicines
� “FDA will continue to make the generic drug
approval process more efficient with the goal of
lowering national health care costs by reducing
the cost of bringing safe and effective generic
drugs to market.” FDA press release August 8,
2003
� Belief by payers, some physicians and some patients that brand products and generic versions are entirely equivalent and
interchangeable
� Generic drugs is cheaper than original drugs because
� No R & D Cost
� No Advertising Cost
� Reduce Cost to bring drugs into the market.
� Same quality and benefit as Original drugs.
� We do not reduce Cost for QA
� BUT WHAT WE REALLY NEED:
Therapeutic Equivalence
� Rate and extent of absorption (bioavailability) differs between different generic versions of branded products
� Generic names are not as easy to remember, spell or pronounce as branded names
� Generic products usually differ in appearance from the brand and from other generic versions of the same product, leading to patient confusion and anxiety
� Excipients and colorants used in generic products may differ from the brand, potentially causing problems
Crawford et al. Seizure 2006;15:168-176
� “Brand drugs are more effective than generic
drugs”
� Generic drugs are required by the Food & Drug
Administration (FDA) to have the same active
ingredient, strength, dosage form and route of administration
� Generic drugs do not require the same inactive ingredients as the brand product
� A Generic drug performs the same in the body as its respective brand (reference) product
� Generic drugs cost less (but are not inferior) because the manufacturers do not engage in
costly advertising, marketing, or research and development
� Brand drug manufacturers make
approximately 50% of the generic drugs themselves
MEDICINE QUALITY ?
�Materials
�Manufacturing process
�Packaging�Transportation
�Storage condition
� Lack of therapeutic effect
Prolonged illnessDeath
� Toxic and adverse reaction
� Waste of limited financial resources
� Loss of credibility
� We can use and SHOULD USE SHOULD USE Generic drugs with Therapeutic Equivalence to Original proved
drugs.
� Therapeutic Equivalence is NOT Bioequivalence
� Efficacy and Safety
� Pharmaceutical Equivalence
� Bioequivalence
� Adequate Labeled
� Current Good Manufacture Practice (cGMP) Manufacture
Not a result of Equivalent Trials
� Bioequivalence is “a part of” NOT “the same as”Therapeutic Equivalence.
� US FDA "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."
� Usually use Cmax, Tmax, and AUC
0
10
20
30
40
50
60
70
80
90
0 5 10 15 20 25 30
Time (hours)
Co
ncen
trati
on
(n
g/m
L)
Test/Generic
Reference/Brand
Cmax
Tmax
AUC
� Active ingredient
� Active ingredient at site of action� Atorvastatin
� Extensive metabolite in Liver to ortho- and para-hydroxy atorvastatin � Half-life only 6 hrs for atorvastatin
� BUT pharmacological half-life 13-57.6 hrs
� Uptake by multiple active transporters into liver in first-pass� Blood level is not associated with pharmacological effects
� No known method to measure level of atorvastatin active metabolite in liver
� Appropriately design study.
� Method: Equivalent Trial
� DataCollection:
� Subject: Healthy vs Diseased
� Time and Condition of Drugs Administration
� Carverdilol
� Coreg® vs Dilatrend®
� Biopharmaceutic Classification System (BCS) Class 2
� Characteristics of AEDs
� Non-linearity: slight increase in PHT bioavailability
can lead to marked increase in serum level and
adverse effects, especially when level is over 15
mg/L
Crawford et al. Seizure 2006;15:168-176
864200
10
20
30
40
50
60
Daily Dose (mg/kg)Ph
en
yto
in C
on
cen
tra
tio
n (
mg
/L)
Therapeutic Window
� Burkhardt et al identified 8 adult patients whose seizures worsened after switching from brand PHT to generic PHT
� Mean total PHT concentration
� on brand (before generic): 17.7 + 5.3 mg/L
� after switch to generic: 12.5 + 2.7 mg/L
� after switch back to brand: 17.8 + 3.9 mg/L
� They concluded brand and generic PHT do not
yield equivalent concentrations in some patients
Burkhardt et al. Neurology 2004;63:1494-6
� Aim to show that the effects differ by no more than a specific amount.
For Superiority Trials: we need low α error
α error = 0.05 or lower
β error = 0.20 or lower
For Equivalent Trials: we need low β error
α error = 0.10 or lower
β error = 0.10 or lower
� Pitfalls and Limitations of Equivalent Trials� Assay Sensitivity
� Superiority Trial always demonstrate assay sensitivity
� Analysis of Equivalent Trials
� ITT vs Per Protocol
� Blinding limitation
� Specifying the noninferiority margin
� Margin could not be zero BUT how much ????
� Sample size� May be larger than Superiority Trails if done correctly
For 2-4 weeks
For 2-4 weeks
� Patients were ACS, PVD or after PCI
� Diseased subjects
� Not normal biotransformation and metabolism
� Patients were on Plavix® for 2 weeks then randomized and cross-over to Study Drug A and B for 2-4 weeks
� No wash-out periods
� Half-life for clopidogrel acid 6 hrs BUT for binded clopidogrel 7-11 days
� Platelet Function assessed by using whole blood aggregometry
� Not sensitive enough to pick up different in P2Y12 inhibition
Eur Heart J 2008;29 (23):2877-2885
Comparison of four tests to assess inhibition of platelet function by clopidogrelin stable CAD patients
P2X1
P2Y12
ATPATP
Shape change
Angiolillo DJ et al JACC 2007
P2Y1
Gq
Initiation of Platelet AggregationInitiation of Platelet Aggregation
IP3
PKC
GP IIb/IIIa
receptor activation
G12
DAG+
Shape change
Granule secretion
Stabilization of Platelet AggregationStabilization of Platelet Aggregation
βγγγγ
GP IIb/IIIa receptor activation
Rap1bPKB/Akt
α iiii
AC
cAMP
VASPVASP VASP-PVASP-P
cAMP
Gi
PI3K
ClopidogrelClopidogrel
15% active metabolite
HOOC
* HS
N
O
Cl
OCH3
N
S
O
Cl
O CH3
C
85% inactive metabolites
(Esterases in blood)
Gastro-intestinal absorption
ADPADP
Ca2+ flux
Ca2+
mobilization
PLCβ
MLCK-P
“Rho”
Hepatic CYP Biotransformation
AC
Gs
GP IIb/IIIa receptor activation
PGE1PGE1
PIP2
Very high standard deviation implied not normal distribution of data or insensitivity of test used
� Sample size was calculated by cross-over design study on the basis of equivalent hypothesis. The
study had a power of test 80% with a two-sided α value of 0.05 and allowable difference for platelet inhibition less than 10%
2N = 4(Zα+Zβ)2
(δ / σ)
2 = 2,572 or 1,286 per group
NOT 36 to 38 per group
Frideman LM Furberg CD and DeMets DL Fundamentals of Clinical Trials 3rd edition 1996
If design for Clinical Endpoint as CURE Trials, it would need N = 30,813 or 15,406 per group
CURE need only 12,562 pts vs Placebo
� The comparison between 2 groups used paired t-test and unpaired t-test. A two-sided P-value of < 0.05 was considered significant� Paired t-test to compare Study Drug A with Plavix®
and Study Drug B with Plavix®
� Unpaired t-test to compare between Study Drug A and Study Drug B
� Should use Anova to show the different between 3 groups otherwise they 4 times more significant i.e. p < 0.0125 to prove it.
� There is no difference of the efficacy on platelet inhibition function between original and generic
Clopidogrel so we concluded that the generic Clopidogrel has the efficacy equivalent to the original one, so it can be use in developing country because of its cost effectiveness.
� Due to multiple weakness of the study, we are unable to conclude that.
Laboratory and animal studies (3 ½ yrs)
Clinical studies safety (1 yr)
Clinical studies effectiveness (2 yrs)
Extensive Human clinical studies (3 yrs)
Board review (2 ½ yrs)
Board approval
Safety and Efficacy
Established by
Clinical Trials of Innovator
Board
approval
Bioequivalence study
Board Review
(1 ½ to 2 ½ yrs)
• Much the same as new, brand name drug review
• 8 major parts
1. FDA-approved generic drugs must have
• same active ingredient(s)
• same labeled strength
• same dosage form
• same administration
2. The drug company must show the generic drug is “bioequivalent”to the brand-name drug.
• active ingredient works in the same way
• active ingredient works in the same amount of time
3. The generic drug’s labeling must be basically the same as that of the approved brand-name drug.
4. The drug company must:
• fully document the generic drug’s
chemistry, manufacturing steps, and
quality control measures
• detail each step of the process
5. The raw materials and the finished
product must meet USP specifications,
if these have been set.
USP-United States Pharmacopeia
6.6. The drug company must:The drug company must:
• show that its generic drug maintains
stability as labeled before it can be sold
• continue to monitor drug’s stability
7.7. The drug company must:The drug company must:
• comply with federal regulations for
current good manufacturing practices
• give a full description of the facilities
it uses to manufacture, process, test,
package, label, and control the drug
8.8. Inspection at the proposed Inspection at the proposed
manufacturing site ensures that the manufacturing site ensures that the
firm:firm:
• is capable of meeting commitments of
the application
• can manufacture the product
consistently
GMP is that part of quality assurance
which ensures that products are
consistency produced and controlled to
the quality, standard required for their
intended use.
� Quality, safety and efficacy must be designed and built in the product.
� Testing alone cannot be relied on to ensure quality.
� Each step in the manufacturing process must be controlled to ensure that the final product within limits and specifications.
� Clearly defined and systematically reviewed processes.
� Critical steps validated.
� Appropriate resources:
� Personnel, buildings, equipment, materials�
� Clearly written procedures.
� Trained operators.
� Complete records and failure investigations.
� Recall system.
� Complaint handling.
GMP aim to ensure that the product is made in a way that :
� Assure consistency of quality, batch-after-batch.
� Ensure that any change is only implemented after impact on quality is assessed.
� Ensure that record keeping ensure traceability of all action and therefore, verification of complaints.
� Batch-to-batch quality consistency is not assured.
� Changes may be implemented without consideration for impact on quality.
� Deficient record keeping make investigation impossible.
� Contamination by other products from poorly cleaned multipurpose equipments.
� Different purity, strength, efficiency, safety and quality.
� Production operation different from the filing at the
authority.
� Poor control and traceability of production.
� Higher standard of facilities.
� Critical changes to procedure, equipment, raw material require validation.
� Stability testing
� Bioequivalence
� Qualified staff.
� More cost
� Reduce speed
� Reduce flexibility
� GMP is very expensive
Hence much temptation to forget GMP and take short-cuts. This can be eliminated by regulate
INSPECTION
� We can and recommend to use generic drug with therapeutic equivalence as original drug.
� Therapeutic equivalence is more than just bioequivalence or Equivalent trials.
� There are a lot of pitfalls and limitations in Bioequivalence test and Equivalent trials.
� GMP and post-marketing survey can ensure efficacy and safety of generic medications.