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.