Same VS Similar?

OR
There exist some difference

No conflict of interest

Dr. Lalit Singh

M.D., FICCM
Critical Care Medicine
SRMSIMS, Bareilly (U.P.)
1
 CONTENTS
Conventional Drugs
Vs
Biological Drugs
The Difference

What we
know
about
Generics

EVIDENCES.
REFERANCES.
EXPERIENCES
Implications on
Mortality & Morbidity
in critically ill patients

2
 Barack Obama

Barack Obama
C.James Kirkpatrick and Ramzan Rangoonwala,University of Mainz
Journal of Applied Therapeutic Research Vol.7 No 2 52-57 2009
ILHAM ANAS 3
 What’s the difference

CONVENTIONAL DRUG BIOLOGICAL DRUG 4

Conventional Drugs vs Biological Products
Conventional Drugs Biological Drugs
Size Small Large
Structure Simple Complex
Manufacturing  Predictable  Unique line of living
chemical process cells
 Identical copy  Impossible to ensure
can be made identical copy

Characterization Easy to characterize Difficult to characterize

fully fully due to a mixture of
related molecules

5
 Complexity and Molecular Size
The molecular weights (in Daltons) of some
popular drugDrugs
Conventional substances Biotechnology Drugs
Glucophage® 166 Neupogen® 18,800
Roferon-A® 19,625
Vioxx® 314
Humatrope® 22,125
Prozac® 346
Avonex® 22,500
Zantac® 351 NeoRecormon® 30,400
Paxil® 375 Pulmozyme® 37,000

Zocor® 419 Enbrel® 75,000

Augmentin® 420
Crixivan® 712
Source: Adapted from 6
 US FDA: NDA Vs ANDA Review Process

Original Research Product Generic Drug

NDA Requirements ANDA Requirements

Chemistry Chemistry
Manufacturing Manufacturing
Controls Controls
Labeling Labeling
Testing Testing
Animal studies
Clinical studies Bio-equivalence
Bioavailability
Guidelines for Bioavailability and Bioequivalence studies state that:2
“ Two products marketed by different licensees, containing the same active
ingredient(s), must be shown to be therapeutically equivalent to one another in
order to be considered interchangeable”
1. Privitera MD. Epilepsy Currents. 2008;8(5):113-117. 2. Guidelines for bioavailability and bioequivalence studies, Central Drugs
Standard Control Organization, DG Health services, Ministry of Health & family welfare. India (March 2005) 7
 Interchangeability of Generic Drug With
Corresponding Original Brand:
Basis of Essential Similarity
 Chemical Equivalence:
• Drugs containing the same quantity and type of active
principle

 Bio-equivalence:1
• Drugs containing the same quantity and type of active
principle
• Having similar rate of absorption (Cmax & AUC)

 Therapeutic-Equivalence:1
• Drugs with similar therapeutic effect (efficacy and safety)2

8
 EVIDENCES

 “Bio-Equivalence and Therapeutic

effectiveness are not necessarily the
same”1

 “Therapeutic equivalence is not directly

tested by FDA but is presumed based on
bioequivalence”2

1. Borgherini G. Clinical Therapeutics. 2003;25(6):1578-92.

2. Privitera MD. Epilepsy Currents. 2008;8(5):113-117. 9
 Structure vs Process

CONVENTIONAL DRUG BIOLOGICAL DRUG 10

 Similar Drugs:
What all We need to know ?

11
India- The Home for generic
Drugs
> 100 Ciprofloxacins
> 125 Piperacillin-Tazobactams
> 50 Meropenems

Do we need so many ?
Do we know them all ?
 Generic Drugs
Are generics safe?

Is their quality as good as that of corresponding

brand?
The answer to the above questions is
“YES”
only if
you live in a country with strict
regulatory control of medicines 13
 Alert :Generic may cause in
treatment failure or serious adverse events
 Generic Drugs
Are generics as effective as newer, medically
innovated and more costly drugs?
Most difficult question to answer but most
important from patient perspective
This is where there is a conflict between the
best medicine and saving money
Innovative drugs are not cheap and should
not be expected to be cheap
They are a result of costly research and
development with high risks of product
failure before it can be proven to be safe 15
Drugs: Expensive to Develop, Easy to Copy

• An average of 14 years and 800

million dollars is spent on each

discovery that reaches the American
public

• A copy can be produced in 1 year for

less than $1 million

Tufts Center for the Study of Drug Development. 2001. 16
Long and uncertain R&D process

High Risk Process

Millions of
Compounds Screened 12-15 years,
A Thousand Hits
$ 900 -1500 Mn.

10-100 for
(Rs. 4000 – 7000 Cr.)
Pre-clinical Safety

2-3 for Phase 1 Studies

1 Product
Discovery Exploratory Development Full Development
Phase I Phase II Phase III

0 5 10 15

Idea 12 - 15 Years Drug

17
 Approval of generic drugs

For drug approval, the

interchangeability of a generic drug and
the corresponding brand-name drug is
based on “essential similarity”
- same amount and type of active
principle
- same route of administration
- same pharmacokinetic profile as
the original drug, as demonstrated by
Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs.
bioequivalence study
Clinical Therapeutics 2003; 25(6): 1578-1592.
18
Potential : Difference between generic
and Branded medication
What are they made of ? – Quality of raw
material
– Raw materials can be more than 50% of the industrial
cost of a generic drug
– Pricing pressure. May cause manufacturer to target
lower quality raw material in order to offer competitive
pricing.
– This parameter is unfortunately rarely taken into
account.

WHO drug information 2000 14(2) 77- 81 19

 Substandard Drugs is a big
Problem
Incorrect Percentage breakdown of
ingredient data on 325 cases of
16% substandard drugs -
including antibiotics,
Incorrect antimalarials and
amount antituberculosis drugs -
reported from around the
17%
world to WHO database

No active
ingredient
Other errors 60%
7%

- World Health Organization

Lembit Rägo, WHO / Essential Drugs and Medicines Policy – Technical briefing seminar, 2 October 2002,
Geneva. 20
 Same Vs Similar
Paracetamol 1 G IV
Original
A- Base is Mannitol
B- Fast onset of action and
crosses the blood brain
warrior in 5 min proved in
clinical trails.
C- Oxygen-free
manufacturing(Empty space
filled with Argon gas and
Cystein Hcl Monohydrate for
avoiding oxidation)
D-Process is patented with 9
step Process
Generics
A- Base is Sodium Chloride.
B- No Trails has been done
with Nacl base Pracetamol.
C- No Oxygen-free
manufacturing.
D- No process has been
patented for sterile
manufacturing of IV solution.
21
 Is quality a problem?

Yes, a HUGE problem

If we would have the same compliance problem with
norms and quality in aircraft industry globally
– Approximately 25% planes would not take off the
ground

– 10% would crash and kill the people (treatment

failure = killing in some cases; toxicity etc.)
- World Health Organization
22
Lembit Rägo, Essential Drugs and Medicines Policy – Technical training 2004, WHO.
Some Latest warnings/alerts/recalls
for Particulate matter in generic drugs
by FDA
Sodium Bicarbonate and
Dexamethasone Products Recalled
Because of Particulates
 Particulates administered intravenously
could
-> damage blood vessels in the lungs.
-> cause local swelling.
-> form granulomas.

12/24/2010 - Firm Press Release - American Regent

Particulate Matter - Matters !!!

Particulate Contamination Particles < 2µm

•Glass
•Latex
•Polymers
Microcirculation
Dysfunction Microcirculation
Disturbances
Kidneys
Liver
Pancreas
Lungs ARDS
Adult Respiratory
MODS Distress Syndrome
DEATH
Multiple Organ
Dysfunction
Syndrome
MOF
Multiple Organ 24
Failure
Membrane Filter Method
1 g cefotaxime sodium vials
Original VS Generic

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27
28
 In vitro potency evaluations of various
Piperacillin/tazobactam products compared with
contemporary branded (Zosyn® ) formulation

Abstract: Twenty-three generic intravenous piperacillin/tazobactam

products were compared for in vitro activity the branded formulation (Zosyn®,
Wyeth, Philadelphia, PA) by disk diffusion and incremental broth micro dilution
assay method. All but 1 lot demonstrated significantly decreased activity (-5 to -
35%), necessitating further investigations regarding the chemical purity, potency
and therapeutic equivalence of these products worldwide. The average -16%
activity across all generic lots was equivalent to under dosing
piperacillin/tazobactam by 2.6 g daily for serious clinical infections

(4.5 g Q6 h)

Diagnostic Microbiology And Infectious Disease, Volume 61, Issue 1,

May 2008, Pages 76-79
Lowest reproducible replicate MIC derived from the generic product vial (23 product lots, 15
manufacturers) compared with a randomly selected contemporary lot of Wyeth- produced
piperacillin/tazobactam (Zosyn® [B75011])
Product Batch No. Manufacturer Country Of Origin Variation %
Zosyn® Control B75011 Wyeth United States NA
Piptaz AUPM-601 Astral Pharmaceuticals industries Philippines -22
Piptaz AUPI-601 Astral Pharmaceuticals industries Philippines -13
Piptaz AUPI-701 Astral Pharmaceuticals industries Philippines -20
Zobactin ZBNPB7048 Aurobindo India -11
Pisutam 58P713 China Chem Taiwan -16
Tarorex 0701172 Demo Greece -23
Fengtailing 070302 Shanghai Asia Pioneer Pharma China -5
Prizma A001 Hikma Jordan -24
Pip/Tazo 70808401 United Laboratories Zhubai China -13
Tazidron 07076 Meditrina Pharmaceuticals Greece -13
Tazidron 07077 Meditrina Pharmaceuticals Greece -27
Zopercin 1517018 Orchid/Zeiss India -21
Piptamate 1517004 Orchid Healthcare India EQ
Vigocid 8002C YSS Laboratories Philippines -13
Vigocid 8003C YSS Laboratories Philippines -20
Vigocid 8004C YSS Laboratories Philippines -6
Vigocid 8001C YSS Laboratories Philippines -35
Tapimycin TY12T039 Yung Shin Taiwan -18
Tazotum 7003 Zuventus India -11
Tazotum 7001 Zuventus India -16
R.N. Jones et al. / Diagnostic Microbiology and Infectious Disease 61 (2008) 366-368
31
 Are all medicines safe, effective and meet
quality criteria?

 No, they are not

 Some are safe, but not effective or necessarily meet the

quality criteria

 Some may be effective, meet quality criteria but are not

safe

 Some meet quality criteria but are not necessarily safe

or have any efficacy
- World Health Organization

Lembit Rägo, Essential Drugs and Medicines Policy – Technical training 2004, WHO. 32
 Use a Generic, But Only If……

FDA requirements for generic drugs

(www.fda.gov/cder/ogd)
Thus, a generic drugs must:
 contain the same active ingredients as the innovator
drug
 be identical in strength, dosage form, and route of
administration
 have the same use indications
 be bio-equivalent
 meet the same batch requirements for strength, purity
and quality
 be manufactured under the same strict standards of
GMP required for innovator products. 33
Nick Richmond(Politician UK) Sir Sean Connery (James Bond)
34
Similar is not Same

35
Original
is One
Thank you

36