Original Drugs (Antibiotics)

1

• Original Drugs (Antibiotics)
• Vs
• Generic Drugs (Antibiotics)
• What we need to know ??

Dr Ankur Gupta, MD (Pharmacology) Medical
Advisor, MSD Pharmaceuticals
2
India- The Home for generic Drugs

• gt 100 Ciprofloxacins
• gt 125 Piperacillin-Tazobactams
• gt 50 Meropenems
• Do we need so many ?
• Do we know them all ?

3
What is a Branded (Original) Drug ?

• The original drug for which production and
  marketing are made possible for the innovator
• WHO Drug Info 2000

4
What is a generic drug

• A copy of an original drug for which production
  and marketing are made possible by the expiry of
  the patent covering the innovator product
• WHO drug Int 2000

5
Quality is the key..

• In the manufacture of generic drugs, the three
  concepts of quality, safety and efficacy apply
  to generic in the same way as they do to the
  innovator product..
• It is a fallacy to believe that quality
  production and assurance can be achieved at no
  great investment !!!

WHO Drug Infor. 2000
6
Components of Branded Drug Cost

• Brand vs. Generic
• Brand
• High drug prices due to Research Development
  costs and Production Quality Assurance Costs

7
Original Drugs Expensive to Develop, Easy to
Copy

• An average of 14 years and 800 million dollars is
  spent on each discovery that reaches the public
• A copy can be produced in 1 year for less than 1
  million

Tufts Center for the Study of Drug Development.
2001.
8
Potential difference between Generic and Branded
Drugs
WHO drug information 2000 14(2) 77- 81

• Quality of Raw material used (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. )
• Method Of Synthesis (There is a risk of toxicity
  from degradation products or impurities in the
  event that the method of synthesis has been
  changed)
• Packaging , Stability, Evaluation ( Plastic in
  packing may chemically interact with drug,
  especially under conditions of high humidity or
  heat (tropical countries) Toxic phenomena can
  result from the stability modifications of the
  product

9
GENERIC DRUGS

• There are 4 main aspects to be considered
• Are generics safe?
• Is their quality as good as that of corresponding
  brand?
• Is doctor wise in switching branded to a generic
  drug?
• Are generics as effective as Innovator drugs?

10
Are generics safe?Is their quality as good as
that branded drug?

• The answer to this questions is Probably YES
• .But only if you live in a country with strict
  regulatory control of medicines

11
Is doctor wise in switching from branded to a
generic drug?

• The answer to this question is less clear cut
• Some doctors are reluctant to switch from a
  branded drug,
• However, doctors will be under pressure not to
  exceed their budget for prescription drugs and
  pharmacist will be under pressure to substitute a
  generic for a brand

12
Are generics as effective as newer, medically
innovated, 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 arises
• Innovative drugs are not cheap
• They are a result of costly research and
  development with high risks of product failure
  before it can be proven to be safe and effective

13
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.

14
(No Transcript)
15
WHO guidelines

• WHO has initiated programs to prevent the
  distribution of substandard preparation.
• Until such time as means can be provided- first
  to enforce internationally accepted production
  standards, and second to permit uniform testing
  of therapeutic agents - the safest clinical
  choice, must remain the branded product

• Drug safety 1996 15(4) 233-242

16

• Original Parenteral Antibiotics Vs Generics.
  Possible implications in critical care ?

17

• All Paonta Sahib facility including Batamandi
  Deficiencies
• Stability testing program
• Inventory management

• US FDA. Warning Letter. 16 Sept, 2008. Available
  at http//www.fda.gov/foi/warning_letters/s6922c.
  htm

• US. FDA. FDA Issues Warning Letters to Ranbaxy
  Laboratories Ltd., and an Import Alert for Drugs
  from Two Ranbaxy Plants in India. FDA News.
  September 16, 2008 http//www.fda.gov/bbs/topics/N
  EWS/2008/NEW01886.html

18
(No Transcript)
19
Particulate Matter Contamination (PMC)

• Particles, degradation products, residual
  solvent and mineral contamination all pose
  potential threats to patient safety.

20
Where does the Contamination arise from?

• 1.Manufacturing process
• 2.Transport and storage
• 3. Filling process
• 4.Clinical dispensing process
• - microscopic glass particles when glass ampoule
  is broken
• - particulate rubber or plastic from septum or
  syringe

21
Significance of Particulates for Multiple Organ
Dysfunction Syndrome MODS/ Acute Respiratory
Distress Syndrome ARDS

• Evidence from scanning electron microscopy (SEM)
  particulates in lungs from patients dying from
  ARDS.
• Principal pathomechanism in MODS/ARDS is
  microcirculatory dysfunction.
• Particulates can act as condensation centres for
  thrombosis or inflammation.

22
Particulate Matter - Matters !!!

• Particles lt 2µm
• Glass
• Latex
• Polymers

Particulate Contamination
Microcirculation Dysfunction
Microcirculation Disturbances
Kidneys
Liver
Pancreas
ARDS Adult Respiratory Distress Syndrome
Lungs
DEATH
MODS Multiple Organ Dysfunction Syndrome
MOF Multiple Organ Failure
23
(No Transcript)
24
(No Transcript)
25
Hamster skin chamber model
What happens to a compromised microcirculatory
network when a gold standard drug is compared
with its generics (particle contaminated) ?
Method 4 h pressure-induced ischaemia, 2 h
reperfusion. Intravenous injection of Claforan
and two cefotaxime generics (Taxim , Cefantral
, manufactured in India). After 15 min,
microcirculatory parameters, morphology.
26
Studying the microcirculation by intravital
microscopy in rodents

• Direct microscopy of microcirculation in the
  awake animal
• Real time recording of dynamics via video camera
  recorder
• Coupling to image analysis system quantitation

27

Membrane Filter Method
1 g cefotaxime sodium vials
28
Membrane Filter Method
1 g cefotaxime sodium vials
29
Particulate Matter of IV Products

• Severely affect tissue perfusion in patients with
  prior microvascular compromise of vital organs
• After trauma, major surgery, sepsis

• Cefotaxime IV
• Can cause acute respiratory distress syndrome or
  multiple organ failure in patients, but not in
  healthy volunteers

• Lehr et al., Particulate Matter Contamination of
  Intravenous Antibiotics Aggravates Loss of
  Functional Capillary Density in Postischemic
  Striated Muscle. American Journal of Respiratory
  and Critical Care Medicine. 2002, Vol 165(514-520)

30
New Investigations
CARBAPENEMS
31
In-vitro investigations

• Visual Inspection fibres and particles
• Light Obstruction Test subvisible particles gt1.1
  till gt 50.0 µm
• Membrane Filtration Test Particle burden.
• Ultra Structure Study of Filters EDAX/ SEM
• Animal Experiment Study Ischemic / Reperfusion
  Hamster model with PMC on the filter.

32
Study Summary

• Study design Double-blind
• Original Zienam, India compared with 13
  Imipenem/Cilastatin Products from
  China,Indien,Taiwan and Thailand
• 7 Meropenem Products from China,India and Taiwan

33
(No Transcript)
34
Filter 14
Filter 19
Filter 24
Filter 26
35
Filter 37
Filter 40
Filter 41
Filter 43
36
Link Between Number of Generics and antibiotic
Resistance ???
37

• Overuse of 3rd Gen cephalosprorind linked to ESBL
  production ( ESBL rate in India between 50-70)
• Overuse of Flouroquinolones and Carbapenems leads
  to MDR pseudomonas and acinetobacter infections (
  MDR rate in India around 20-30)
• Overuse of Vancomycin leads to VRE and VRSA

38
Recommendations

• More Regulatory Control and Tighten the
  Guidelines
• Choice of brand should be with the prescriber and
  not with administration or pharmacist
• Original Research should be strongly driven.
• In critical care, for IV antibiotics, Original
  drugs should be preferred
• Over the counter sale of IV antibiotics should be
  restricted

39
Thankyou