Importance of Drug Quality: Impact on Clinical Outcomes Around the World by Carlo Nalin, Ph.D., Global Head of Brand Integrity, Novartis Oncology

1. Importance of Drug Quality: Impact on
Clinical O
C Outcomes Around the World
Carlo Nalin, Ph D
Nalin Ph.D.
Global Head of Brand Integrity
Novartis Oncology

2. Overview of Presentation Today
Drug Approval Requirements and Substandard copies
● How drugs are approved around the world
● What we know about substandard copies
● Clinical implications for patients from substandard drugs
Quality issues are a global concern
This presentation concerns substandard copy products not
legitimate generic pharmaceuticals.
Novartis supports legitimate, high-quality g
pp g , g q y generics and has a
major generic business in its portfolio: Sandoz

3. Globalization of Pharmaceutical
Markets & Drug Production
● M di i
Medicines and pharmaceutical t t
d h ti l treatments are
t
manufactured, sold, distributed, and dispensed
across th globe t d
the l b today
– This has had enormous benefits for patients who can
now access medicines that were in the past either not
produced locally or were far too expensive to import and
access1
● World Health Organization (
g (WHO) has said that
)
globalization has also increased the spread and
p
prevalence of medicines that are unsafe or may be
y
ineffective2 1 Torstensson, D. and M. Pugatch, “Keeping Medicine Safe” Stockholm Network 2010
2 WHO, “The World Medicines Situation” 2004

4. Substandard Copies:
A Global Concern
The
Th quality of medicines varies greatly, and not just in low- and middle-income countries
lit f di i i tl d tj ti l d iddl i ti
China (2007)
200 patient with serious side
effects taking contaminated
methotrexate (nonGMP)
Sources: Various Media

5. How Should We Define a
Substandard Therapy?
A Regulatory View
Originator Drug Generic Substandard Counterfeit
Therapy
Evidence based Bioequivalence and Relies on originator No data. Unknown
clinical efficacy, quality testing documentation and origin and composition
quality and safety label.
label Has no
bioequivalence and/or
quality demonstrated
Legally Approved Illegal Drug
Substandard Therapy 1: a Substandard Therapy 1: a drug that
py drug that
g py g
1) Does not not meet specifications necessaryensure quality, efficacy andand safety
1) Does meet specifications necessary to to ensure quality, efficacy safety
2) Has not demonstrated bioequivalence or similarity* to the originator; or may not meet
2) Has not demonstrated bioequivalence or similarity* to the originator; or may not meet
EU or US quality standards EU or US quality standards
3) Does not have sufficient evidence to demonstrate originator data can be referenced
3) Does not have sufficient evidence to demonstrate originator data can be referenced
* as required for biosimilar approved pathways

6. How Quality is Determined in
Pharmaceuticals
● International standards & ● Internal Standards
guidelines – Good Manufacturing Practice
– International Conference on (GMP)
Harmonization (ICH)1 – Standard operating procedures
– Pharmacopeias like EU, US, – Supplier vetting and inspection
Japan etc. – Specifications
● International and stringent • Raw materials
standards • Finished product
– EMEA2 or FDA3 requirements – Process control
for drug approval, incl. • Quality control
Bioequivalence where
Bi i l h • Q lit assurance
Quality
necessary (e.g. new drug
forms)
1 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
2EMA = European Medicines Agency, Committee for Medicinal Products for Human Use
3 FDA = US Food and Drug Administration, Code of Federal Regulations

7. Substandard Copies May Gain
Registration Without Evidence
Countries differ on legal approval of medicines
Registration requirements for Generics by authorities EMA1 FDA2
that are usually used as a reference (examples) Other countries
Bioavailability and bioequivalence testing with sound
Bi il bili d bi i l i ih d
scientific methodology and ethical committee
surveillance
  Not a common
Evaluation of active ingredient quality including requirement,
identification and quantification of impurities (e.g.
genotoxic impurities)
  in some not
required at all
Pre and post approval when source of active
ingredient changes  
Identification and qualification of degradation
production in medicines, not just stability testing   Not a
requirement
Strict cGMP and field inspections of plants   Just a few
countries require
Not a
Actual laboratory testing of finished product, not
“stamping and paper work”   requirement in
most
1 EMA = European Medicines Agency, Committee for Medicinal Products for Human Use
2 FDA = US Food and Drug Administration, Code of Federal Regulations

8. Bioequivalence for Generic Drugs
● Two drugs are bioequivalent if they are
pharmaceutically equivalent, and if their
bioavailability is similar so that the effects
on efficacy and safety are essentially the
same
● H
How d you prove bi
do bioequivalence?
i l ?
– Two period, two crossover design, single
dose study is usually needed (minimum of
12 h lth volunteers)
healthy l t )
– Most important parameters: AUC, Cmax
ratios
– Limits: AUC 90% confidence interval
between 0.8 – 1.25
● Comparative in vitro dissolution data have
to be provided to complement
bioequivalence study US Food and Drug Administration,
Center for Drug Evaluation and Research (CDER) 2003

9. Impurities in the Drug Substance
may be pharmacologically active
● Quality of drug substance is key for clinical outcome and safety
● Action of a pharmaceutical formulation may be severely impaired by
p y y p y
– Impurities:
• Resulting from the manufacturing process
• Intentionally or unintentionally added
– Different polymorph (= a different drug substance)
• e.g. different bioequivalence
• e.g. diff
different dissolution rate
t di l ti t
● Science and Technology advances must not be ignored
– State of the art methods and technologies should be used
– Continuous improvement of GMP1 processes (cGMP)
GMP = Good Manufacturing Practice

10. Detect Quality Issues Before Patients
Are Exposed to Potential Risks
Level 3 –Clinical Use
Evidence about
● Clinical outcome not comparable
● Patients lose disease control
Clinical Outcomes
Patient
Exposure
Level 2 – Laboratory Testing
Post-Registration Process Evidence about
● Identifying toxic impurities Drug Quality
● Quality inconsistencies
Level 1- Hypothesis / Concerns
Registration process:
Evidence about
● Data reliance not appropriate
● Registration data incomplete
Regulatory Surveillance
● N t perfectly interchangeable
Not f tl i t h bl

11. Genotoxic Impurities
Potentially carcinogenic – dose and exposure important
● EMA Specifications1: Limit for sum of all genotoxic impurities
combined ≤ 1 5 micrograms per d f chronic d
bi d 1.5 i day for h i drug
• Chemicals used for synthesis:
Esters of methanesulfonic acid from reaction of mesylate ion and alcohol
y
• Potential degradation product
4-Hydroxybenzoic Acid is a by-product from synthesis and degradation
• May form during shelf life under adverse storage conditions
● Rationale: ICH guidelines say reduce genotoxic impurities to
levels ‘as low as reasonably possible’
1 EMA/CHMP/QWP/251344/2006 - GUIDELINES ON THE LIMITS OF GENOTOXIC IMPURITIES

12. Daily Patients Exposure to
Genotoxic Impurities1
Amount
Amo nt patient would recei e each da of treatment with cop dr g
o ld receive day ith copy drug
10003
High: 535 ug daily
erial Ingested
per high dose
2.5
25
Median: 27.8 ug
1002 per high dose
ose
otoxic Mate
scribed Do
1.5
(Lo Scale)
EMA
10 Daily Limit
1 < 1.5 ug
og
at Pres
Micrograms Geno
0.5
1
0
Low: 0.4 ug
per low dose n=41
-0.5
0.1
-1
Copy Products Tested1
in 2010
1 Quantitative analysis of qualified impurities with genotoxic potential
Source: Novartis Quality Systems (data on file)

13. Detect Quality Issues Before Patients
Are Exposed to Potential Risks
Patient
Exposure Level 3 –Clinical Use
● Clinical outcome not comparable
● Patients lose disease control
Clinical evidence
C
Level 2 – Laboratory Testing
Post-Registration Process
● Identifying toxic impurities
Drug Quality evidence
● Quality inconsistencies
Level 1- Hypothesis / Concerns
Registration process:
● Data reliance not appropriate Document only evidence
● Registration data incomplete
● Not perfectly interchangeable

14. Common Issues with Substandard Therapiesp
and Potential Implications for Patients
Common Issues of Copies Potential consequences for patients
● Potentially increased risk of developing cancer
High level of known genotoxic
edient
erties
● Potential risk is particularly important in chronic, long-term
impurities
treatments
(API) Prope
Active Ingre
● Interruption of treatment due to potentially serious side effects
High level of unknown ● Impurities may be carcinogenic
impurities ● Increased resistance to treatment
A
(
● Turn a potentially beneficial treatment into failure
● Ineffective treatment
Poor in vitro dissolution rate ● Increased resistance to treatment leaving the patient without
treatment option or in need for a more expensive alternative
Drug Product
roperties
● Higher content may lead to increased toxicity
High or low content of active
● Lower content may lead to sub-therapeutic doses
ingredient
● Treatments may be either toxic or ineffective
Pr
● Every time a patient take a pill a different dose may be applied
● Treatments may become less effective
Poor content uniformity
● Higher doses may increase the risk of toxicity
● Lower doses may increase the risk of treatment resistance
Lack of quality consistency ● All mentioned above

15. Treatment Expectations vs
Individual Response
How to assess individual patient outcomes?
Standard of Care or Treatment Guidelines1,2 based on long
term patient follow-up from controlled clinical trials
follow up
If treatment expectations are not met, what are the
possible reasons?
● Disease features?
● Therapy selection?
py
● Bad luck?
● Small sample size?
p
● Original drug or substandard copy product?
1Baccarani M, Cortes J, Pane F, et al: Chronic myeloid leukemia: an update of concepts and management recommendations of
European LeukemiaNet. J Clin Oncol 2009 27:6041-51 2 National Comprehensive Cancer Network: NCCN: Clinical practice
guidelines in oncology. Chronic Myelogenous Leukemia. Version 2. 2010. 1. OBrien, et al. Imatinib compared with interferon and
low-dose cytarabine for newly diagnosed CP-CML. NEJM 2003; 348: 994-1004.

16. A call for action for High Regulatory
Standards and Pharmacovigilance
General recommendations:
G l d ti
1. Create better understanding at the regulatory, policy
and public level of the differences between drugs
● Originator vs substandard vs generics vs counterfeit
2. Recognize that substandard drugs puts patients at risk
3. Acknowledge the extent to which governments can
control access to drugs that may be substandard
Some problems can be addressed relatively easily, while
others require hard thinking, large resources, and national
– or even international – coordination.
Source: “Keeping Medicine Safe” Stockholm Network 2010

17. Drug Quality: a Commitment to
Patients and Healthcare Professionals
● Hi h manufacturing standards are needed for quality drugs
High f t i t d d d df lit d
– Commitment to international guidelines and regulations
– Continuously improved manufacturing processes
– Reducing exposure to potential impurities for patient safety
● Bioequivalence to the originator needs to be demonstrated
● Sufficient evidence should be provided to show that the
originator data can be referenced
Assure patients of access to high quality
drugs for life-changing therapies