Assignment for the course "Drug Discovery and Commercialization" by Williams S. Ettouati, Joseph D. Ma, UC SAN DIEGO.

1. SINEMET ®
(Merck & CO., INC.)
Levodopa/Carbidopa for Parkinson’s Disease
Treatment
Alessandra Franchino
Nadezhda Nikolova
Toka Nael Omar
Chrysopigi Vardikou
Life Cycle Strategic
Plan

2. SINEMET ®
(Merck & CO., INC.)
Levodopa/Carbidopa for Parkinson’s Disease Treatment
Alessandra Franchino
LCSP – Part 1
• MARKET ASSESSMENT
• SINEMET®
PRODUCT DESCRIPTION

3. What is Parkinson’s Disease
(PD)?• Chronic progressive neurodegenerative disorder, usually affecting people
over the fifth of sixth decade of life
• Slow loss of dopamin-producing neurons in the Substantia
Nigra and dopamine decline in CNS
CLINICAL FEATURES:
• Tremor, rigidity, bradykinesia, postural instability
• Depression, dementia, psycosis.

4. What is Parkinson’s Disease
(PD)?• Chronic progressive neurodegenerative disorder, usually affecting people
over the fifth of sixth decade of life
• Slow loss of dopamin-producing neurons in the Substantia
Nigra and dopamine decline in CNS
CLINICAL FEATURES:
• Tremor, rigidity, bradykinesia, postural instability
• Depression, dementia, psycosis.
EPIDEMIOLOGY:
PD affects individuals worldwide
• incidence: 4.5-19 / 100’000 persons per year
• prevalence: 100-200 / 100’000 persons (all ages)
1% of the global population is affected by PD

5. Economic Burden of PD
PD is a non-fatal condition which impairs the quality of life of patients.
The direct cost of the PD population is more than double that of a control
population.
Annual spend increase for medical
care per PD patient: $ 10,000
Productivity Loss accounts for
around 50% of the total burden
of disease.
Combining direct and indirect costs, the total burden of annual cost of PD
in US is $23 bn (expected to reach $ 50 bn in 2040).

6. Medications for PD
None of 15 Approved anti-PD drugs is able to arrest or reverse the
disease progression (UNMET MEDICAL NEED)
All the approved medications are intended as symptomatic treatment
aimed to restore/increase dopamine in the brain.
• Levodopa: converted to dopamine in the brain; Gold Standard Therapy, often in
combination with carbidopa (branded as SINEMET®). Generics Available.
• Dopamine Agonists: not as potent as Levodopa; administered in monotherapy
in younger patients or in combination with levodopa in late stage PD patients.
• COMT inhibitors: in combination with levodopa to prolong its half-life.
(Stalevo® is a combination of Carbidopa/Levodopa/Entacapone)
• MAO B Inhibitors: provide mild benefits, prevent dopamine metabolism in the
brain. Generics Available.

7. The Market
• More than 3.2 million patients in the western World, of whom around
90% are believed to receive treatment.
• The number of people in the western World being treated for Parkinson’s
disease is expected to grow by about 3% per annum until 2019.
MARKET SIZE :
2006-2007: $ 3.7 bn
2009-2010: about $ 4 bn
• Dopamine Agonists account for more than
50% of the sales
• Levodopa alone rapresents about 1/3
of the global sales

8. SINEMET®
Product
Description
• Combination of carbidopa and levodopa for the treatment of PD
(approved in 1975; Merck & CO., INC.)
• Levodopa (L-DOPA): aromatic amino acid, precursor of Dopamine
• Carbidopa: inhibitor of aromatic amino acid decarboxylation
CarbidopaL-DOPA
• SINEMET® (sin èmetos, “without vomiting”)
GOLD STANDARD FOR THE TREATMENT OF PD SYMPTOMS

9. SINEMET®
Mechanism of
Action
• L-DOPA is SINEMET® active ingredient
- L-DOPA can cross the Blood Brain Barrier (BBB) while dopamine cannot;
- Prodrug converted to Dopamine by L-aromatic amino acid decarboxylase.
- Dopamine in CNS activates D2 post-synaptic receptors
= promotes voluntary movement

10. SINEMET®
Mechanism of
Action
• L-DOPA is SINEMET® active ingredient
- L-DOPA can cross the Blood Brain Barrier (BBB) while dopamine cannot;
- Prodrug converted to Dopamine by L-aromatic amino acid decarboxylase.
- Dopamine in CNS activates D2 post-synaptic receptors
= promotes voluntary movement
• Carbidopa does not cross the BBB
- NO pharmacological effect;
- inhibits DOPA decarboxylase
in periferal tissues;
- increases L-DOPA bioavailability in CNS
Carbidopa-mediated
inhibition

11. Advantages of combination
therapy• Levodopa given alone:
- Plasma half-life is about 50 min.
- 1% crosses the BBB because of extracerebral metabolism.
- high doses required for proper treatment (4000 mg/day)
- dopamine-mediated side effects (e.g. nausea, anorexia, confusion)
• Levodopa + Carbidopa (SINEMET®):
- Levodopa plasma half-life 1.5 hours.
- 5-10% of levodopa crosses the BBB
- levodopa daily dosage can be reduced up to 70% (700 mg/day)
- reduced peripheral side effects.

12. • Levodopa given alone:
- Plasma half-life is about 50 min.
- 1% crosses the BBB because of extracerebral metabolism.
- high doses required for proper treatment (4000 mg/day)
- dopamine-mediated side effects (e.g. nausea, anorexia, confusion)
• Levodopa + Carbidopa (SINEMET®):
- Levodopa plasma half-life 1.5 hours.
- 5-10% of levodopa crosses the BBB
- levodopa daily dosage can be reduced up to 70% (700 mg/day)
- reduced peripheral side effects.
Advantages of combination
therapy
OPEN CHALLENGES:
• Wearing off – long term resistance to levodopa
• “On-off” effect – motor fluctuation and dyskinesia
• Need for frequent drug administration
(up to 6-7 tablets/day)

13. Product Formulation and
Dosage
- 100 mg / 10 mg
- 100 mg / 25 mg
- 250 mg / 25mg
FORMULATION : tablets for oral administration
• SINEMET® - Immediate release (appr. in 1975)
Available in a 10:1 or 4:1 ratio L-DOPA to Carbidopa
for fine dosage tuning.
• SINEMET® CR - Sustained release tablets (appr. in 1991)
Released over a 4-6 hour period;
Treatment available in 4:1 ratio L-DOPA:Carbidopa
- 100 mg / 25 mg
- 200 mg / 50 mg

14. Thank you for your
Attention

15. LCSP – Part 2
Preclinical, Early & Late Clinical
Studies

16. Preclinical studies
 Levodopa increases motor activity, irritability and
electroencephalographic alerting behavior and antagonizes reserpine-
induced hypothermia, suppressed locomotion and ptosis in mice.
 All these effects are enhanced 2-6 fold by pre-treatment with carbidopa.
 Increased motor activity induced by levodopa in rats also is enhanced by
pre-treatment with carbidopa
 In contrast, levodopa-induced vomiting is decreased significantly in dogs
and pigeons by pre-treatment with carbidopa.
Animal model data : Pharmacology - Efficacy

17. Preclinical studies
Animal model data : Pharmacology - Metabolism
 14
C labelled drug orally administered
Incomplete absorbtion of Carbidopa in the rat, dog and rhesus monkey.
% of radioactive carbon excreted in
urine and feces 
 An intravenous dose of 20 mg/kg of 14
C-carbidopa
 Tissue distribution of radioactivity in rats(after 1 hr) showed the major portion
of radioactivity to be concentrated in the kidneys, lungs, small intestine, and
liver – but none in the brain .

18. Animal model data : Toxicity studies
 Carbidopa showed no evidence of teratogenicity in mice or rabbits at doses of 120
mg/kg/day.
 Levodopa produced visceral and skeletal malformations in rabbits at doses of 125
and 250 mg/kg/day.
 Combinations of carbidopa and levodopa ranging from 25/250 to 100/500
mg/kg/day, there was no evidence of teratogenicity in mice, but in rabbits visceral and
skeletal malformations occurred which were similar to those seen with levodopa
alone.
 Carbidopa had no effect on the mating performance, fertility or survival of the
young when administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The
highest dose caused a moderate decrease in body weight gain in males.
 Carbidopa+levodopa at dose levels of 10/20, 10/50 or 10/100 mg/kg/day did not
adversely affect the fertility of male or female rats, their reproductive performance or
the growth and survival.
Results from dose ranging studies:

19. Animal model data : Toxicity studies

20. Early Clinical
DevelopmentFormulation: SINEMET® and SINEMET® CR were developed in a controlled-
release formulation in the tablet form with non-medicinal ingredient
pregelatinized starch for the oral administration.
Dose ranging studies:
(1)Studies have shown that peripheral dopadecarboxylase is saturated by
carbidopa at doses between 70 to 150 mg per day. Patients receiving less than
70 mg per day of carbidopa are more likely to experience nausea and vomiting.
Experience with total daily dosages of carbidopa greater than 200 mg is limited.
(2)Chronic three month, open-label, twice daily dosing with SINEMET® CR
100/25 (range: 200 mg levodopa, 50 mg carbidopa up to 600 mg levodopa, 150
mg carbidopa per day) did not result in accumulation of plasma levodopa.

21. Early Clinical
Development
The absorption of levodopa following SINEMET® CR 200/50 is gradual and
continuous for 4 to 5 hours although the majority of the dose is absorbed in 2 to
3 hours.
With conventional SINEMET® Tablets, absorption is rapid and is virtually
complete in 2 to 3 hours.
The dose-adjusted bioavailability for one SINEMET® CR 100/25 tablet was
equivalent to that for one SINEMET® CR 200/50 tablet.
The mean peak concentration of levodopa following the administration of
one SINEMET® CR 100/25 tablet was greater than 50% of that following one
SINEMET® CR 200/50 tablet.
Mean time-to-peak plasma levels may be slightly less for SINEMET® CR
100/25 than for SINEMET® CR 200/50.
Results from studies with different dose regimens:

22. Early Clinical
Development
 Carbidopa reduces the amount of levodopa required to produce a given
response by about 75 percent -
 When administered with levodopa, increases both plasma levels and the plasma
half-life of levodopa, and decreases plasma, urinary dopamine and homovanillic
acid.
 The plasma half-life of levodopa is about 50 minutes, without carbidopa.
When carbidopa and levodopa are administered together, the half-life of
levodopa is increased to about I.5 hours.
 At steady state, the bioavailability of carbidopa from SINEMET tablets is
approximately 99% relative to the concomitant administration of carbidopa and
levodopa.
Pharmacokinetics

23. Early Clinical
Development
Mean Pharmacokinetic Parameters of Levodopa Following the Administration
of Two SINEMET® 100/25 Tablets or One SINEMET® CR 200/50 Tablet in Healthy
Elderly Volunteers
Pharmacokinetics

24. Early Clinical
Development
 Large doses of levodopa are required for adequate therapeutic effect and
these may often be accompanied by nausea and other adverse reactions,
some of which are attributable to dopamine formed in extracerebral tissues.
 Since levodopa competes with certain amino acids for transport across the
gut wall, the absorption of levodopa may be impaired in some patients on a
high protein diet.
 Carbidopa inhibits decarboxylation of peripheral levodopa. It does not
cross the blood-brain barrier and does not affect the metabolism of levodopa
within the central nervous system.
 The incidence of levodopa-induced nausea and vomiting is less with
SINEMET than with levodopa. In many patients, this reduction in nausea and
vomiting will permit more rapid dosage titration.
 Since its decarboxylase inhibiting activity is limited to extracerebral tissues,
administration of carbidopa with levodopa makes more levodopa available for
transport to the brain.
Pharmacodynamics

25. Late Clinical
DevelopmentSafety
In controlled clinical trials with 748 patients with moderate to severe motor
fluctuations, SINEMET® and SINEMET® CR produce similar side effects.

26. Late Clinical
DevelopmentPivotal clinical trial
 170 patients with fluctuating Parkinson's disease participated in an international
clinical trial
 to compare the effects of controlled-released Sinemet 200/50 (mg levodopa/mg
carbidopa; Sinemet CR) with standard Sinemet 100/25 (Sinemet STD).
 Study design –
o 8-week open-label titration (dose-finding) phase (STD and CR
preparations given individually during weeks 1-4 and 5-8 respectively)
o 24-week double-blind, double-dummy (placebo) treatment period.
 Drug efficacy was assessed using:
(a) data from patients' diaries (i.e. "on-off" periods)
(b)the functional disability profile (Northwestern University Disability
Scale),
(c) the neurological signs and symptoms (New York University Parkinson's
Disease Scale, NYUPDS),
(d)global evaluations made by the patient and treating physician and
(e)the patient's evaluation of sleep.

27. Late Clinical
DevelopmentPivotal clinical trial
 The results indicate that the number of "off" periods and the total NYUPDS
score decreased significantly in the patients treated with Sinemet CR
compared with those treated with Sinemet STD.
 The patient's global evaluation was significantly better in the Sinemet CR
group.
 The number of drug-related adverse experiences was similar in the two
groups and only one serious event of this nature was reported.

28. Late Clinical
Development
RESULTS:
 Total daily medication costs increased by
21%, with a comparable or an improved degree
of disease control with Sinemet CR.
The costs of other adjunctive medications did
not differ significantly after conversion.
 The cost-effectiveness analysis increased on
time by 2.2 hours (p = 0.0001) and a $2.85
decrease in total cost per hour on without
chorea (p = 0.11).
Pharmacoeconomic trial : Costs of pharmacotherapy
DESIGN:
Records reviewed for efficacy and
total drug costs
 Cost-effectiveness was evaluated
PATIENTS:
100 patients @Parkinson's disease clinic at a
tertiary care university teaching hospital
6 months each - SINEMET® SINEMET® CR
CONCLUSIONS:
Sinemet® CR more costly, but cost-
effective in patients with motor
fluctuations.
Reduced adjunctive medications for
some patients

29. SINEMET ®
(Merck & CO., INC.)
Levodopa/Carbidopa for Parkinson’s Disease Treatment
Nadezhda Nikolova
LCSP – Part 3
• REGULATORY STRATEGY
• INTELLECTUAL PROPERTY STRATEGY

30. Regulatory Background
• 1938 – the Federal Food, Drug, and Cosmetic Act requires all new drugs to
show safety before being sold;
•1966 – Fair Packaging and Labeling Act – all products to be honestly and
informatively labeled;
• 1968 – FDA requires for first time package insert – medicines must come with
information for the patient about risks and benefits;
•1984 – “Approved Drug Products with Therapeutic Equivalence Evaluations”
-the List, known as the Orange Book - the products listes are subjects of an
applications with an effective approvals that have not been withdrawn for
safety or efficacy reasons;
• mid-90s first good practices established on clinical research – GCP and its
adoption;

31. On the way to the market
After the findings of Arvid Carlsson that dopamine is a neurotransmitter in the
brain and not just a precursor for norepinephrine, and the dopamine’s influence
on the movement control, other doctors tried L-Dopa with human Parkinson's
patients and found it to alleviate some of the symptoms in the early stages of
Parkinson's. Unlike dopamine, its precursor L-Dopa could pass the blood
brain barrier. The validity of the approach was shown by the transient benefit
seen after injection of L-dopa. However, it was not of practical value as a
treatment because of the severe toxicity associated with the injection. At this
point George C. Cotzias made a critical observation that converted the transient
response into a successful, large-scale treatment. By starting with very small
doses of DOPA, given orally every two hours under continued observation, and
gradually increasing the dose (up to 16 grams per day) he was able to stabilize
patients on large enough doses to cause a dramatic remission of their
symptoms. The first study reporting improvements in patients with Parkinson's
disease resulting from treatment with L-dopa was published in 1968.
This result was soon confirmed by other investigators.

32. New Drug Application
• “Sinemet” approved on 02 May 1975 with NDA 017555;
• Manufacturer - Merck Sharp Dohme;
• Dosage - oral tablet of 10 mg and 100 mg;
• Indication - for treatment of Parkinson’s disease;
• Chemical type – New molecular entity and new combination;
• 38 years since its first approval – about 70 FDA regulatory revisions including:
manufacturing changes - 9; package changes – 7; formulation revisions – 6;
labeling revisions – 23;

33. Post-approval development
• L-dopa combined with the decarboxylase inhibitor carbidopa was
commercially launched in 1972 as Sinemet. Carbidopa made the product
more effective by delaying the conversion of L-dopa into dopamine until the
drug passed into the brain.
• Sinemet is included in the “Orange book”;
• The product was improved in 1991 when approval was given for Sinemet CR
• Sinemet CR is a controlled release version of Sinemet, which could be taken
less frequently.
• late 2009 – 2011: Merck stopped manufacturing the drug while awaiting
regulatory approvals due to a change in the supplier of the active ingredient.
This resulted in shortages of the brand name products Sinemet and Sinemet
CR.

34. Patent
• patent of the drug is filed end 80s with application number EP19880202760
(also published as CA1318602C, DE3875705D1, DE3875705T2, EP0320051A1
and US4832957) by Merck & Co., Inc.
• The listed inventors are Robert E. Dempski, Donald W. Nibbelink, Scott A.
Reines, Edward C. Scholtz
• The patent was designated to all US states, Austria, Belgium, Switzerland,
Germany, Spain, France, United Kingdom, Greece, Italy, Liechtenstein,
Luxembourg, the Netherlands and Sweden.

35. SINEMET ®
(Merck & CO., INC.)
Levodopa/Carbidopa for Parkinson’s Disease Treatment
Toka Nael Omar
LCSP – Part 4
•TIMELINE
• SINEMET®
MANUFACTURING

36. I. Sinemet Timeline

37. • Levodopa and the carbidopa/levodopa formulation in
which it is widely distributed has been the gold standard
for the care of Parkinson’s disease patient since the late
1960’s.
• In 1959 Arvid Carlsson speculated that Parkinson’s
disease (PD) was related to dopamine.
• In 1960 Oleh Hornykiewicz confirmed Carlsson’s work,
and began to test levodopa as a potential therapy for PD.
• Later in 1967 George Cotzias demonstrated the
benefit of dopamine replacement therapy in PD.

38. • By 1971, Victor Lotti of Merck, based at that
time in West Point, Pennsylvania, added the
important observation that levodopa in
combination with carbidopa provided a safe and
tolerable formulation for PD patients.
• 1975-05-02 FDA Approval
• 1991, The manufacture and sale of Sinemet
was taken over by a new joint venture, Dupont
Merck Pharmaceutical Company. That same year
approvals for a sustained release formulation
(Sinemet CR) which could be taken less
frequently were also obtained.

39. The 2010-2011 Worldwide
Sinemet Shortage
• Merck had applied to the FDA to change manufacturers of
Sinemet from Merck to Mylan, and Merck took over the
distribution of Sinemet from Bristol Myers Squibb. Merck
reported that a temporary shortage might occur “across some
of the dosages.”
• But there was a severe shortage worldwide in many dosages
mainly CR.

40. Figure 1: Volume of calls regarding the Sinemet shortage. Note that the first
call came in before NPF began marketing the helpline in October 2010.

41. Mylan Sinemet
• The new Mylan Sinemet, once available, has been reported to
be different from the prior formulation. These differences
have been reported not only clinically but also in the pills
physical characteristics.
• Old Sinemet was scored for easy splitting, and many
patients commonly split their pills to manage their dosing.
The new pills were not scored and patients reported the pills
crumbling unless split with a razor blade—a clear safety
issue for a person with Parkinson’s.
• Beyond this, the new pills seemed to dissolve easily.

42. • Patient-reported perception of the efficacy of the Mylan
Sinemet has been uniformly negative. Reports of the
medication wearing off an hour sooner than previously were
common and independently reported. Other reports were
that the medication effects took longer to be felt than
previously. Multiple patients reported that Mylan Sinemet at
its maximum effect was less than Merck Sinemet despite
attempts to optimally titrate it. The NPF Helpline received no
positive reports.

43. II. Dosage forms, composition
and packaging
• SINEMET® is formulated as oral dosage form, TABLETS.
• SINEMET® tablets contain levodopa and carbidopa in ratios of
4:1 and 10:1.
• There are 5 forms, 3 of them are conventional tablets and the
other 2 are sustained release.

44. I. SINEMET® , 100/25, contains 100 mg of levodopa and 25 mg
anhydrous equivalent of carbidopa. They are yellow, round,
uncoated tablets, plain on one side and “650” on the other.
They are supplied in bottles of 100 tablets.

45. II. SINEMET®, 100/10, contains 100 mg of
levodopa and 10 mg anhydrous
equivalent of carbidopa. They are light
dapple-blue, round, uncoated tablets,
plain on one side and “647” on the other.
They are supplied in bottles of 100
tablets.

46. iii. SINEMET®, 250/25, contains 250 mg of
levodopa and 25 mg anhydrous equivalent of
carbidopa. They are light dapple-blue, round,
uncoated tablets, plain on one side and “654”
on the other. They are supplied in bottles of
100 tablets.

47. Sinemet CR Dosage
• SINEMET CR contains carbidopa and levodopa in a 1:4 ratio as
either the 50-200 tablet or the 25-100 tablet.

48. Non-medicinal ingredients
• Crospovidone, hydroxypropylcellulose, magnesium
stearate, microcrystalline cellulose, pregelatinized starch
Storage and stability
• Store your tablets at room temperature (15°C–30°C).
Store in tightly closed container, protected from light and
moisture.

49. • According to National Parkinson Foundation
2011:
• New formulations need to take into
account real-world patient needs.
The ability to score medications for
Parkinson’s patients is a critical
patient-care requirement that was
not met in the Mylan formulation.
The formal clinical instructions for
the administration of levodopa
include the use of half tablets. In
addition, the “crumbling” and
“melting” aspect of the new
formulation is highly important to
people who must carry around
multiple pills during the day. Any
patient-centric effort must take
such matters into account.

50. • The discovery of levodopa yielded a Nobel prize and
the launch of Sinemet revolutionized Parkinson’s
care, to the point that carbidopa/levodopa is so
much a staple of PD care that we can’t imagine a
world without it. In the first half of 2011, because
of uncertainty and confusion some people were
faced with a loss of this drug. It didn’t have to be
and, with all the stakeholders working more
closely together with good information, we
sincerely hope this way we could avoid this in the
future.
Thank you

51. SINEMET ®
(Merck & CO. INC.)
Levodopa/Carbidopa for Parkinson’s Disease Treatment
Chrysopigi Vardikou
LCSP – Part 5
• MARKETING STRATEGY
• SALES STRATEGY AND MANAGED
MARKETS

52. Overview of Marketing & Sales
Strategy
Marketing Sales
Merck’s core marketing principle:
“Customer is at the center of all
activities”
Strategy: “More information, less
advertising”
Regulation: Adhere to or exceed the
guidelines
Online Marketing: Technology at the
center of the strategy
Strategy: Allianced
•External Alliance with
Dupont
Sales Volume (decline)
Forecasting

53. About the brand
Sinemet and Sinemet CR from Bristol-Myers Squibb
(previously Merck and Dupont) is the only brand for
levodopa/carbidopa.
Thus one company defines the second-largest, but oldest
class of the Parkinson's disease therapeutics markets.

54. Total Market Size
•Market Size of Parkinson’s Disease
• 2006-2007: $ 3.7 bn
• 2009-2010: about $ 4 bn
• 1 million patients in the US
• $150 million in the US
(around 35% of the market)
• 1.5 million patients in Europe
(more than 40% of the market)
• 5 million patients worldwide

55. Pharmaceutical Marketing
The centre of pharmaceutical marketing is the brand.
•Long marketing-planning horizon
•Highly regulated industry
•Highly regulated marketing communications
•Targeting Healthcare Professionals and Consumers
•Evolving selling environment
•Use of e-channel still in infancy, e-commerce opportunities mostly
with wholesalers
• Change of e-health landscape

56. Merck’s Marketing
Principles
•Understand the customer’s perspective
•Carry out programs to educate physicians on products and on its DTC
advertising
•Have a new product approved before launching DTC broadcast advertising
•Anticipate and outmaneuver the competition
The center of Merck’s marketing strategy is the consumer, whether
patient or doctor.

57. SWOT Analysis
Strengths
•Cornerstone innovation
•Price
•Higher efficacy than 78% of Parkinson drugs.
•Advanced formulation in comparison with
“Madopar”
Weaknesses
•Side effects
•Only pill form-not capsule
•Non dispersible
•inconsistent efficacy
Opportunities
Merck can introduce innovations because of its
edge in R&D
Expanded patient population
Highly fragmented market
Long term potential due to demographic trends
Research on the positive effects of carbidopa
Threats
Threat of new entrants (moderate)
Medium threat of substitutes
Generic Competition
More Competitive drugs Madopar & Requip
Political risk – Increased Regulation
Patent expiry

58. Merck’s Marketing Strategy
•Focus on selected audiences
•Define the product’s distinctive value to the public/
customers
•Plan for sequenced growth through the LCSP
•Shape perceptions
•Ensure that execution is consistent and well integrated
•Track results and re-evaluate

59. Merck and Advertising
RegulationsMerck claims to adhere to the FDA regulations
and that all PhRMA guidelines are met or exceeded
It voluntarily submits advertising campaigns to FDA
for pre-review.
On the other hand,
there were claims that Merck
has used the following inappropriate tactics for other
products:
“marketing framed as science” for Vioxx, 1999
Judge imposed $321.6 million in criminal fines and $628.4
million as a civil settlement For Illegal Marketing.
“overly aggressive marketing strategy” for Gardasil, 2006
Advertisements promoted fear, e.g. “your daughter
could become one less life affected by cervical cancer”

60. SINEMET®
Ad
2002 - 2003
Printed Advertisement of SINEMET ® CR
“Parkinson Post”
Type: Informational

61. Education: a core marketing
principleMerck created a more informative/educational and less advertising oriented
approach to healthcare professionals
Created online medical education resources for physicians and
patients
MerckMedicus, MerckSource (later:MerckEngage)
to offer evidence-based resources and to support dialogue
Delivered “Merck’s manuals”

62. Online marketing
Merck created websites with product information
• These sites can be accessed directly through a www.product.com or a
www.product.org form
• They can also be accessed through third party sites or web banners

63. • Merck
• Dupont (for US and Canada)
• Bristol Myers Squibb (recent past)
SOCIAL MEDIA- Analysis on the three
main suppliers of SINEMET

64. Merck
• Facebook,Twitter and Youtube
• uses social media but not extensively.
• A couple of facebook applications e.g.”Merck manual quiz”
• There was no specific mention about SINEMET in Merck’s
social media platforms.

Use of Social Media

65. Dupont
• Facebook,Twitter, Linkedin,Youtube and RSS Feed plus Slideshare (via
their advertising agency)
• uses social media extensively
• There was no specific mention about SINEMET in Dupont’s social media
platforms.
Use of Social Media

66. Bristol Myers Squibb
Twitter and RSS Feed
Doesn’t use social media extensively.
There was no specific mention about SINEMET in BMS’s social media
platforms.
Use of Social Media

67. Merck uses technology extensively
•through its “Merck Medicus” platform  mobile and tablet applications
•published its “Merck’s Manuals” also as an app (online version)
•many apps are created for healthcare professionals and patients, e.g.
“Cardiolinks” Mobile App, Adherence Estimator Widget
Use of Technology

68. MerckMedicus Apps

69. MerckEngage: A unique platform
for the patient and the healthcare
professional

70. a patient-centered resource,
helps the physician identify his patients who may be at risk of medication non
adherence.
The Adherence Estimator asks questions about key areas known to impact
medication adherence. After the patient responds to 3 quick statements, the
resource gauges the patient's likelihood of adhering to a newly prescribed oral
medication for certain chronic, asymptomatic conditions.
In addition, the resource provides personalized feedback that helps support
conversations with the patients about adherence.
The Adherence Estimator Widget
a tool designed for physicians to monitor patient’s reactions to
medication

71. A set of leaflets, letters and ads in a printable pdf format, available at
http://merckengage.qualitysolutionnavigator.com
Range of information for the patient
e.g. “Keep track of your vaccinations”
e.g. “Effect of age and your fertility”
The common characteristic among all files is their educational character
Quality Solution Navigator
(QSN)

72. Pricing
Year Type Quantity Price Price per pill
2013
USA
25 -100 mg 90 36.9 0.41$
2013
Europe
25-100mg 90 81.12 0.9€
2013 USA
generic
25-100mg 90 32.1 0.35$
There’s a long debate about Sinemet price differences.
This year (2013) European price is 3 times higher than US price.
In 1996 Sinemet was sold in Australia at 61% of the european price.
DIFFERENCES IN PRICE
BUT: 45% of the world Parkinson’s patients are located in Europe.

73. Pricing-Some Facts
Excessive Price Guidelines
VOLUNTARY COMPLIANCE UNDERTAKING
OF BRISTOL-MYERS SQUIBB CANADA CO.
In 2009, the average transaction price (ATP) of Sinemet CR 200/50 began to exceed the
Guidelines by an amount which did not trigger the investigation criteria. The ATP of
Sinemet CR 200/50 exceeded the Guidelines in 2010 by an amount that resulted in
excess revenue triggering the investigation criteria.
•Cumulative excess revenues were $64,442.01 as of June 1, 2010.
•no admission by Bristol-Myers Squibb Canada Co. that the prices of Sinemet CR
200/50 were excessive for purposes of the Patent Act.
•Bristol-Myers Squibb Canada Co. Undertakes to offset the cumulative excess revenues
received from 2009 to June 1, 2010 in the amount of $64,442.01 by making a payment
to Her Majesty in right of Canada within 30 days of the acceptance of this VCU.

74. Sinemet was cheaper than most parkinson drugs since its launch
After the entrance of generics, Merck introduced SINEMET® Patient Assistance
Program
It allows patients with a valid PrSINEMET® (levodopa and carbidopa tablets,
USP) or PrSINEMET®CR (controlled release levodopa and carbidopa
tablets) prescription (new or refill) to obtain brand name SINEMET® or
SINEMET®CR at NO ADDITIONAL COST versus obtaining an available
generic version.
Value Proposition
Sinemet is the original brand for
carbidopa/levodopa, and in his Parkinson’s Disease
Treatment Guide, Eric Ahlskog wrote that
Sinemet, “generic formulations... are substantially less
expensive,” but that the physician
may “stipulate brand-name if the patient reports better
results with that formulation.”

75. SINEMET® is an innovative yet affordable drug seeking to relieve the symptoms
of the Parkinson’s Disease and to improve the patients’ quality of life by
reducing the side effect of nausea, common among other antiparkinson drugs.
With the combination of levodoba/carbidopa being used for the first time,
SINEMET ® blocks the enzyme DDC which causes nausea and vomiting and can
even raise blood pressure.
Positioning statement (at the time
of launch)
A positioning statement addressing to patients and
healthcare professionals at the same time.
A positioning statement addressing to patients and
healthcare professionals at the same time.

76. The product’s reimbursement strategy is included in the corporate
reimbursement strategy
Reimbursement strategy of
SINEMET®
https://mvrscportal.com/
A portal intented for use by
physicians, to provide them with
insurance coverage information
about their patients.

77. SINEMET® CR
• Sustained-Release
• available to control fluctuations for some people
•patients on Sinemet CR tend to experience a better quality of life
Line extension: SINEMET® CR

78. Markets:
Merck’s Human Health Divisions
• Asia and Pacific
• Europe, Middle East and Africa
• The Americas
• US & CANADA
Sales Strategy
Merck provides its products through wholesale,
retail drug and food chain and mass merchandiser
outlets worldwide
US & CANADA: product launched by DuPont

79. Establishing external alliances
• approximately 60 percent of the company's revenue comes from
alliance-related products and enabling patents
• more than 50 actively managed alliances
• Dupont
• Bristol Myers Squibb
Aggressive licensing and external alliance strategy includes:
• upfront payments
• royalty or profit share payments
• expense reimbursements or payments to the third party.
Sales strategy- External Alliances

80. 1989: Agreement of old Merck and E.I. duPont de Nemours for a long-term
research and marketing collaboration
DuPont would have exclusive rights of Sinemet in North America
DuPont and Merck would continue to share marketing rights to "Sustiva“
DuPont Merck had $1.3 billion in sales in 1997
External Alliance with DuPont for
SINEMET®

81. DUPONT SALES OF SINEMET 1999-2nd Q: $ 85 millions
DUPONT ANNUAL SALES OF SINEMET 1999: $ 331 millions
DUPONT SALES OF SINEMET 2000-2nd
Q : $ 37 millions -56,4%
US Annual Sales Volume 2nd
quarter 2000-2002

82. BRISTOL-MYERS SQUIBB SALES OF SINEMET 2003
WORLDWIDE SALES BY PRODUCT $108 millions
INTERNATIONAL SALES BY PRODUCT $85 millions
US SALES BY PRODUCT $23 millions
BRISTOL-MYERS SQUIBB SALES OF SINEMET 2004
WORLDWIDE SALES BY PRODUCT $106 millions -2%
INTERNATIONAL SALES BY PRODUCT $85 millions -
US SALES BY PRODUCT $21 millions -9%
Annual Sales Volume 2003 &2004

83. BRISTOL-MYERS SQUIBB SALES OF SINEMET 2004, 1st semester
WORLDWIDE SALES BY PRODUCT $50 millions
INTERNATIONAL SALES BY PRODUCT $43 millions
US SALES BY PRODUCT $7 millions
BRISTOL-MYERS SQUIBB SALES OF SINEMET 2005, 1st
semester
WORLDWIDE SALES BY PRODUCT $49 millions -2%
INTERNATIONAL SALES BY PRODUCT $40 millions -7%
US SALES BY PRODUCT $9 millions +29%
Sales Volume 1st
semester 2004
&2005

84. BUT:
generic (brand name Sinemet) had approximately 2.7 million prescriptions in the United
States in 2010 according to IMS Health, Inc.
SINEMET’s & its GENERIC’s US prescription annual sales
2002: $154 million year ended- the company’s annual sales (all products) were $3,4
billion
2003: $126 million (year ended February 29,2004)
•Its sales volume continues to decline
and so does the generic’s sales volume.
Sales Volume
Current Stage of the life of the product
Phase 3 to 4-Maturity to Decline stage

85. The number of individuals with PD over age 50 in these countries was between
4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by
2030.
Forecasting

86. “By 2021, the several key Parkinson’s disease therapies will have created a
fragmented market with no clear leader, as a large number of similarly priced
drugs compete for the same patient share”
Decision Resources Analyst Nadja Rozovsky, Ph.D.
“Future therapies will need to clearly differentiate themselves from other
therapies to gain a competitive edge in this mature market.”
Forecasting

87. Thank you !
Chrysopigi Vardikou

88.  Sinemet was able to partially meet an unmet medical need.
 The launch of Sinemet CR (1991) represented for Merck & Co. a strategic
choice to prolong its revenues.
The safety and tolerability of Sinemet STD Vs. Sinemet CR were similar - so,
the improved clinical efficacy in the latter was not at the cost of drug-related
adverse effects.
Concluding Remarks (1)

89. Although the causes of the motor fluctuations are not completely
understood, it has been found that they can be treated with proper dose
regimen of Sinemet.
 A problem in manufacturing change from Merck to Mylan in 2010 lead
to worldwide shortage.
 Despite the differences of Mylan Sinemet from Merck Sinemet, it is still
more
effective than generic formulations.
Concluding Remarks (2)

90.  Merck chose some external alliances to build its sales strategy. Sinemet was
(and still is) one of the leading products in its category.
However, we cannot say for sure if this strategy could have proven more
successful, given the global shortage in late 00’s and the recent steady drop in
sales volume.
 Since the launch of Sinemet’s generics, its pricing strategy changed in order
to be more competitive.
Concluding Remarks (3)

91. Thank you for your
Attention