Parkinson drug sinemet-LIFE CYCLE STRATEGIC PLAN

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

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  • Neuromuscolar symptoms Neurologic symptoms
  • Neuromuscolar symptoms Neurologic symptoms
  • Inpatient care costs, largely attributed to nursing home care, Given the prolonged disability, about 50% of the total cost is given by productivity loss.
  • GOAL: keep the patient functioning independently as long as possible
  • Among the neurodegenerative disorders, the treatment of PD appears to have the highest probability of technical success. This makes the market for anti-parkinson drugs quite appetibile February 6, 2013 Annual Report 2012 for H. Lundbeck A/S Annual report 2012 http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=738265
  • motor fluctuation and dyskinesia (develop in 50% patients ofter 5 year levodopa treatment)
  • Close to steady plasma levels of levodopa.
  • Parkinson drug sinemet-LIFE CYCLE STRATEGIC PLAN

    1. 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. 2. SINEMET ® (Merck & CO., INC.) Levodopa/Carbidopa for Parkinson’s Disease Treatment Alessandra Franchino LCSP – Part 1 • MARKET ASSESSMENT • SINEMET® PRODUCT DESCRIPTION
    3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14. Thank you for your Attention
    15. 15. LCSP – Part 2 Preclinical, Early & Late Clinical Studies
    16. 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. 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. 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. 19. Animal model data : Toxicity studies
    20. 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. 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. 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. 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. 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. 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. 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. 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. 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. 29. SINEMET ® (Merck & CO., INC.) Levodopa/Carbidopa for Parkinson’s Disease Treatment Nadezhda Nikolova LCSP – Part 3 • REGULATORY STRATEGY • INTELLECTUAL PROPERTY STRATEGY
    30. 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. 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. 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. 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. 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. 35. SINEMET ® (Merck & CO., INC.) Levodopa/Carbidopa for Parkinson’s Disease Treatment Toka Nael Omar LCSP – Part 4 •TIMELINE • SINEMET® MANUFACTURING
    36. 36. I. Sinemet Timeline
    37. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 60. SINEMET® Ad 2002 - 2003 Printed Advertisement of SINEMET ® CR “Parkinson Post” Type: Informational
    61. 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. 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. 63. • Merck • Dupont (for US and Canada) • Bristol Myers Squibb (recent past) SOCIAL MEDIA- Analysis on the three main suppliers of SINEMET
    64. 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. 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. 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. 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. 68. MerckMedicus Apps
    69. 69. MerckEngage: A unique platform for the patient and the healthcare professional
    70. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 87. Thank you ! Chrysopigi Vardikou
    88. 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. 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. 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. 91. Thank you for your Attention

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