generic entries of new chemical for controlling promotion ... · generic entries of new chemical...
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Generic entries of new chemical entities: challenges for controlling promotion and ensuring safety.
Prof Rohini Fernandopulle MBBS,PhDProfessor in clinical pharmacology,
Faculty of MedicineUnivesity of Colombo
Sri Lanka
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Sri Lanka Population: 20,450 (2009) Area: 25,332 square miles (65,610 sq km)
State provides free health and education Infant mortality: 10 /1000 LB
Average Life expectancy at birth: 74y
Adult literacy 92%
Population below US $ 2 a day (1990‐2005) : 41.6 %
Total state health budget 2009 = LKR 71.4 billion (1.5 per cent of GDP). 7.5 billion on pharmaceuticals
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Office of
MT&S DirectorDeputy Director
Administration
Unit
Registration &
Licensing Unit
GMP
Unit
Pharmacovigilance
Unit
Law Enforcem
entUnit
Control Substance Unit
Post‐Marketing
Unit
No of Pharmacist attached to NRA – 11Pharmacologists , scientists – Permanent NilUniversity academics provide advice as a voluntary service
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Need for generic versions of NCEs in Sri Lanka?
Ensure timely access to possibly life saving
medications at a price affordable to the
government and consumer
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NCE generics in Sri Lanka
• Country of origin 100% from India
• In India “the unrestrained generic proliferation that follows the introduction of a new molecule is a phenomenon without parallel elsewhere in the world” 1.
• Annual rate of approval of new drugs in India is comparable with US FDA (median, 24 v. 27; mean [SD] 26.4 [9.52] v. 26.6 [6.73]). EMEA =24 1
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Ensure timely access‐1
India1,2
• Clopidogrel, approved in February 2001, spawned at least 16 generics within a year of approval, presently 62
• Gatifloxacin, approved in October 2001, had at least 20 generics by 2002
• Valdecoxib, cleared only in August 2002, had at least 10 generics by end of 2002.
• Rosiglitazone to date has approximately 32 generics• Enoxaparin – 13 biosimilars
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Ensure timely access ‐ 2
Sri Lanka
• Indian manufacturers seek registration in Sri Lanka
• Past 5 years 70 new molecular entities registered
• Do they meet the WHO criteria for a generic medicine? Most are “ pharmaceutically similar" may not necessarily be therapeutically equivalent
• Rofecoxib (Vioxx) licensed in USA, European Union Countries and Australia in 1999. In Sri Lanka two years later (June 2001)
• By November 2004, 25 branded generics registered
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Ensure affordability ‐ 1
• Yes, only silver lining, competition forces lowering of prices
• Most innovators are not available in Sri Lanka after introduction of generic NCEs
• Why? unable to compete with lower price of generic NCEs
• Avandia not registered in SL after 2006
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Ensure affordability ‐ 2
• Enoxaparin‐ both innovator and generic available
• Cost difference between innovator and generic is 3USD (1 USD = LKR112)
• Annual requirement difference is USD30,000
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? What is the problem
• Safety and rational use
• Despite rapid proliferation of NCEs it is an acknowledged fact that real therapeutic advances are relatively rare
• From 1995, 21 drugs in U.S.A removed from the market for safety reasons
– 50% involved heart complications
– on the market from 11 months to 30 years
– average time to recall was 8 years
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Challenges unique to resource limited settings ‐1
• Ensuring safety, quality and rational use • Inability to monitor promotional activities though ethical code for promotion is available
• MT&S has regulations but committee reviews printed and broadcast promotion of OTC medicines only
• Many pharmaceutical delegates verbally promoting generic NCEs ‐ Roughead et al3, analysed meetings between PD and GPs ‐ omission of risk information was common, and that adverse reactions and interactions were mentioned only in statements that minimised the risk of the product being detailed.
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Challenges unique to resource limited settings ‐2
• Innovator not in market – no obligation to inform safety concerns issued from stringent authorities
• Innovator should act as reference product to each generic ‐ regulator could make it an obligation to the generic manufacturer to update any change happening with originator such as new safety concerns, new indications/more precise indications etc.
• High cost of internet and maintenance of web site• Doctors prescribe NCEs, without a balanced judgment of their risks and benefits in a given situation
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Case study of Avandia
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Approved Indications for Avandia
• Treatment of type 2 diabetes mellitus: • asmonotherapy in adults (particularly overweight adults)
inadequately controlled by diet and exercise.• as dual oral therapy in combination with
– metformin, in adults (particularly overweight adults) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin
– a sulphonylurea, only in adults who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea
• as triple oral therapy in combination with – metformin and a sulphonylurea, in adults (particularly
overweight adults) with insufficient glycaemic control despite dual oral therapy
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Rosiglitazone Sri Lankan scenarioMedicine Registration in
US, FDARegistration in Sri Lanka Country of
Manufacture
Avandia In USA May 25, 1999
October 2002 USA / Spain
Generic 1 February 2003 India
Generic 2 November 2003 India
Generic 3 January 2004 India
Generic 4 March 04 India
Generic 5 December 04 India
Generic 6 January 05 India
Generic 7 November 06 India
Generic 8 March 07 India
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Avandia
• Avandia case is instructive, as it follows the well‐worn path of so many drugs, hailed as miracles at their inception, advertised widely led to more generics, both reap huge revenues, before their dangerous, poorly understood characteristics are exposed
• No continuous update from innovator ‐ not re‐registered since 2006
• EMEA decision communicated through WHO
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Risk Management strategy for NCEs
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REMS
• Risk evaluation and minimization strategy
• The Food and Drug Administration Amendments Act of 2007 (FDAAA) granted the FDA the authority to require the submission and implementation of a REMS if the FDA determines a REMS is necessary to ensure that a drug’s benefits outweigh its risks.
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REMS for Avandamet by US FDA
A. Medication Guide • The goal of the REMS is to communicate the risks of
AVANDAMET. A Medication Guide will be dispensed with each AVANDAMET prescription.
B. Communication Plan • The REMS for AVANDAMET does not include a
Communication Plan. C. Elements to Assure Safe Use • The REMS for AVANDAMET does not include elements to
assure safe use. D. Implementation System • Because the REMS for AVANDAMET does not include
elements to assure safe use, an implementation system is not required.
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Medicines promotion in Risk Mitigation
• Not mentioned in the REMS guidance document• WHO definition of medicines promotion “All informational and persuasive activities by manufacturers and distributors, the effect of which is to induce the prescription, supply, purchase and/or use of medicinal drugs.“By definition the aim of promotion is to stimulate product sales.
• At present, even the United States does not have the capacity to adequately control promotion of the products on its own.
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Medicines promotion in Risk Mitigation‐ 2
• REMS proposed by manufacturer to the regulator
• How about “Promotion Regulation for Risk Mitigation ” (PRORMS) by regulator to the manufacturer at the time of approval with monitoring for compliance till safety is well established
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PRORMS
• Promotion to whom? to all doctors, pharmacist / only specialists till effectiveness and safety is established
• Submission of all promotional material of NCEs (including generics) for regulatory approval ‐ studies suggest that the guidelines and regulations for self control by industry are not effective 4.
• NRA could appoint a team of popular specialists to monitor the activities of PD
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References
1. Ghosh A, Hazra A, Mandal SC. New drugs in India over the past 15 years: Analysis of trends. Natl Med J India 2004;17:10–16
2. Med India on mobilhttp://www.medindia.net/drug‐price/index accessed on November 6th 2010
3. Roughead EE. The pharmaceutical representative and medical practitioner encounter: implications for quality use of medicines www.camtech.net.au/malam accessed on November 6th 2010
4. Norris P, Herxheimer A, Lexchin J. Drug promotion what we know, what we have yet to learn. Reviews of materials in the WHO/HAI database on drug promotion http://apps.who.int/medicinedocs/fr/d/Js8109e
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Thank You