Importance of drug quality impact on clinical outcomes around the world


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

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Importance of drug quality impact on clinical outcomes around the world

  1. 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. 2. Overview of Presentation TodayDrug 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. 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. 4. Substandard Copies: A Global ConcernTheTh 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. 5. How Should We Define a Substandard Therapy? A Regulatory ViewOriginator 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 DrugSubstandard Therapy 1: a Substandard Therapy 1: a drug that py drug that g py g1) Does not not meet specifications necessaryensure quality, efficacy andand safety 1) Does meet specifications necessary to to ensure quality, efficacy safety2) Has not demonstrated bioequivalence or similarity* to the originator; or may not meet2) Has not demonstrated bioequivalence or similarity* to the originator; or may not meet EU or US quality standards EU or US quality standards3) 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. 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. 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 most1 EMA = European Medicines Agency, Committee for Medicinal Products for Human Use2 FDA = US Food and Drug Administration, Code of Federal Regulations
  8. 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. 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. 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 PatientExposure 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. 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. 12. Daily Patients Exposure to Genotoxic Impurities1AmountAmo 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. 13. Detect Quality Issues Before Patients Are Exposed to Potential RisksPatientExposure 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. 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) PropeActive Ingre ● Interruption of treatment due to potentially serious side effects High level of unknown ● Impurities may be carcinogenic impurities ● Increased resistance to treatmentA( ● 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 alternativeDrug 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. 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 practiceguidelines 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. 16. A call for action for High Regulatory Standards and PharmacovigilanceGeneral recommendations:G l d ti1. Create better understanding at the regulatory, policy and public level of the differences between drugs ● Originator vs substandard vs generics vs counterfeit2. Recognize that substandard drugs puts patients at risk3. Acknowledge the extent to which governments can control access to drugs that may be substandardSome problems can be addressed relatively easily, whileothers require hard thinking, large resources, and national– or even international – coordination. Source: “Keeping Medicine Safe” Stockholm Network 2010
  17. 17. Drug Quality: a Commitment toPatients 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