Materiały dydaktyczne do kursu specjalistycznego: Rola i zadania przemysłu farmaceutycznego w systemie opieki zdrowotnej

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1 Nowoczesne metody, leki i terapie w ochronie zdrowia i gospodarce Europy XXI wieku interdyscyplinarne kształcenie w obszarze nauk biomedycznych na studiach II i III stopnia, POKL /12 Zadanie nr 2: Przygotowanie, otwarcie i realizacja wielodziedzinowych anglojęzycznych studiów doktoranckich Life Sciences for Biomedical Research Materiały dydaktyczne do kursu specjalistycznego: Rola i zadania przemysłu farmaceutycznego w systemie opieki zdrowotnej Autor: dr hab. Tomasz Grabowski, Polpharma SA Projekt realizowany ze środków Unii Europejskiej w ramach Europejskiego Funduszu Społecznego

2 Kształtowanie rynku leków przez przemysł farmaceutyczny Dr hab. Tomasz Grabowski UW

3 Prezentacja przygotowana została w oparciu o materiały własne, dane z bazy Datamonitor oraz dane pochodzące z domeny publicznej. Materiał stworzono wyłącznie w celach dydaktycznych. 2

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10 Kształtowanie rynku leków przez przemysł farmaceutyczny - Lobby na rzecz wytycznych (guideline, guidance) w kluczowych agencjach - W zakresie: jakość, bezpieczeństwo, skuteczność - Lobby na rzecz zapisów prawnych poszczególnych państw - Wpływ na decyzje o wprowadzaniu do leczenia nowych leków poprzez systemy refundacyjne - Wpływ na środowiska opiniotwórcze - Elity naukowe, polityczne, biznesowe - Wpływ na dostępność leków generycznych poprzez kształtowanie polityki cenowej i patentowej 9

11 Japanese Pharmaceuticals Medical Devices Agency World Health Organization European Parliament and the Council The International Conference on Harmonisation US Food and Drug Administration Joint FAO/WHO Expert Committee on Food Additives Health Canada European Medicines Agency Pharmacokinetics, bioequivalence, toxicokinetics studies according to drug registration in Japan, US, CA, and/or EU Organisation for Economic Co-operation and Development 10

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15 1. International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) is a non-profit, non-governmental Organisation (NGO) representing national industry associations and companies from both developed and developing countries. Member companies of the IFPMA are researchbased pharmaceutical, biotech and vaccine companies. 2. Pharmaceutical Research and Manufacturers of America PhRMA - represents the research-based industry in the USA. The Association has 67 companies in membership which are involved in the discovery, development and manufacture of prescription medicines. There are also 24 research affiliates which conduct biological research related to the development of drugs and vaccines. 3. Japan Pharmaceutical Manufacturers Association (JPMA) is a voluntary association comprising 68 research-oriented pharmaceutical companies. 4. European Federation of Pharmaceutical Industries and Associations EFPIA, is situated in Brussels and has, as its members, 31 national pharmaceutical industry associations and 40 leading pharmaceutical companies involved in the research, development and manufacturing of medicinal products in Europe for human use. 5. The European Free Trade Association (EFTA) Norway and Switzerland were among the founding Member States of EFTA in Iceland joined EFTA in 1970, followed by Liechtenstein in Norway, Iceland (from 1994) and Liechtenstein (from 1995) are also parties to the European Economic Area (EEA) Agreement with the European Union, while Switzerland has signed a set of bilateral agreements with the EU. 14

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35 New drug price controls in effect from January 2011 will bring down prices of patent-protected medicines The second part of the AMNOG law, passed in November 2010, introduced a requirement for price negotiation for newly launched drugs. Key proposed changes within the second part of the law include the following (IHS, 2010a, Bruce, 2010a): Innovative drugs will be subject to benefit assessment by G-BA followed by price negotiations with the public health insurers, SHI. The reference pricing system is to be expanded to include me-too drugs for any therapeutic class. Their reimbursement level will be defined by the reference price, which will be determined by the interval between the cheapest and most expensive drug in each therapeutic group. Drugs included in the reference pricing system will be increasingly targeted by discounted contracts. Introduction of a new performance-based remuneration for wholesalers (fixed fee of 0.60 ($0.84) plus 1.7%). Pharmaceutical companies will be obliged to publish all clinical trial results. 34

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37 1. Patient co-pays Patients pay for a proportion of their prescription. 2. Formulary positive/negative lists Positive lists include drugs that receive some level of reimbursement, negative listed drugs receive no reimbursement. 3. Volume limitations Limits the overall volume of drugs prescribed, through the setting of pre-established volume limitations based on a set price-volume agreement. 4. Pharmacoeconomics Cost-effectiveness analysis of a drug and how it fits within a given payer s budget. 5. Risk-sharing A form of conditional therapeutic coverage that entails a contractual agreement between a payer and a healthcare supplier or manufacturer, based on a "guaranteed" outcome resulting from the treatment. If the outcome is achieved the payer will pay, if not, the pharmaceutical company refunds the payer for the cost of the drug. 6. OTC switching Switching a branded prescription drug to one of over-the-counter (OTC) status. 7. Pharmacist/automatic substitution Pharmacists must substitute a prescription for a branded drug for an identical cheaper generic where possible without consent of the prescribing physician. 8. Budget caps Setting limited budgets for drug expenditure which if exceeded may trigger a payback from the manufacturers. 9. Generic-name prescribing When physicians are encouraged to prescribe generic drugs rather than branded drugs. 36

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41 Personalized medicine can be defined as the tailoring of medical treatment to the individual characteristics of each patient. Moreover, it is the classification of individuals into subpopulations that vary based on their vulnerability to a particular disease or their response to a specific treatment so that the preventative or therapeutic interventions can be focused on those who will benefit. 1. Diagnostics Evaluation of genetic sequences to confirm the presence of disease (often used in oncology monitoring). 2. Prognostics Evaluation of genetic mutations to determine susceptibility to a future condition (for example, cystic fibrosis genotype testing, or Genomic Health Oncotype Dx [a test that quantifies the likelihood of disease recurrence in women with early-stage HER2+ breast cancer]). 3. Pharmacogenetics (PGx) Evaluation of genetic variations to identify patients likely to respond to a particular therapy (used in HER2+ breast cancer, lung cancer, and colorectal cancer). to identify and select those patients that will benefit from a specific treatment to identify those at risk for atypical adverse reaction to identify biomarkers for specific therapies to determine the optimal dosing of a treatment. 40

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44 Ahmed et al..clinical Therapeutics/Volume 34, Number 2,

45 Comparability study Forced degradation comparability Immunogenicity (Fc ADCC/CDC) In vitro / in vivo PD target affinity (Fab) In vitro / in vivo Binding studies (FcRn, FcγRI, FcγRII FcγRIII) In vitro / in vivo Formulation comparability PK Comparability In vivo QbD finger-print CQA comparability Predefined acceptace criteria (signifficant differences) CI 95% PK/PD Comparability In vivo Impiurities profile - product-related impurities; - product-related substances; comparability Toxicological observations after PK/PD or PK Comparability Structural Comparability 1. ph 2. apperance 3. osmolality 4. concentration 5. charge 6. mass 7. sequence 8. glycosylation 9. sialylation 10. galactosylation 11. fucosylation 12. sialic acid 13. H,L chain seq. 14. oxidation 15. deamidation 16. agreagtion 44

48 QbD stanowi zespół działań pozwalający w sposób racjonalny wykorzystujący takie narzędzia jak DOE na optymalizację procesu wytwarzania. Implementacja QbD do procesu wytwarzania oznacza poruszanie się w zakresie wielu czynników jakościowych dotyczących różnych cech-atrybutów materiałów, surowców i procesu. Przestrzeń tą określa się, jako DSp. W przypadku implementacji QbD i zdefiniowania zakresu DSp każda zmiana wykraczająca poza tą przestrzeń, czyli jej rozbudowa traktowana jest, jako zmiana typu II (EC 2003, 2008). Wymogi dotyczące QbD stanowią przedmiot harmonizacji pomiędzy FDA i EMA, który zainicjowano się 16 marca Pilotowy program harmonizacji wymogów w zakresie QbD rozpoczęto 1 kwietnia 2011 a czas jego trwania przewidziano na trzy lata czyli do kwietnia 2014 (EMA 2011b). Program realizowany jest przy udziale EU-US Bilateral Technical Working Group on Medicines Quality and Manufacturing. 47

49 Kluczowe dokumenty prawne i wytyczne: 1. EC 2003, Commission Regulation (EC) No 1084/2003, EC 2008, Commission Regulation (EC) No 1234/2008, EMA 2006, Mandate for Process Analytical Technology Team, Doc. Ref: EMEA/48327/2006, EMA 2011a, European Medicines Agency and U.S. Food and Drug Administration announce pilot program for parallel assessment of Quality by Design applications. EMA/197051/2011, EMA 2011b, Guidance document on the content of the co rapporteur day 80 critical assessment report. Quality aspects. EMA/627553/2011, EMA 2011c, ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) EMA/CHMP/ICH/425213/201, FDA 2004a, Pharmaceutical Cgmps For The 21st Century A Risk-Based Approach Final Report FDA 2004b, Guidance for Industry PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance FDA 2008, Submission of Quality Information for Biotechnology Products in the Office of Biotechnology Products; Notice of Pilot Program. FDA-2008-N-0355, Federal Register, 73:128, HC 2011, Post-Notice of Compliance (NOC) Changes: Quality Document ICH 2009, Topic Q 8 (R2) Pharmaceutical Development, EMEA/CHMP/167068/2004 ICH & Annex To Note For Guidance On Pharmaceutical Development (EMEA/CHMP/ICH/167068/2004)., 2009, WHO 2008, International Harmonization. WHO Drug Information 22:4, EMA (2007) Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing proces non-clinical and clinical issues. Doc. Ref. EMEA/CHMP/BMWP/101695/2006, EMA (2005) ICH Topic Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process. CPMP/ICH/5721/03,

50 Status QbD i potrzebę implementacji takiej strategii rozwoju DS i drug product (DP) określa między innymi dokument ICH z 2009 roku. W dokumencie tym znajdujemy informację o tym, że: ( ) this annex describes the principles of quality by design ( ) it shows how concepts and tools (e.g., design space) ( ) could be put into practice by the applicant for all dosage forms. W wytycznej mówi się o tym, że aplikant może wybrać trzy drogi rozwoju produktu leczniczego: empiryczną opartą o QbD mieszaną - opartą częściowo o QbD i drogę empiryczną: ( ) Strategies for product development vary from company to company and from product to product. The approach to, and extent of, development can also vary and should be outlined in the submission. AN APPLICANT MIGHT CHOOSE EITHER AN EMPIRICAL APPROACH OR A MORE SYSTEMATIC APPROACH TO PRODUCT DEVELOPMENT, OR A COMBINATION OF BOTH.. Definicja more systematic approach, czyli definicję QbD podano w dalszej części dokumentu: ( ) A more systematic approach to development (also defined as quality by design) can include, for example, incorporation of prior knowledge, results of studies using design of experiments, use of quality risk management, and use of knowledge management (see ICH Q10) throughut the lifecycle1 of the product.. 49

51 Proces decyzyjny i ocena po złożeniu dokumentacji musi być oparty na przesłankach naukowych oraz analizie QRM. Obecnie brak jakichkolwiek wiążących dokumentów FDA, EMA lub innych agencji w zakresie dotyczącym szczególnego toku oceny dokumentacji zawierającej elementy QbD. Dokumentacja formułowana na podstawie procesu przeprowadzonego bez implementacji Qbd również musi być oceniana w oparciu o dane naukowe. Możliwość weryfikacji i zbadania wielu zależności pomiędzy różnymi elementami procesu pod kątem ich wpływu na parametry jakościowe DP. Ma duże znaczenie w odniesieniu do optymalizacji procesu. W przypadku procesów realizowanych poza PB element ten pozwalać będzie na weryfikację skali i zakresu optymalizacji procesu wytwarzania. Zwiększenie elastyczności procesu i wprowadzania zmian w obrębie DSp, poruszanie się w ramach DSp nie wymaga zgłaszania zmiany (typ II) w procesie i pozwala na jego modyfikowanie w trybie ciągłym. Element ten jest również możliwy do realizacji w przypadku tradycyjnej drogi rozwoju produktu wprowadzanie zmian w granicach specyfikacji. 50

52 ICH Topic Q 5 C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products stability data in the initial submission should be determined on a case-by-case the minimum amount of stability data in the initial submission should be determined on a case-by-case conditions should be carefully selected on a case-by-case applicants should consult the appropriate regulatory authorities on a case-by-case. individual types or groups of biotechnological/biological products but are considered on a case-by-case 51

53 No. Document name Publication date GLP paragraphs 1. 4 Guidance for Industry Population (FDA, 1999) A population PK study should be conducted according to current good clinical practice (GCP) and good laboratory practice (GLP) standards. Pharmacokinetics Guidance for Industry, 1. 5 Investigators, and Reviewers Exploratory (FDA, 2006) ( ) all preclinical safety studies supporting the safety of an exploratory IND application will be performed in a manner consistent with good laboratory practices (GLP) (21 CFR Part 58) IND Studies Inspections of Clinical Facilities and Analytical Laboratories Conducting Bioequivalence Studies Submitted in ANDAs Guidance for Reviewers Pharmacology /Toxicology Review Format (FDA, 2001c) (FDA, 2001d) 1. 8 Redbook (FDA, 2000) Guidance for Industry Bioequivalence Guidance Guidance for Industry Target Animal Safety for Veterinary Pharmaceutical Products VICH GL43 (FDA, 2006) (VICH, 2009) Office of Generic Drugs ( ) requests information on the compliance status of ( ) the Good Laboratory Practice (GLP) ( ). GLP compliance: Toxicology, genetic toxicology, carcinogenicity, reproductive and developmental toxicology, special toxicology studies. Nonclinical laboratory studies must be conducted according to U.S. FDA good laboratory practice (GLP) regulations, issued under Part 58. Title 21. Code of Federal Regulations. Bioequivalence studies (i.e., blood level, pharmacologic endpoint, and clinical end-point studies) and tissue residue depletion studies should be conducted in accordance with good laboratory practice (GLP) regulations (21 CFR Part 58). Margin of safety and other laboratory safety studies must be performed in conformity with the principles of Good Laboratory Practices (GLP). ( )See 21 CFR Part 58. It is recommended that safety evaluation ( ) in early to midlactation animals (data collected in conformity with the principles of GLP) ( ) See 21 CFR Part

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71 keyword: cardiac 70

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78 OECD FDA System GLP tworzony przez OECD swoim obszarem obejmuje między innymi Unię Europejską System GLP tworzony przez FDA swoim obszarem obejmuje między innymi obszar obu Ameryk 77

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80 Dziękuję za uwagę UW

81 Nowoczesne metody, leki i terapie w ochronie zdrowia i gospodarce Europy XXI wieku interdyscyplinarne kształcenie w obszarze nauk biomedycznych na studiach II i III stopnia, POKL /12 Projekt realizowany ze środków Unii Europejskiej w ramach Europejskiego Funduszu Społecznego