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Legal requirements for generics and abridged products and bioequivalence


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PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education"
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Legal requirements for generics and abridged products and bioequivalence

  1. 1. Legal Requirements for Generics and Abridged Products and Bioequivalence I.Kanzik IDE PharmaConsult PharmaCon 2007 May 22 – 27, 2007 DUBROVNIK, Hotel Dubrovnik Palace
  2. 2. TOPICS <ul><li>Definitions </li></ul><ul><li>Regulations </li></ul><ul><li>Bioequivalence </li></ul><ul><li>Pros and cons of generic drugs </li></ul>
  3. 3. Career in Pharmacy <ul><li>A career in pharmacy, unfolds a vista full of opportunities leading to a golden future for a young career aspirant. </li></ul><ul><li>Excellent opportunities for the professionals are available in regulatory affairs also. </li></ul><ul><li>This is highly respected and sought after profession. </li></ul>
  4. 4. Pharmaceutical Industry <ul><li>T he pharmaceutical industry is the most regulated of all industries. No drug would be available without the teams of medical researchers and other specialists who worked to make sure it received approval from competent authorities. </li></ul>
  5. 5. Regulatory Affairs <ul><li>Regulatory affairs professionals are key, but perhaps overlooked, players in drug development. They are the primary communications link between the company and agencies such as FDA, EMEA, etc. and they are responsible for keeping up with the increasing scope and complexity of regulations both local and abroad. </li></ul><ul><li>In the pharmaceutical industry, regulatory affairs professionals have expertise in the legal and regulatory environments, as well as in clinical research protocols. They are the primary interpreters of the laws and regulations for other members of the company's R&D, manufacturing, and compliance staff. </li></ul>
  6. 6. <ul><li>Drugs have only </li></ul><ul><li>ONE </li></ul><ul><li>quality! </li></ul>
  7. 7. <ul><li>No medicinal product may be placed on the market unless a marketing authorisarion has been issued by a competent authority. </li></ul>
  8. 8. Three important requirements for Registration of NCE <ul><li>Quality </li></ul><ul><li>Efficacy </li></ul><ul><li>Safety </li></ul>
  9. 9. I nnovator P roduct <ul><li>An ' innovator ' product is a medicinal product authorised and marketed on the basis of a full dossier . </li></ul>
  10. 10. Marketing Authorization I nnovator product <ul><li>Results of: </li></ul><ul><li>Physico-chemical, biological or microbiological tests, </li></ul><ul><li>pharmacological-toxicological tests, </li></ul><ul><li>clinical trials. </li></ul>
  11. 11. Drug Registration <ul><li>T he quality , safety and efficacy of a medicine on any market is assured by the national medicines agencies. </li></ul>
  12. 12. International Conference on Harmonisation <ul><li>In the last two decades significant progress was achieved concerning the harmonisation of the existing (national or regional) guidelines by organising international conferences (namely, ICH) on the requirements for medicinal products. </li></ul>
  13. 13. EU Regulations <ul><li>Directive 2004/27/EC which came into force by 30 October 2005 and made significant changes to the current EU requirements under 2001/83/EC is designed to bring some harmonisation in this regard. </li></ul>
  14. 14. 2004/27/EC: Article 10.1: Reference and Generic Products <ul><li>A generic medicinal product shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalance with the reference medicinal product has been demonstrated by appropiate bioavailability studies. </li></ul>
  15. 15. Generic Medicines <ul><li>Generic medicines use the same procedures as originator products and are carefully assessed by the competent authorities before a market approval is granted. </li></ul>
  16. 16. GENERIC APLICATIONS CONTENT OF THE FILE <ul><li>C hemical, biological, pharmaceutical, </li></ul><ul><li>X pharmacological-toxicological and </li></ul><ul><li>X clinical data. </li></ul><ul><li> Appropriate bioavailability studies </li></ul>
  17. 17. Marketing Authorisation Generics <ul><li>To receive a market approval for a generic medicine, the product must be “ bioequivalent ”, that is, “ essentially similar ” to the originator (reference) product. </li></ul><ul><li>Therefore, a 'Reference Product ' must be an 'innovator' product. </li></ul>
  18. 18. Essentially similar products European Court of Justice <ul><li>&quot;A medicinal product is essentially similar to an original product where it satisfies the criteria of having the same qualitative and quantitative composition in terms of active substances, of having the same pharmaceutical form, and of being bioequivalent unless it is apparent in the light of scientific knowledge that it differs from the original product as regards safety and efficacy&quot;. </li></ul>
  19. 19. Essentially similar products <ul><li>Different salts, esters, ethers, isomers, complexes or derivatives are now considered to be the same substance unless they differ significantly in regard to safety or efficacy in accordance with the December 1998 European Court of Justice ruling in the &quot;Generics&quot; case. </li></ul>
  20. 20. <ul><li>Paroxetine hydrochloride hemihydrate / Paroxetine mesylate </li></ul>
  21. 21. ECJ Case C-74/03 of January 2005: Active Substance in Different Forms of Salt <ul><li>Reference to the European Court by the Danish courts in case of SmithKline Beecham PLC versus Laeggemiddelstyrelsen on the interpretation of Article 4.8.(a)(iii) of 65/65/EEC </li></ul><ul><li>SKB is the MA holder of Seroxt tablets – containing paroxetine hydrochloride hemihydrate </li></ul><ul><li>Synthon BV and Genthon BV submitted MA applications using a different salt – paroxetine mesylate, and demonstrated that their product was bioequivalent to Seroxat in volunteers, with no clinical data </li></ul><ul><li>MA granted on the basis that the pharmacological effect and related side effects are due to paroxetine not salt </li></ul><ul><li>Court ruled that the product should “ be handeld under the abridged procedure under that provision where that product contains the same therapeutic moiety as the reference product but combined with another salt” </li></ul>
  22. 22. Article 10a: Well Established Medicinal Use <ul><li>The applicant shall not be required to provide the results of preclinical tests and clinical studies if he can demonstrate that the active substances of the medicinal product have been in well-established medicinal use within the Community for at least 10 years with recognised efficacy and an acceptable level of safety </li></ul><ul><li>In this event, the test and trial results can be replaced by appropriate scientific literature </li></ul>
  23. 23. Generic drugs Bioequivalence <ul><li>With the great increase in the availability of generic drugs in recent years, the matter of bioavailability and bioequivalence has received increasing attention. </li></ul><ul><li>For a drug product to be interchangeable with the original brand-name product, it must be both pharmaceutically equivalent and bioequivalent . </li></ul>
  24. 24. GENERIC APLICATIONS <ul><li>Appropriate bio equivalence studies are essential. </li></ul>
  25. 25. Pharmaceutical Equivalence <ul><li>Medicinal products are pharmaceutically equivalent if they contain the same amount of the same active substance(s) in the same dosage forms that meet the same or comparable standards. </li></ul><ul><li>e.g. 550 mg naproxene sodium Tablet / </li></ul><ul><li>550 mg naproxene sodium Tablet </li></ul>
  26. 26. Pharmaceutical Alternatives <ul><li>Medicinal products are pharmaceutical alternatives if they contain the same active moiety but differ in chemical form (salt, ester, etc.) of that moiety or in the dosage form or strength. </li></ul><ul><li>e.g. paroxetine hydrochloride hemihydrate / paroxetine mesylate </li></ul>
  27. 27. Therapeutic E quivalence <ul><li>A medicinal product is therapeutically equivalent with another product if it contains the same active substance or therapeutic moiety and, clinically, shows the same efficacy and safety as that product, whose efficacy and safety has been established. </li></ul><ul><li>In practice, demonstration of bioequivalence is generally the most appropriate method of substantiating therapeutic equivalence between medicinal products . </li></ul><ul><li>e.g. 550 mg naproxene sodium Tablet / </li></ul><ul><li> 550 mg naproxene sodium Tablet </li></ul><ul><li>+ BIOEQUIVALENCE </li></ul>
  28. 28. BIOAVAILABILITY (according to EU guidance note) <ul><li>T he rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action. </li></ul>
  29. 29. BIOEQUIVALENCE (according to EU guidance note) <ul><li>Two medic in al products are bioequivalent if they are pharmaceutical equivalent or pharmaceutical alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same. </li></ul>
  30. 30. <ul><li>The bioavailability of a drug formulation often determines its therapeutic efficacy , as bioavailability affects the onset, intensity, and duration of the therapeutic response . </li></ul><ul><li>In pharmacokinetics, the term bioavailability describes the rate of absorption of the active ingredient in a drug and the extent to which it is absorbed and becomes available at the site of action. </li></ul>
  31. 31. <ul><li>As the pharmacologic response is generally related to the concentration of drug at the receptor site, the availability of drug from a particular formulation is a crucial element in that product’s clinical efficacy. </li></ul><ul><li>However, drug concentrations cannot usually he measured easily at the site of action. Therefore, based on the premise that the drug concentration at the site of action is in equilibrium with that in the blood, most bioavailability studies determine the drug concentration in blood or urine . </li></ul>
  32. 32. Bioavailability/Bioequivalence Guidelines <ul><li>In the last 15 years significant progress was achieved concerning the harmonisation of the existing (national or regional) guidelines by organising international conferences on the requirements for bioavailability/bioequivalence studies. </li></ul>
  33. 33. Global harmonisation <ul><li>During the last two years new guidelines have been drafted by CPMP in Europe and US-FDA. While the European Note for Guidance is a consequent up-date of the previous document considering the most relevant aspects of the latest scientific development, FDA developed a completely new concept. </li></ul><ul><li>Consequently, there are still significant differences between both documents. Thus, further harmonisation seems necessary considering the global marketing of pharmaceutical products in the future . </li></ul>
  34. 34. Differences among the authorities <ul><li>Ensuring that the adopted procedure does not conflict with operating guidelines and the relevant scientific literature </li></ul><ul><li>does not guarantee the approval of generic drugs in all European countries, as they can be interpreted differently by individual agencies for several reasons. </li></ul>
  35. 35. <ul><li>PROS AND CONS OF GENERİC DRUGS </li></ul>
  36. 36. Pros of generic drugs <ul><li>The streamlining of the procedures for registration of generic drugs has many advantages for consumers and health care providers, as it means that when the patent for a brand-name drug expires, a substantially lower-priced generic formulation can be marketed quickly. </li></ul>
  37. 37. Cons of generic drugs <ul><li>Several studies have reported that slight variations in doses of antiarrhythmic drugs may mean the difference between therapeutic success and relapse into arrhythmia, appearance of proarrhythmia, or even death. </li></ul>
  38. 38. Cons of generic drugs <ul><li>Thus, a change in drug formulation can have a significant effect on the risk-benefit ratio in therapeutic situations in which the patient’s life is at risk. </li></ul>
  39. 39. Cons of generic drugs <ul><li>Generic drugs may use different excipients from those in the brand-name drug, and patients may have adverse reactions to the excipients in a particular product. </li></ul><ul><li>Changing a substance from its free base or acid form to a salt form is a recognized means of modifying an agent’s chemical and biological properties without modifying its structure and is commonly done to improve a drug’s kinetics, absorption, or physicochemical properties. </li></ul>
  40. 40. <ul><li>Different salts of the same active drug have distinct chemical and biological profiles that may underlie differences in their clinical efficacy and safety There is as yet no reliable way of predicting such effects, and when the effects cannot be predicted, it is necessary to consider all possible risks. </li></ul>
  41. 41. Substitution <ul><li>Substitution of a brand-name drug with a generic drug requires particular care on the part of the clinician to ensure the safest and most effective treatment. </li></ul><ul><li>This is a particularly important concern for general practitioners (who are not always aware of possible generic substitution by the pharmacist), as the current standards applied to the equivalence of generic and brand-name drugs could result in unsatisfactory outcomes. </li></ul>
  42. 42. <ul><li>THANK YOU </li></ul>