Drug development and regulation


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Drug development and regulation

  1. 1. DRUG DEVELOPMENT AND REGULATION www.freelivedoctor.com
  2. 2. Historical Background Why were Laws Needed? <ul><li>Adulteration for economic gain </li></ul><ul><li>Early English Law - King John promulgates rules on contamination of flour – Assizes of Bread </li></ul><ul><li>Quack medicines, hidden ingredients, misbranding in early America </li></ul><ul><li>American meat products rejected by Europe </li></ul><ul><li>Publication of The Jungle by Upton Sinclair </li></ul><ul><li>Tetanus contaminated diphtheria vaccine </li></ul>www.freelivedoctor.com
  3. 3. Virus  Toxin Act of 1902 <ul><li>premarket clearance for safety and efficacy </li></ul><ul><li>factory inspection </li></ul><ul><li>batch certification </li></ul>www.freelivedoctor.com
  4. 4. Food and Drug Act of l906 (Wiley or Heyburn Act) <ul><li>first main federal drug law </li></ul><ul><li>targeted adulteration and misbranding </li></ul><ul><li>established the U.S. Pharmacopeia and National Formulary to establish and regulate reference standards </li></ul>www.freelivedoctor.com
  5. 5. The Sherley Amendment of l912 <ul><li>prohibited use of fraudulent therapeutic claims </li></ul><ul><li>placed burden of proof on government and resulted in weak or non-enforcement due to the paucity of modern scientific techniques and tools </li></ul>www.freelivedoctor.com
  6. 6. The Food, Drug and Cosmetic Act of l938 (Copeland Act) <ul><li>premarket clearance for safety only </li></ul><ul><li>factory inspection instituted </li></ul><ul><li>drug could become approved if FDA did not act within a specified deadline </li></ul>www.freelivedoctor.com
  7. 7. The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Act – l947 <ul><li>defined the LD-50 </li></ul><ul><li>established classes of toxicity based on order of magnitude of dose producing an LD-50 </li></ul><ul><li>require a label to be written for a pesticide as well as registration with USDA </li></ul>www.freelivedoctor.com
  8. 8. The Durham Humphrey Amendment of l951 <ul><li>defined the modern practice of pharmacy </li></ul><ul><li>established pharmacist - physician relationship </li></ul><ul><li>established a separate class for narcotics and physician registration numbers </li></ul><ul><li>deals with &quot;Legend Drugs&quot; – drugs which bear the warning &quot;Caution Federal Law Prohibits Dispensing Without Prescription&quot; e.g. Rx drug </li></ul>www.freelivedoctor.com
  9. 9. Insulin and Antibiotic Certification Amendments ’41, ’43, ’45, ’49, ’52 <ul><li>required batch certification of all Master Lots (bulk product) as well as all lots of finished product </li></ul><ul><li>required batch certification of all lots of antibiotics before they could be sold </li></ul>www.freelivedoctor.com
  10. 10. The Kefauver – Harris Act of l962 <ul><li>premarket clearance for safety and efficacy </li></ul><ul><li>establishment of &quot;Investigational Exemption for a New Drug (IND) which required animal data to be submitted and evaluated before clinical trial could begin </li></ul><ul><li>established 3 phases of clinical testing </li></ul><ul><li>made approval or denial of an NDA an FDA requirement rather than the default approval of the 1938 law </li></ul><ul><li>established modern drug review and approval procedures </li></ul>www.freelivedoctor.com
  11. 11. DESI Evaluation of l966; completed l969-70 <ul><li>Established panels that rated pre 1966 drugs as: effective; probably effective; possibly effective and ineffective and drove the last two categories off the market unless new evidence was presented </li></ul>www.freelivedoctor.com
  12. 12. Comprehensive Drug Abuse Prevention and Control Act of 1970 <ul><li>Established the DEA in the Dept of Justice </li></ul><ul><li>Established 5 schedules for drugs of abuse </li></ul><ul><li>Established penalties for misuse </li></ul><ul><li>Established quotas for manufacturing of narcotics </li></ul>www.freelivedoctor.com
  13. 13. Important Legislative Developments of the 70’s <ul><li>Over-the-Counter (OTC) Evaluation Monographs l972 – present </li></ul><ul><li>Supreme Court Ruling of 1973 concerning the authority of FDA </li></ul><ul><li>Drug Listing Act of l972 </li></ul><ul><li>Good Laboratory Practices regulations; proposed 1976; finalized l979 </li></ul>www.freelivedoctor.com
  14. 14. Orphan Drug Act of 1983 <ul><li>defined orphan drugs </li></ul><ul><li>encouraged their manufacture by giving companies exclusivity and tax relief </li></ul>www.freelivedoctor.com
  15. 15. Drug Price Competition and Patent Term Restoration Act – 1984 <ul><li>established the &quot;so called&quot; generic drug </li></ul><ul><li>established the concept of bioequivalence for generic drugs ( + 20% of the rate and extent of absorption of the innovator drug and the generic is considered to be equivalent to the innovator brand) </li></ul><ul><li>established the abbreviated NDA called ANDA that did not require a repeat of safety and efficacy studies of the innovators, just bioequivalency studies </li></ul>www.freelivedoctor.com
  16. 16. Generic Drugs Act – 1990 <ul><li>established criteria and standards for generic drug manufacture </li></ul><ul><li>established the FDA Office of generic drugs to oversee the law and administer the approval process </li></ul>www.freelivedoctor.com
  17. 17. Prescription Drug User Fee Act (PDUFA) of l994; l997; 2000; 2003 <ul><li>industry provides FDA funds in the form of fees to pay for positions and resources to review new drug application </li></ul><ul><li>review time speeded up and drug lag shortened </li></ul>www.freelivedoctor.com
  18. 18. FDA Modernization Act - l997 <ul><li>abolishes insulin certification </li></ul><ul><li>abolishes antibiotic monographs </li></ul>www.freelivedoctor.com
  19. 19. Pediatric Exclusivity Act of 1998 <ul><li>Provides for FDA to request non-manditory research studies on drugs with toxicity issues that are used in children </li></ul><ul><li>Provides exclusivity or drug patent extension for those companies willing to perform these voluntary studies </li></ul>www.freelivedoctor.com
  20. 20. Drug Development - Methods used to identify compounds with potential therapeutic usefulness <ul><li>Screening – most new drugs discovered this way </li></ul><ul><li>screen is a specified set of procedures to which a series of compounds is subjected to both in vivo and in vitro </li></ul><ul><li>quantitative part of screening is the bioassay </li></ul><ul><li>bioassay used to establish relationship between dose and response and compare unknowns to standards </li></ul>www.freelivedoctor.com
  21. 21. Synthesis, Purification & Data Mining <ul><li>Synthesis of drug de novo </li></ul><ul><li>Modification of structure of existing drugs – structure – activity studies (SAR) </li></ul><ul><li>Purification of drugs from natural sources such as native, folklore or herbal medicines </li></ul><ul><li>Exploration of side effects of existing drugs - awareness of potential usefulness of side effects </li></ul>www.freelivedoctor.com
  22. 22. Animal Studies - Preclinical Studies <ul><ul><li>Acute toxicity tests </li></ul></ul><ul><ul><ul><li>one administration of chemical to each animal </li></ul></ul></ul><ul><ul><ul><li>generation of dose – response curves </li></ul></ul></ul><ul><ul><ul><li>Appropriate pharmacological testing to determine ED50 </li></ul></ul></ul><ul><ul><ul><li>Develop analytical methods for determining absorption, excretion, distribution and metabolism of chemical </li></ul></ul></ul>www.freelivedoctor.com
  23. 23. Animal Studies - Preclinical Studies <ul><ul><li>Subchronic toxicity tests </li></ul></ul><ul><ul><ul><li>usually 60 –90 days duration </li></ul></ul></ul><ul><ul><ul><li>multiple administrations or continuous exposure via food or water to one dose level of a chemical per animal </li></ul></ul></ul>www.freelivedoctor.com
  24. 24. Animal Studies - Preclinical Studies <ul><ul><ul><li>Chronic toxicity tests </li></ul></ul></ul><ul><ul><ul><ul><li>2 to 5 years duration depending on species </li></ul></ul></ul></ul><ul><ul><ul><ul><li>multiple administrations or continuous exposure via food or water to one dose level of a chemical per animal </li></ul></ul></ul></ul>www.freelivedoctor.com
  25. 25. Clinical Studies <ul><ul><li>Notice of Claimed Investigational Exception for a New Drug (IND) </li></ul></ul><ul><ul><li>Phase I of clinical studies </li></ul></ul><ul><ul><li>pharmacological investigation </li></ul></ul><ul><ul><li>one or two clinical pharmacologists </li></ul></ul><ul><ul><li>healthy volunteers – informed consent – one tenth of dose for PK studies </li></ul></ul>www.freelivedoctor.com
  26. 26. Clinical Studies (continued) <ul><ul><li>Phase II of clinical studies </li></ul></ul><ul><ul><li>initial controlled clinical evaluation </li></ul></ul><ul><ul><li>more than two clinical pharmacologists </li></ul></ul><ul><ul><li>selected volunteer patients with specific disease indication for drug </li></ul></ul><ul><ul><li>double blind studies </li></ul></ul>www.freelivedoctor.com
  27. 27. Clinical Studies (continued) <ul><ul><li>Phase III of clinical studies </li></ul></ul><ul><ul><li>extended clinical evaluation </li></ul></ul><ul><ul><li>usually 50 – 100 clinicians </li></ul></ul><ul><ul><li>usually 500 – 1000 patients </li></ul></ul>www.freelivedoctor.com
  28. 28. www.freelivedoctor.com
  29. 29. DEFINITION OF A NEW DRUG <ul><li>Any chemical or substance not previously used in humans for the treatment of a disease </li></ul><ul><li>Combinations of approved drugs or of old drugs even though the individual components are not new drugs </li></ul><ul><li>An approved drug employed for uses other than those approved </li></ul><ul><li>Anew dosage form of an approved drug; and </li></ul><ul><li>Even a drug used in vitro as a diagnostic agent when its uses will influence the diagnosis or treatment of disease in a human patient </li></ul>www.freelivedoctor.com
  30. 30. INVESTIGATIONAL NEW DRUG APPLICATION (IND) <ul><li>The IND submitted to the FDA contains the results of all preclinical investigations carried out in animals, including complete toxicity data, the full pharmacologic spectrum of the drug and any studies of absorption, distribution, biotransformation and excretion. In addition, the IND must provide the following information: </li></ul>www.freelivedoctor.com
  31. 31. INVESTIGATIONAL NEW DRUG APPLICATION (IND) <ul><li>Complete composition of the drug, its source and manufacturing data with details of all quality control measures employed to ensure exact reproducibility of manufacture and identification of all ingredients </li></ul><ul><li>Specifications of the dosage forms to be given to humans </li></ul><ul><li>A description of the investigations to be undertaken, including the doses to be administered, the route and duration of drug administration and the specific clinical observations and laboratory observations to be performed </li></ul><ul><li>The names and the qualifications of and the facilities available to, each investigator who will participate in the initial studies (Phase I) </li></ul>www.freelivedoctor.com
  32. 32. INVESTIGATIONAL NEW DRUG APPLICATION (IND) <ul><ul><li>Copies of all informational material supplied to each investigator (the data sheets supplied to the investigator incorporate the data supplied in the IND itself) </li></ul></ul><ul><ul><li>An agreement from the sponsor to notify FDA and all investigators of any adverse effects that arise during either the continuing animal studies or human tests </li></ul></ul><ul><ul><li>Agreement to submit annual progress reports </li></ul></ul><ul><ul><li>Certification that &quot;informed consent&quot; will be obtained from the subjects or patients to whom the drug will be given </li></ul></ul>www.freelivedoctor.com
  33. 33. PHASE I STUDIES <ul><li>Requires an FDA approved IND to commence </li></ul><ul><li>Conducted in normal healthy human volunteers </li></ul><ul><li>Performed under carefully controlled conditions </li></ul><ul><li>Toxicological and pharmacological data obtained by a trained clinical pharmacologist </li></ul><ul><li>Drug first administered at one tenth the ultimate projected effective dose </li></ul>www.freelivedoctor.com
  34. 34. PHASE I STUDIES <ul><li>Primary objective is to obtain a safe and tolerated dose in humans </li></ul><ul><li>Parameters of absorption, metabolism and excretion are measured </li></ul><ul><li>The pharmacokinetic study relies on measurements of levels of the test drug in blood and urine at various times after administration (route usually oral) </li></ul><ul><li>If drug is ineffective at the given dose, the above measurements resolve issues of efficacy vs. poor absorption or rapid elimination </li></ul>www.freelivedoctor.com
  35. 35. PHASE II STUDIES <ul><li>Randomized control trials in patients with the disease for which the drug is intended or as a pretreatment to prevent disease </li></ul><ul><li>Numbers of patients are limited, but may be up to several hundred </li></ul><ul><li>Doses are higher than those in Phase I </li></ul><ul><li>Studies may last several months to two years </li></ul>www.freelivedoctor.com
  36. 36. PHASE II STUDIES <ul><li>Safety still an important concern, but efficacy is the major emphasis </li></ul><ul><li>Flexibility in the design of studies is very desirable at this stage </li></ul><ul><li>Extremely slow metabolism of drug with accumulation of subsequent doses and toxicity might require additional studies at this point </li></ul><ul><li>Changes in the original protocol require the submission of amendments to IND and additional review by IRB’s </li></ul>www.freelivedoctor.com
  37. 37. PHASE III STUDIES <ul><li>Large-scale controlled studies </li></ul><ul><li>Major objective is to develop data to permit the drug to be marketed and used safely and effectively </li></ul><ul><li>Multi-patient – multi-center study </li></ul><ul><li>May involve as many as 150 clinicians, many of whom are experienced clinical pharmacologists </li></ul><ul><li>Usually involves 1500 to as many as 4000 patients </li></ul>www.freelivedoctor.com
  38. 38. PHASE III STUDIES <ul><li>Study generally lasts anywhere from 2 –10 years with an average length of 5 years </li></ul><ul><li>Study examines safety and effectiveness, but emphasizes proper dose determination </li></ul><ul><li>The following studies may be conducted at this stage: </li></ul><ul><ul><li>drug biotransformation </li></ul></ul><ul><ul><li>capacity of drug to bind to plasma proteins </li></ul></ul><ul><ul><li>to induce or inhibit enzymes </li></ul></ul><ul><ul><li>to interact in various ways with other drugs </li></ul></ul>www.freelivedoctor.com
  39. 39. THE NEW DRUG APPLICATION (NDA)   <ul><li>When the sponsor is convinced that the data obtained in Phase III studies justify approval for safety and efficacy for the use(s) intended, the NDA is submitted </li></ul><ul><li>Usually, at least 5 years has elapsed since the drug was originally screened </li></ul><ul><li>The NDA contains all of the chemical, pharmacologic, toxicologic., clinical and maufacturing data that have been collected in the whole process </li></ul><ul><li>The NDA also contains bioequivalence and bioavailability data </li></ul>www.freelivedoctor.com
  40. 40. THE NEW DRUG APPLICATION (NDA)   <ul><li>Samples of the drug, its labels and the package insert that will accompany the drug in all shipments to physicians and pharmacies </li></ul><ul><li>Submission of the NDA starts a &quot;review clock&quot; in which the FDA has 180 days to respond </li></ul><ul><li>The NDA submission generally occurs essentially when the sponsor and FDA agree that studies are complete. Thus the NDA is approved fairly promptly </li></ul><ul><li>926 NDA’s were approved between 1980 and 1986 </li></ul>www.freelivedoctor.com
  41. 41. THE NEW DRUG APPLICATION (NDA)   <ul><li>If the NDA is deemed for some reason to be incomplete, the sponsor is required to resubmit additional </li></ul><ul><li>If there is a disagreement between FDA and the sponsor then a hearing may be held and the outcome is appealable in Court </li></ul><ul><li>Less than 25% of all new drugs for marketing are novel or new molecular entities (NME’s). The rest are new salts, new formulations, new indications or duplicates of drugs previously approved for marketing </li></ul><ul><li>  </li></ul>www.freelivedoctor.com
  42. 42. PHASE IV – POSTMARKETING SURVEILLANCE <ul><li>Applies to all aspects of investigation following NDA approval and general availability of drug in widespread clinical use </li></ul><ul><li>Claims for safety and efficacy appearing or advertising are reviewed and approved by FDA </li></ul><ul><li>Reports concerning clinical studies must be sent to FDA: </li></ul><ul><ul><li>every three months during the first year </li></ul></ul><ul><ul><li>every six months in the second year </li></ul></ul><ul><ul><li>annually thereafter </li></ul></ul>www.freelivedoctor.com
  43. 43. PHASE IV – POSTMARKETING SURVEILLANCE <ul><li>Reports must include the following information about: </li></ul><ul><ul><li>quantity of drug distributed </li></ul></ul><ul><ul><li>copies of mailing pieces and labeling </li></ul></ul><ul><ul><li>examples of advertising for prescription drugs </li></ul></ul><ul><li>Immediate reports on unexpected side-effects, injury, toxic or allergic reactions and failure of the drug to exert its expected pharmacologic reaction </li></ul>www.freelivedoctor.com
  44. 44. CLASSIFICATION SYSTEM Type - Review Priorities <ul><li>New Molecular Entity (NME) </li></ul><ul><li>P - Priority review – clear therapeutic gain </li></ul><ul><li>New salt </li></ul><ul><li>S– Std Review – similar to previously marketed drug </li></ul><ul><li>New Formulation </li></ul><ul><li>New Combination </li></ul><ul><li>AA – AIDS/HIV – Related </li></ul>www.freelivedoctor.com
  45. 45. CLASSIFICATION SYSTEM Type - Review Priorities <ul><li>Already Marketed Drug Product – Duplication (New MFR) </li></ul><ul><li>V – Designated Orphan Drug or E -Subpart E Drug </li></ul><ul><li>New Claim for already Marketed Drug </li></ul><ul><li>F – Pending Outcome of Validity Assessment </li></ul><ul><li>Already Marketed Drug Product – No Approved NDA </li></ul><ul><li>G – Data Validated </li></ul>www.freelivedoctor.com