Historical aspects of drug approval process

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how misfortunes and tragedies has created the approval process


  • 1. Historical AspectsofNew Drug Approval ProcessPrepared by:Paresh K BharodiyaExecutiveFormulation DevelopmentJ.B Chemicals and Pharmaceuticals,Panoli, Gujarat, India

2. New drug Approval. Today, the drug review process in the United States isrecognized worldwide as the gold standard. Drugs mustundergo a rigorous evaluation of safety, quality, andeffectiveness before they can be sold. The Center for Drug Evaluation and Research (CDER) is thearm of the FDA that, as its name suggests, evaluates newdrugs before they are sold. This process requires multiple levels of research to makesure that medications are safe and effective before theyare made available to the public. And that takes time andmoney 3. Overview of the drug approval process Drug development can generally be dividedinto phases.1.The Preclinical phase2.Clinical phases 4. subjectsPurposeTimecorseNewdrugspassLaboratory&Animal studyAccess safety &Biological activity1-2 years100 %20-100volunteersSafety &Dosage3-4 years70 % of IND100-300patientsEffectiveness.Side effects4-5years33 %IND1000-3000patientsVerifyeffectiveness.longter6-8 years27 %FileINDFileNDAPreclinicalPhaseClinicalPhasesPhase 1 Phase 2 Phase 3 5. FDA Review and Approval After phase III, the pharmaceutical companyprepares reports on all studies conducted onthe drug and submits the reports to the FDA ina New Drug Application (NDA). The FDA then reviews this information todetermine whether the drug is safe andeffective for its intended use. If the drugpasses this review, it is approved for use. 6. A Historical Perspective of drugregulation and approval At the turn of the 20th century, there were nofederal regulations to protect the public fromdangerous drugs Misfortune, disaster, and tragedy havetriggered most of the advances in drugregulation 7. The First Federal Drug Law The original Pure Food and Drugs Act was passed byCongress in 1906 and signed by President TheodoreRoosevelt. concerns about worthless or even dangerous medicinesled to the enactment of the Food and DrugAdministration Act of 1906. This law1. Required that drugs meet official standards of strengthand purity,2. Defined the terms adulterated and misbranded, and3. Prohibited the shipment for sale of misbranded andadulterated foods, drinks, and drugs 8. There was no requirement that any information besubmitted to the FDA before marketing the law required only that drugs meet standards ofstrength and purity The burden of proof was on the government to showthat a drugs labeling was false and misleading beforeit could be taken off the market.Limitations of the first federal drug law 9. Sherley Amendment in 1912 US v Johnson case The act did not prohibit false therapeutic claims,only false claims about ingredients. Sherley Amendment - 1912 specifically prohibits false claims 10. The Food, Drug, and Cosmetic Act 1938 Revised legislation wasnt passed until 107 peopledied from a poisonous ingredient in ElixirSulfanilamide. The S.E. Massengill Co. of Bristol,Tenn. As a consequence of this event, Congress passed theFederal Food, Drug, and Cosmetic (FD&C) Act of 1938with new provisions 11. 1. manufacturers were required to show that a drug wassafe before it could be marketed.2. Manufacturers had to submit an application to the FDAbefore marketing a drug. If the FDA didnt act on theapplication in a certain time period, the applicationautomatically became approved.3. The 1938 act also eliminated the Sherley Amendment,which called for adequate labeling for safe use4. set safe tolerances for unavoidable poisonoussubstances, and authorized factory inspections This mandate for premarket evidence of a drugs safetyrepresented the birth of the new drug application, orNDA. 12. Durham-Humphrey Amendment, In 1951 Following the 1938 Act, the FDA began to distributepublic notices (known as trade correspondences) to theindustry regarding the labeling and dispensing of drugs It was in these public notices that the FDA firstdistinguished medications that should be available onlyby prescription At this point the decision about which drugs shouldreceive a caution label was largely at the discretion of themanufacturer. In 1951, the Durham-Humphrey Amendment set forththe basis for distinguishing between prescription andnonprescription drugs. 13. The DH amendments gave FDA theresponsibility to clarify which drugs are: Habit-forming, Not safe except under a practitioners supervision, and, Drugs limited to prescription sale as part of the approvalof a New Drug Application. Required Caution: Federal Law Prohibits DispensingWithout a Prescription. (Today Rx Only.) Prescription exemption (for manufacturers) Pharmacists must label prior to dispensing. 14. The Kefauver-Harris Drug Amendments In 1961, an Australian obstetrician, William McBride, reported anincrease of fetal malformations in association with the hypnotic drugthalidomide. Although thalidomidewas heavily marketed inWestern Europe, approvalof this drug was delayedby the FDA in the UnitedStates and never made it tomarket In October 1962, Congresspassed the Kefauver-HarrisDrug Amendments to theFederal FD&C Act 15. As per The Kefauver-Harris Drug Amendments1. Before marketing a drug, firms now had to prove notonly safety, but also provide substantial evidence ofeffectiveness for the products intended use2. Kefauver-Harris Drug Amendments also asked theSecretary to establish rules of investigation of new drugs,including a requirement for the informed consent ofstudy subjects.3. The amendments also formalized good manufacturingpractices,4. required that adverse events be reported,5. and transferred the regulation of prescription drugadvertising from the Federal Trade Commission to theFDA. 16. In 1981,1.formal standards for the Protection ofHuman Subjects and2. Institutional Review Boards (IRBs) werestrengthened. The IRBs are panels of scientists and non-scientists in hospitals and research institutionswho ensure the safety and well-being ofhuman subjects involved in research 17. Anti-Tampering Regulations 1982 After seven people in Chicago died fromswallowing Tylenol capsules laced withcyanide, the FDA issued Tamper-ResistantPackaging Requirements in 1982. The FederalAnti-Tampering Act, passed in 1983, makes ita crime to tamper with packaged consumerproducts. 18. 1983 - Orphan Drug Act the Orphan Drug Act (ODA) was passed in 1983 It allowed the FDA to encourage research anddevelopment of drugs needed to treat rare diseases The ODA created financial incentives, including taxcredits for the costs of clinical research and seven years of marketing exclusivity for the firstsponsor of an orphan product who receives FDAapproval for a particular indication Examples of rare diseases that can now be treatedwith orphan medications include sickle cell anemia,cystic fibrosis, and T-cell lymphoma. 19. Encouraging Generic Drugs1984 - Drug Price Competitionand Patent Term Restoration Act Expanded the number of drugs for which anabbreviated new drug application (ANDA) could besubmitted. Generic drug companies dont have to repeat theexpensive clinical trials that brand companies havealready conducted to show safety and effectiveness But they must perform tests and show the FDA thattheir drugs are equivalent to the brand name in termsof therapeutic effect. 20. Drugs for Life-Threatening Illnesses In 1987, partially in response to the humanimmunodeficiency virus (HIV) epidemic, new regulationswere developed to accelerate approval for high-prioritymedications. Another example of improving access to treatment is"accelerated approval," which was formalized in 1992 This type of drug approval is based on an encouragingeffect such as tumor shrinkage, before there is actualevidence of improved survival or other clinical benefit, The FDA approves a drug under accelerated approval onthe condition that the drug manufacturer verify theactualclinicalbenefit. 21. The Prescription Drug User Fee Act The Prescription Drug User Fee Act (PDUFA)was passed in 1992, and mandated that drugcompanies pay user fees so the FDA couldadd more resources and speed up drug reviewtimes, without compromising standards. 22. The Food and Drug ModernizationAct of 1997 In 1997, the PDUFA was renewed under theFood and Drug Administration ModernizationAct and then renewed again in 2002 for fivemore years In addition, the Food and Drug ModernizationAct (FDAMA) supported accelerated approvaland gave an extra period (six months) ofmarketing exclusivity to manufacturers thatcarried out studies in children. 23. Expanding Demographicsin Clinical Trials In the 1980s and 1990s, several FDA guidances andrules drew attention to the need to includerepresentative populations in clinical trials The inclusion of such populations has helped expertsanalyze results for possible differences in drugresponse among demographic subsets. Here are some key changes that have helpedexpand demographic evaluation in drug research: 24. 1. In 1989, the FDA issued guidelines asking manufacturers to determinewhether a drug is likely to have significant use in older people, and toinclude older patients in clinical studies.2. In 1993, the FDA issued the Gender Guideline, which called forassessments of medication responses in both genders3. In 1998, the FDA required that a marketing application analyze data onsafety and effectiveness by age, gender, and race. This is known as theDemographic Rule.4. In 1998, the FDA promulgated the Pediatric Rule, a regulation thatrequired manufacturers of selected drugs to conduct studies to assesstheir safety and efficacy in children.5. In 2002, the Best Pharmaceuticals for Children Act was passed to improvethe safety and effectiveness of medicines for children.6. In 2003, the FDA was given clear authority under the Pediatric ResearchEquity Act to require drug sponsors to conduct clinical research intopediatric applications for new drugs. 25. References1. US Food and drug administration.Historiesof Product Regulation , available at http:/www.fda.gov . Accessed 12 may 20102. Susan Berg,From test tube to medicinechest, the approval process for new drug,Asthma magazine, pg 243. Martin S. Lipsky, MD, and Lisa K. Sharp,From Idea to Market: The Drug ApprovalProcess. JABFP SeptemberOctober 2001Vol. 14 No. 5, pg-362