Investigational Drugs Drug Laws, Drug Approval Process
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<ul><li><p>Investigational DrugsDrug Laws, Drug Approval Process</p></li><li><p>History of Drug Development Regulation in the USImport Drug Act of 1848: passed after it was discovered that US troops in Mexican War were given substandard drugs.Purpose: provide for inspection, detention and destruction or re-export of imported drug shipments that failed to meet US standards</p></li><li><p>History...Pure Food and Drug Act of 1906Required that drugs not be mislabeled or adulterated and they must meet recognized standards for strength and purityMislabeling: identity or composition of drugsSherley Amendment 1912:Prohibited false therapeutic claims for drugs</p></li><li><p>History.Food, Drug and Cosmetic Act 1938After 107 people died after taking sulfanilamide prepared in diethylene glycol (solvent similar to ethylene glycol (antifreeze)Purpose: require safety of drugs when used in accordance with the labeled instructions; be proven through testing before marketingSubmission of NDA to the FDA first established</p></li><li><p>History.Durham-Humphrey Amendment 1951Purpose: divide drugs into 2 categories:OTC (safely self-administered)Rx (potentially dangerous side effects- required medical expert supervision)Required following statement on all Rx labels: Caution: Federal Law prohibits dispensing without a prescription</p></li><li><p>History...Kefauver-Harris Drug Amendment 1962Purpose: 1)Manufacturer has to demonstrate proof of _________and _______ prior to marketing any new drug. 2) manufacturer comply with CGMP (current good manufacturing practices. 3) FDA has to formally approve an NDA before drug is marketed.</p></li><li><p>History...1992 PDUFA (Prescription Drug User Fee Act): Defines time frames for NDA reviews and establishes revenues to fund increased demands on new time frames for approval process.1997 FDAMA (Food and Drug Administration Modernization Act): Allows other technology to facilitate regulatory review process (FAX, Internet etc)</p></li><li><p>History...ICH (International Conference on Harmonization): Cooperation between Japan, Europe, US to develop common guidelines for ensuring quality, safety, and efficacy of drugs between countries.Goal: ensure a method for submission and rapid regulatory approval in approval process and availability world wide</p></li><li><p>Drug Approval ProcessStep 1Pre-Clinical Drug testingIn vitro or animal testingDevelop a pharmacologic profile of the drugDetermine acute toxicity in at least two species of animals Conduct short term toxicity studies (2 weeks- 3 months)</p></li><li><p>Investigational New Drug Application (IND)File IND with the FDAContains chemical information, preclinical data, detailed description of planned clinical trials.Purpose: to get approval to begin clinical trials in humans.It can only be filed after the study sponsor has identified the pharmacological profile of the drug and has results from both acute and short term toxicity studies in animals.</p></li><li><p>FDA Responsibilities for the INDIND will be forwarded to one of nine divisions for review based on therapeutic category of the drugFDA has ____ days after the receipt of the IND to respond to the sponsor.After this 30 days the sponsor can begin clinical trials if no response from FDA w/in 30 days. FDA will respond with a clinical hold w/in 30 days to stop clinical trial initiation.</p></li><li><p>Clinical Trial PhasesPhase 1Purpose: determine basic safety and pharmacologic information.To identify preferred routeTo identify safe dosage rangeTo identify toxicityPharmacokineticsTreat: 20-80 patients over 6 months-1 yearhealthy adult volunteers w/ no pre-existing conditions, or in patients who have exhausted all other options (cancer patients, AIDs patients)use cautious (low) dosages</p></li><li><p>Phases of Clinical TrialsPhase IIPurpose: Evaluate the study drug in subjects who suffer from the disease or condition that the drug is proposed to treat.Evaluate efficacyIdentify group of patients most likely to benefitTreat: 100-200 patients over 2 year duration</p></li><li><p>Phases of Clinical TrialsPhase IIIPurpose: Further define efficacy and safetyNew agent compared to current therapyTrials usually multicenter studiesTreat 600-1000 patientsLast 3+ yearsThese trials serve as basis for ______ for marketing approval</p></li><li><p>New Drug Application (NDA)After phase 3 trials completed, sponsor submits NDA to the FDA requesting approval for marketing.Includes: pre-clinical data, clinical data,2 well designed controlled clinical trials info, manufacturing methods,kinetics, pharmacology, product quality assurance, relevant foreign clinical testing, published reports, proposed package insert for drug.</p></li><li><p>Phase IV (Post Surveillance Studies)Drug is on the market.Purpose: gather more data on safety and efficacy and identify an advantage over other therapiesThese are conducted for the approved indication, but may evaluate:different doseseffects of extended therapydrugs safety in other populations (pregnancy, children, elderly)New indications</p></li><li><p> Drug to Market Approval ProcessInitial synthesis of an agent to approval of NDA = 8-9 years.NDA process = ave. 2 years (2 mo.-7 yrs)Procedures to expedite process for AIDs, Cancer drugs etc.:Emergency Use IND Parallel trackTreatment INDCompassionate IND</p></li><li><p>Emergency Use INDPurpose: allow shipment of drug by sponsor for desperately ill patients prior to the submission of an IND.Can only be used for life threatening diseases where all other options have been exhausted.FDA approval required and must authorizeIRB approval not required</p></li><li><p>Parallel TrackPurpose: increase accessibility of experimental drugs for AIDS patients.Drug becomes available after phase I studies to patients who are ineligible for enrollment via controlled trials and are unable to benefit from current therapies.Drug is still monitored for safety and efficacy while clinical trials going.</p></li><li><p>Treatment INDPurpose: accessibility of experimental drugs for desperately ill patients.Criteria for use:drug must be intended to treat a serious or immediately life threatening disease.No other alternative therapiesDrug is under investigation in CCT (clinical trials)Sponsor must be actively pursuing FDA approval</p></li><li><p>Treatment IND2 categories of treatment IND:life threatening conditions (death likely in months)Tx allowed with drug after phase II but earlier than phase III.serious conditions (disease causes irreversible morbidity- Alzheimers)tougher requirements for safety and efficacytx allowed with drug during phase III or later.</p></li><li><p>Compassionate Use INDIndividual investigator INDallow release of drug for use on a single patient basis.Use this IND to obtain a drug from a foreign country for emergency use in a single patient.Both FDA and IRB approval are required.</p></li><li><p>Expedited Approval ProcessAccelerated Drug Approval ProgramUsed when drug is intended for tx of serious or life threatening condition and no other drug works in same way for condition.Can be approved as early as post-phase II.Needs 2 pivotal phase II studies completed.FDA can put restrictions on marketing and distribution</p></li><li><p>Orphan Drug Act (1983)Provides incentives for manufacturers to develop orphan drugsOrphan drug: Drug used for tx of a rare disease (affecting fewer than 200,000 people in US) or one that will not generate enough revenue to justify the costs of research and development.</p></li><li><p>Orphan Drug Act IncentivesTax incentives: sponsor is eligible to receive 50% tax credit for money spent on R&D Protocol assistance: if drug shown to be used for rare disease, FDA will provide assistance in pre-clinical and clinical trialsGrants and contracts: FDA budget may allot up to $12 million/yr for developing orphan drugsMarketing exclusivity: 1st sponsor of orphan drug is allowed 7 years of marketing exclusivity for that indication.</p></li><li><p>Generic Drug Approval ProcessManufacturer submits an Abbreviated New Drug Application (ANDA) to obtain FDA approval to market the drug.ANDA data is submitted to the Center for Drug Evaluation and Research (CDER).CDER provides the review and approval of a generic drug product.</p></li><li><p>CDER (Center for Drug Evaluation and Research)Approves generic drugs manufactured in the USchecks patent laws before approvalApproves imported drug productsprevents unapproved new drugs or misbranded drugs from entering our country.Issue product certifications to foreign governments-- state that these products are manufactured according to the GMP (good manufacturing practice) bylaws.</p></li><li><p>Generic Drug Manufacturer RequirementsDocument its compliance with GMPProvides full description of facilities used for manufacturing, packaging, labeling, and quality controlDemonstrates bioequivalence to the brand drugProvide a chemistry review to assure it is manuf. in a reproducible manner under controlled conditions</p></li><li><p>Role of the Pharmacist in Investigational Drug ProcessServing on the Institutional Review Board (IRB)- sets up guidelines, reviews financial evaluations, review of proposal to investigateDisseminating communication (preparation of DDS (drug data sheets), protocols for IDPAccountability records of drug usageOrdering, maintaining, returning drug supplies for clinical trialsRandomizing and blinding drugs for trialsReporting adverse eventsPreparing the IND</p></li><li><p>Investigational Drug Procedure (IDP)When reviewing protocol for clinical trial, it should contain:Name and synonyms of study drugChemical structure of study drugMechanism of action of study drugDosage range, route of administrationAnimal toxicologic and pharmacologic infoDosage form and strength to be suppliedPreparation guidelines (stability, compatibility)Storage requirements, toxicities</p></li><li><p>Drug Data Sheet (for use by Pharmacy, Nursing, MDs)Drug name and synonyms, status, chairperson of studyTherapeutic class, mechanism of actionPharmaceutical dataStability and storage dataDose preparation guidelinesUsual dosage range, route of administrationSide effects, toxicitiesEffective datesReferences</p><p>Before the 1800s drug products were not regulated in this country. Available drugs were often inefective, but some were addictive, toxic or even lethal. Doctors were not licensed and anyone could practice medicine. The public was, for the most part, responsbible for using common sense when evaluating which products they would use.The first federal law developed to deal with drug quality and safety was the Import Drug Act of 1848. This law was passed after it was discovered that American troops involved in the Mexican War had been supplied with substandard imported drugs. The act provided for the inspection, detention, and destruction or re-export of imported drug shipments that failed to meet prescribed standards.</p><p>The Pure Food and Drug Act was passed in 1906. This law required that drugs not be mislabeled or adulterated and stated that they must meet recognized standards for strength and purity. Mislabeling in this context only referred to the idenity or composition of drugs (not false therapeutic claims). False therapeutic claims were prohibited with the passing of the Sherley Amendment in 1912.In 1937, the drug sulfanilamide was released. This drug showed promise as an anti-infective agent and was prepared as an oral liquid. The vehicle used for this preparation was diethylene glycol ( a sweet tasting solvent similar to ethylene glycol, which was used as an automobile antifreeze). A total of 107 people died after taking this preparation. Within 1 year of this tragedy, the Food, Drug and Cosmetic Act of 1938 was enacted. This law required that the safety of drugs, when used in accordance with the labeled instructions, be proven through testing before they could be marketed. It was in this law that the submission of an NDA to the FDA was first described. The NDA was required to list the drugs intended uses and provide scientific evidence that the drug was safe. If after 60 days the FAD had not responded to the manufacturer regarding the NDA, the manufacturer was free to proceed with marketing of the product.In 1951, the Durham-Humphrey Amendment was passed. This law divided pharmaceuticals into two distinct classes. 1. Over the counter (OTC) medications that could be safely self-administered. 2. Prescription (Rx) medications that had ptoentially dangerous side effects and therefore required expert medical supervision.This law required the following statement be added to the labels for all prescription medications: Caution: Federal Law prohibits dispensing without a prescription.</p><p>In 1962 another drug tragedy occurred that resulted in additional regulations. In that year, a large number of pregnant women in Western Europe gave birth to children with severe deformities. These deformities were related to the used of the drug thalidomide. Although US consumers were not directly affected by this tragedy (because thalidomide had not been released in the US market), it was a compelling reason for the government to develop stronger laws regarding the testing of new drug products.The Kefauver-Harris Drug Amendment was passed this year. This law specified that the manufacturer had to demonstrate proof of efficacy, as well as safety prior to marketing any new drug. Additionally, this law required that the drug manufacturers operate in conformity with current good manufacturing practices (CGMP). Finally, it stated that the FDA had to formally approve an NDA before the drug could be marketed.The ICH has brought together officials from Europe, the US and Japan to develop common guidelines for ensuring the quality, safety, and efficacy of drugs. The FDA has been very involved in the development of the ICH guidelines. The ultimate goal of these guidelines is to provide pharmaceutical firms a method to ensure simultaneous submission and rapid regulatory approval in the the world. This would minimize duplication of effort, improve efficiency and increase the quality and consitency of medical treatments available to patients worldwide.</p><p>In additon to the regulatory review of investigational drugs by the FDA, research protocols are also reviewed for ethical appropriateness by Institutional Review Boards. The formalized process for protecting human subjects became an issue when the Nazis were conducting human experiementation without the consent of the subjects.Worldwide there have since been put in place many laws and acts to ensure human consent and safety with investigational drugs and clincial trials.The Nuremberg Code states that the voluntary consent of the human subjects is absolutely essential. The Declaration of Helsinki reemphasized the Code in 1964 and 1989. NIH developed policies in 1966 and established the IRB in 1974. Belmont report released in 1978 talks about ethical medical research. In 1981, the Code of Federal Regulations designed to protect human subjects in all federal agencies.The first step in the drug approval process is preclinical testing. This testing is either in vitro or in animals. Before filing an IND (investigational new drug), the sponsor must have developed a pharmacologic profile of the drug, determine its acute toxicity in at least two species of animals and conducted short term toxicity studies (2 weeks to 3 months). </p><p>After the prclinical t...</p></li></ul>
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