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  1. Premarket Testing and Validation Charles Lankford PharmaSys, Inc. 216 Towne Village Drive Cary, NC. 27513

  2. Scientific, regulatory, and public health agency oversees items accounting for 25 cents of every dollar spent by consumers. Jurisdiction most food products (other than meat and poultry) human and animal drugs therapeutic agents of biological origin medical devices radiation-emitting products for consumer, medical, and occupational use cosmetics animal feed U S. Food and Drug Administration

  3. History of the FDA • single chemist U.S. Department of Agriculture in 1862 • Regulatory functions added in1906 • The Bureau of Chemistry's name changed to the Food, Drug, and Insecticide Administration in July 1927, • nonregulatory research functions of the bureau were transferred elsewhere

  4. Events Leading to Formation of FDA 1905 - Samuel Hopkins Adams :11 articles The Great American Fraud in Collier's Weekly. • analyzed the contents of some of the country's most popular medicines. • argued that many of the companies producing these medicines were making false claims about their products. • some cases, these medicines were actually damaging the health of those people using them 1906 - Upton Sinclair: The Jungle • fictional portrait of life and death of working class immigrates in turn-of-the-century Chicago • filled with page after page of nauseating detail he had researched about the meat-packing industry Public demanded sweeping reforms in the food industry 30 June 1906 President Roosevelt signed the Food and Drugs Act, known simply as the Wiley Act.

  5. 1906 Food and Drugs Act • Prohibited interstate transport of unlawful food and drugs under penalty of seizure of the questionable products and/or prosecution of the responsible parties • Basis on regulation of product labeling rather than pre-market approval • Drugs, defined in accordance with the standards of strength, quality, and purity in the United States Pharmacopoeia and the National Formulary, could not be sold in any other condition unless the specific variations from the applicable standards were plainly stated on the label

  6. 1906 Food and Drugs Act • Foods were not defined according to analogous standards, but the law prohibited the addition of any ingredients that would substitute for the food, conceal damage, pose a health hazard, or constitute a filthy or decomposed substance • If the manufacturer opted to list the weight or measure of a food, this had to be done accurately • The food or drug label could not be false or misleading in any particular, and the presence and amount of eleven dangerous ingredients, including alcohol, heroin, and cocaine, had to be listed

  7. 1911 • Supreme Court ruled that the law did not--apply to false therapeutic claims.

  8. The 1938 Food, Drug, and Cosmetic Act • A Tennessee drug company marketed a form of the new sulfa wonder drug, Sulfanilamide, a drug used to treat streptococcal infections, that would appeal to pediatric patients, Elixir Sulfanilamide. • 100 people in 15 states died, many were children • Dissolved in diethylene glycol, a highly toxic chemical analogue of antifreeze • Not tested for toxicity… food and drugs law did not require safety studies for new drugs

  9. The 1938 Food, Drug, and Cosmetic Act • legally mandated quality and identity standards for foods • prohibition of false therapeutic claims for drugs • coverage of cosmetics and medical devices • clarification of the FDA's right to conduct factory inspections • control of product advertising, among other items

  10. Kefauver-Harris Amendments • Thalidomide, chiefly sold and prescribed during the late 1950s and 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep • Drug stunted the growth of fetal arms and legs, 10,000 babies affected, never approved in US • Now approved for the treatment of MULTIPLE MYELOMA and ERYTHEMA NODOSUM LEPROSUM • Resulted in Kefauver-Harris Amendments

  11. Kefauver-Harris Amendments • mandates efficacy & safety before a drug could be marketed • requires FDA to assess the efficacy of all drugs introduced since 1938, • institutes stricter agency control over drug trials (including a requirement that patients involved must give their informed consent) • transferred from the Federal Trade Commission to the FDA regulation of prescription drug advertising, • established good manufacturing practices by the drug industry • granted the FDA greater powers to access company production and control records to verify those practices

  12. Drug or Device Deemed Adulterated if • If it consists in whole or in part of any filthy, putrid, or decomposed substance;

  13. Drug or Device Deemed Adulterated if • prepared, packed, or held under insanitary conditions • do not conform to or are not operated or administered in conformity with current good manufacturing practice • are not operated or administered in conformity with the positron emission tomography compounding standards and the official monographs of the United States Pharmacopoeia

  14. Drug or Device Deemed Adulterated if • composed, in whole or in part, of any poisonous or deleterious substance • a color additive which is unsafe • animal feed bearing or containing a new animal drug, and such animal feed is unsafe

  15. Drug or Device Deemed Adulterated if • strength differs from, or its quality or purity falls below, the standards • strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium

  16. Drug or Device Deemed Adulterated if • mixed or packed therewith so as to reduce its quality or strength or • substituted wholly or in part

  17. PART 211 – DRUG GMP • A--General Provisions • B--Organization and Personnel • C--Buildings and Facilities • D--Equipment • E--Control of Components and Drug Product Containers and Closures • F--Production and Process Controls • G--Packaging and Labeling Control • H--Holding and Distribution • I--Laboratory Controls • Subpart J--Records and Reports • K--Returned and Salvaged Drug Products

  18. Part 820 – Device QSR • A--General Provisions • B--Quality System Requirements • C--Design Controls • D--Document Controls • E--Purchasing Controls • F--Identification and Traceability • G--Production and Process Controls • H--Acceptance Activities

  19. Part 820 – Device QSR • I--Nonconforming Product • J--Corrective and Preventive Action • K--Labeling and Packaging Control • K--Labeling and Packaging Control • L--Handling, Storage, Distribution, and Installation • M—Records • N—Servicing • O--Statistical Techniques

  20. FDA Documentation • Regulation – Codified and Law • Preamble – Dialog of FDA’s thinking when reg was codified • Guidance - FDA’s current thinking about reg

  21. GCP and Clinical Trials • Electronic Records; Electronic Signatures (21 CFR Part 11) • Human Subject Protection (Informed Consent) (21 CFR Part 50) • Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products (Interim Rule) (21 CFR Part 50, subpart D) • Financial Disclosure by Clinical Investigators (21 CFR Part 54) • Institutional Review Boards (21 CFR Part 56)

  22. GCP and Clinical Trials • Forms 1571 (Investigational New Drug Application) and 1572 (Statement of Investigator) • Applications for FDA Approval to Market a New Drug (21 CFR Part 314) • Applications for FDA Approval of a Biologic License (21 CFR Part 601) • Investigational Device Exemptions (21 CFR Part 812) • Premarket Approval of Medical Devices (21 CFR Part 814

  23. Drug Approval Process

  24. Drug Development and Approval Process • U.S. system most rigorous in the world • On average, it costs a company $360 million to get one new medicine from the laboratory to the pharmacist's shelf • It takes 12 years on average for an experimental drug to travel from lab to medicine chest. • Only five in 5,000 compounds that enter preclinical testing make it to human testing. • One of these five tested in people is approved.

  25. Biological Screening and Pharmacological Testing • Studies to explore the pharmacological activity and therapeutic potential of compounds. • animals, isolated cell cultures and tissues, enzymes and cloned receptor sites as well as computer models.

  26. Pharmaceutical Dosage Formulation and Stability Testing • The process of turning an active compound into a form and strength suitable for human use .

  27. Toxicology and Safety Testing • Tests to determine the potential risk a compound poses to man and the environment • These studies involve the use of animals, tissue cultures, and other test systems to examine the relationship between factors such as dose level, frequency of administration, and duration of exposure to both the short- and long-term survival of living organisms. • LD50

  28. Regulatory Review: Investigational New Drug (IND) Application • An application filed with the U.S. FDA prior to human testing. • The IND application is a compilation of all known information about the compound. It also includes a description of the clinical research plan for the product and the specific protocol for phase I study. • Unless the FDA says no, the IND is automatically approved after 30 days and clinical tests can begin.

  29. Phase I Clinical Evaluation • The first testing of a new compound in human subjects, for the purpose of establishing the tolerance of healthy human subjects at different doses • defining its pharmacologic effects at anticipated therapeutic levels • studying its absorption, distribution, metabolism, and excretion patterns in humans

  30. Phase II Clinical Evaluation • Controlled clinical trials of a compound's potential usefulness and short term risks. • A relatively small number of patients, usually no more than several hundred subjects, enrolled in phase II studies.

  31. Phase III Clinical Evaluation • Controlled and uncontrolled clinical trials of a drug's safety and effectiveness in hospital and outpatient settings. • gather precise information on the drug's effectiveness • determine adverse effects • identify the best way of administering and using • phase III studies can involve several hundred to several thousand subjects.

  32. Institutional Review Boards • used to ensure the rights and welfare of people participating in clinical trials both before and during their trial participation. • make sure that participants are fully informed and have given their written consent before studies ever begin. • monitored by the FDA to protect and ensure the safety of participants in medical research. • An IRB must be composed of no less than five experts and lay people with varying backgrounds to ensure a complete and adequate review of activities commonly conducted by research institutions. • In addition to possessing the professional competence needed to review specific activities, an IRB must be able to ascertain the acceptability of applications and proposals in terms of institutional commitments and regulations, applicable law, standards of professional conduct and practice, and community attitudes. • Therefore, IRBs must be composed of people whose concerns are in relevant areas.

  33. Bioavailability Studies • The use of healthy volunteers to document the rate of absorption and excretion from the body of a compound's active ingredients. • Companies conduct bioavailability studies both at the beginning of human testing and just prior to marketing to show that the formulation used to demonstrate safety and efficacy in clinical trials is equivalent to the product that will be distributed for sale. • Companies also conduct bioavailability studies on marketed products whenever they change the method used to administer the drug (e.g., from injection or oral dose form), the composition of the drug, the concentration of the active ingredient, or the manufacturing process used to produce the drug.

  34. Process Development for Manufacturing and Quality Control (CMC) • Engineering and manufacturing design activities to establish a company's capacity to produce a product in large volume and development of procedures to ensure chemical stability, batch-to-batch uniformity, and overall product quality.

  35. Regulatory Review: New Drug Application (NDA) • An application to the FDA for approval to market a new drug. All information about the drug gathered during the drug discovery and development process is assembled in the NDA. • During the review period, the FDA may ask the company for additional information about the product or seek clarification of the data contained in the application.

  36. Postapproval Research • Adverse events must be reported • Additional indications

  37. Basic Regulatory Requirements for Medical Devices • Premarket Notification 510(k), unless exempt, or Premarket Approval (PMA) • Establishment registration on form FDA-2891 • Medical Device Listing on form FDA-2892 • Quality System (QS) regulation • Labeling requirements • Medical Device Reporting (MDR)

  38. Premarket Notification 510(k) - 21 CFR Part 807 Subpart E • If device requires the submission, • can not commercially distribute until you receive a letter of substantial equivalence from FDA authorizing you to do so.

  39. Premarket Notification 510(k) - 21 CFR Part 807 Subpart E • A 510(k) must demonstrate that the device is substantially equivalent to one legally in commercial distribution • Application fee applies to Traditional, Abbreviated, and Special 510(k)s. Small businesses may pay smaller fee.

  40. Premarket Notification 510(k) - 21 CFR Part 807 Subpart E • Most Class I devices and some Class II devices are exempt • A list of exempt devices is located at:

  41. Premarket Approval (PMA) - 21 CFR Part 814 • Product requiring PMAs • Class III devices, high risk devices, pose a significant risk of illness or injury • devices found not substantially equivalent to Class I and II predicate

  42. Premarket Approval (PMA) - 21 CFR Part 814 • PMA process is more involved • includes the submission of clinical data to support claims made for the device. • The PMA is an actual approval of the device by FDA. • Medical device user fees apply to original PMAs and certain types of PMA supplements.

  43. Investigational Device Exemption (IDE) - 21CFR Part 812 • Clinical studies with devices of significant risk must be approved by FDA and by an Institutional Review Board (IRB) before the study can begin. • Studies with devices of nonsignificant risk must be approved by the IRB only

  44. Establishment Registration form FDA-2891 - 21 CFR Part 807 • Manufacturers must register their establishments with the FDA • Once a year, FDA sends the registration form FDA-2891(a) to all registered firms to be verified, corrected, and returned by the firm as a yearly registration • foreign manufacturers must also designate a U.S. Agent

  45. Medical Device Listing form FDA-2892 - 21CFR Part 807 • All medical devices are required to be listed with the • Firms that are required to list their devices are those that: • manufacture, • repackage and relabel, • develop specifications, • reprocess single-use devices, • remanufacture • manufacture accessories and components sold directly to the end user

  46. Labeling - 21 CFR Part 801 • Labeling includes labels on the device as well as descriptive and informational literature that accompanies the device. Labeling requirements can be accessed on the web at:

  47. Medical Device Reporting - 21 CFR Part 803 • Incidents in which a device may have caused or contributed to a death or serious injury must to be reported to FDA under the Medical Device Reporting program. • The MDR regulation is a mechanism for FDA and manufacturers to identify and monitor significant adverse events involving medical devices. The goals of the regulation are to detect and correct problems in a timely manner.

  48. Medical Device Classification • classifications for approximately 1,700 different generic types of devices • three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device.

  49. Device Class and Regulatory Controls • Class I General Controls • With Exemptions • Without Exemptions • Class II General Controls and Special Controls • With Exemptions • Without Exemptions • Class III General Controls and Premarket Approval

  50. Class I Devices • Class I devices are subject to the least regulatory control. • They present minimal potential for harm to the user and are often simpler in design than Class II or Class III devices. • Most Class I devices are exempt from the premarket notification and/or good manufacturing practices regulation. Information on Class I exempt devices is located under the heading What are Class I/II Exemptions?.