Drug development process and regulatory submissions


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4. IND
5. NDA
7. Conclusion &

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Drug development process and regulatory submissions

  1. 1. By Suyog Pratap Sulake M.Pharm (Sem-I) Under the Guidance of Dr. N.H. Aloorkar (M.Pharm Ph.D) (Head of Department of Pharmaceutics) Satara College of Pharmacy,Satara. “DRUG DEVELOPMENT PROCESS AND REGULATORY SUBMISSIONS” A SEMINAR ON
  2. 2. A) Pre- Drug discovery • Understanding the disease : to discover underlying cause • Target identification : e.g Protein, genes • Target validation : to confirm its role. B)Drug discovery • Finding a lead : Nature, Denovo, Highthroughput Screening • Early safety tests : ADME/Tox properties • Lead optimization : to optimze lead properties viz. toxicity, potency,etc C) Post- drug discovery • Pre- Clinical testing :To assess the safety of drug (animals) • IND (Investigational New Drug Application) • Clinical trials : conducted in 3 Phases, Safety and efficay. • NDA (New Drug application) • Post marketing Surveillance: Expanded safety, PV, Rare side effects.
  3. 3. 2. DEFINITIONS i) Sponsor: individual, company, institution or an organization, responsible for initiation, management and financing of clinical trials. ii) Innovator Drug: drugs with patents on their chemical formulations or production process.
  4. 4. Laws, Regulations, Policies and Procedures 21CFR Part 312 Investigational New Drug Application 21CFR Part 314 INDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval) 21CFR Part 50 Protection of Human Subjects
  5. 5. IND Review Process
  6. 6. 5. NEW DRUG APPLICATION Submitted when: • clinical testing has been completed • final manufacturing processes and procedures are in place • and the company has ready other required information The Drug and/or the formulation cannot be marketed until the FDA has approved an NDA.
  7. 7. Goals of the NDA To assess whether: • the drug is safe and effective (benefits of the drug outweigh the risks) • the drug’s proposed labeling (package insert) are appropriate • the methods used in manufacturing (& controls) the drug are adequate to preserve the drug’s identity, strength, quality, and purity
  8. 8. Classification of drugs in NDA 1) New Molecular Entity 2) New Salt of Previously Approved Drug (not a new molecular entity) 3) New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) 4) New Combination of Two or More Drugs 5) Already Marketed Drug Product - Duplication (i.e., new manufacturer) 6) New Indication (claim) for Already Marketed Drug 7) Already Marketed Drug Product - No Previously Approved NDA
  9. 9. Laws, Regulations, Policies and Procedures: 21 CFR Part 314 Applications for FDA Approval to Market a New Drug or an Antibiotic Drug.
  10. 10. NDA Content and Format: A) SUMMARY B) THE SAFETY UPDATE REPORTS C) CHEMISTRY, MANUFACTURING AND CONTROL An overview of the drug substance and drug product. • Drug substance: Description including physical and chemical characteristics and stability • Drug product: Composition and type of dosage form, manufacture, specifications and analytical methods, container/closure system, stability,
  11. 11. D) NON CLINICAL PHARMACOLOGY AND TOXICOLOGY Toxicological effects of drugs on reproduction and the developing fetus,ADME animal experiments of the drugs E) HUMAN PHARMACOKINETICS AND BIOAVAILABILTY F) MICROBIOLOGY Applicable to anti-infective and to antiviral drugs. G) CLINICAL DATA
  12. 12. H) STATISTICS I) LABELING • Critical part of the NDA , • Sponsors often "push the envelope”—by wording the indications for the drug as widely as possible, and by downplaying the importance of the drug’s side effects—in their proposed labeling, and negotiations to finalize the labeling often occur when the NDA has been reviewed and deemed "approvable” by the Agency
  13. 13. J) CASE REPORT FORMS ANDTABULATIONS The sponsor must submit case study report form for every clinical trial patient who died or withdrew from the study because of an adverse event. K) PATENT INFORMATION Patent related information that covers the drug substance, formulation, or method of use. Upon approval of the NDA, this information is published in the FDA’s Orange Book serves as a guide to firms wishing to develop generic copies of the innovator’s product.
  14. 14. L) DRUG SAMPLES Submitted upon the FDA’s request to the District Laboratory assigned to test them. GENERAL REQUIREMENTS FOR FILING AN NDA: Submitted in two copies : i)An Archival copy (permanent record ) ii)A Review copy Both are submitted in hard copy, the regulations permit an applicant to submit the archival copy as microfiche.
  15. 15. NDA REGULATIONS ReviewTime Frames (21 CFR 314.100): • 180-day period is called the ‘review-clock’ •The FDA will review and issue an approval, approvable, or not approvable letter. •The time period may be extended by mutual agreement between the FDA and the applicant.
  16. 16. FilingTime Frames (21 CFR 314.101): •Within 60 days after the receipt of an application, FDA decides whether the application may be filed or not. • If FDA files the application, the applicant will be notified in written. If FDA refuses to file the application, the sponsor will be given the opportunity to meet with FDA to discuss the reasons why the application is not file able.
  17. 17. Computer assisted NDA: Concept: It is designed to shorten FDA review time by submitting data to FDA in a form ready for manipulation by a computer. Importance is given on the clinical sections of the NDA, as they require the maximum time to review by FDA.
  19. 19. 6 ABBREVIATED NEW DRUG APPLLICATION (ANDA) Submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, for review and ultimate approval of a generic drug product. Generic Drug product : comparable to an innovator drug • in dosage form, • strength, • route of administration, • quality, • performance characteristics and • intended use.
  20. 20. Why Abbreviated ? because it is not necessary to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, applicant must demonstrate that their product is bioequivalent . E.g. time taken by the generic drug to reach the bloodstream healthy volunteers is measured and compared with the Innovator drug
  21. 21. Laws, Regulations, Policies and Procedures 21 CFR Part 314 Applications for FDA Approval to Market a New Drug or and Antibiotic Drug. 21CFR Part 320 Bioavailability and Bioequivalence Requirements.
  22. 22. THE HATCH- WAXMAN ACT Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and `PatentTerm Restoration Act of 1984," also known as the HATCH -WAXMAN ACT.
  23. 23. Concept of PARAGRAPH ITO IV For filing ANDA, generic company must include a patent certification as per section 505(j) (2) (A) (vii) of the Hatch Waxman Act. I. No patent information on the drug product that is the subject of the ANDA has been submitted to FDA II. That such patent has expired III. The date on which such patent expires IV. That such patent is invalid or will not be infringed by the manufacture, use, or sale of the drug product which the ANDA is submitted.
  24. 24. The first three paragraphs (I, II, III) results in no generic drug being sold during the term of the innovator’s patent protection. In case paragraph IV certification generic drugs can be sold during the term of the innovator’s patent protection. Substantially complete ANDA: Only the applicant submitting the first "Substantially complete ANDA” with a paragraph IV certification would be eligible for exclusivity.
  25. 25. According to FDA all ANDA applications containing : Paragraph IV certifications for a particular drug product received by the FDA on the same day will be eligible for exclusivity if no other ANDA with a paragraph IV certification for the drug product had been filed on an earlier day.All such same day applicants would be considered first applicants.
  26. 26. Trigger Period Sometime there is unnecessary delay in entry of generic drug into the market due to: i) delay in approval of ANDA by FDA or ii) some kind of settlement between first generic (first ANDA approver) and innovator.
  27. 27. e.g. first generic tells to innovator that it will not start its 180 days until “x” number of days in return to “Y” number of dollars from innovator. Thus as per rule until first generic finishes 180 day exclusivity period no other generic manufacturer can be granted 180 exclusivity period. As a result innovator and first generic enjoys undue advantage.
  28. 28. To overcome this FDA has introduced "Triggering period” Under this concept the commencement of the 180-day exclusivity period for the first applicant is either the first commercial marketing of the first applicant’s product, or a decision of a court holding the patent invalid, not infringed, or unenforceable, whichever is earlier. If neither of these events occurs in the triggering period then the first generic would lose its eligibility for exclusivity and subsequent generic filers for ANDA would be eligible for immediate approval.
  29. 29. ANDA Review Process
  30. 30. CONCLUSION Regulatory submissions forms a very important part of Drug development process. The extensive review process done by the regulatory bodies, ensures that not only effective but also a safe Drug product reaches the market.
  31. 31. REFERENCES