Investigational new drug

intoduction, classification, content and format, applications

1. SUBMITTED BY- SANTHOSH KUMAR T S M.PHARM 1 ST YEAR PRESENTATION ON : INVESTIGATIONAL NEW DRUG [IND] KARNATAKA COLLEGE OF PHARMACY BANGALORE FACILITATED TO- Dr. C. SREEDHAR SIR HEAD OF THE DEPARTMENT (PH. ANALYSIS)

2. CONTENTS Introduction Classification Content and format of IND Laws, regulation and policies IND application process

3. Pharmaceuticals may move across state lines during two stages of human use Research prior to “approval” e. g . , New D r u g application – Requires research permit: New Drug Exemption (IND) e.g ., Investigational application Marketing after “approval” – R e q u ires m a r keting per m i t : Application (NDA )

4. Pre-clinical testing When new drugs show promise in lab testing , studies are designed to evaluate them further. These studies in animals are referred to as “pre-clinical studies.”

5. Pre-clinical testing Pre-clinical studies help establish boundaries for safe use of the treatment if/when human studies begin. (Animal Models :- to test drugs & side effects) Many new drugs and treatments are abandoned at this step because they are proven unsafe.

6. Clinical research and development The application to the FDA to request permission to begin human testing is called an Investigational New Drug application , or IND. The IND permits the use of an investigational new drug for the sole purpose of conducting clinical trials.

7. Drug-Discovery, Development & its Approval It takes 12-15 years on an average for an experimental drug to travel from the lab to the patients. Only 5 in 5000 compounds that enter the pre-clinical testing stage, make it to the human-testing stage. One of these 5 tested on people is approved. Discovery/ Pre- C l inic a l Testing Phase I Phase II Phase III FDA Phase IV Years 5 - 6.5 F ile IND at FDA 1.5 2 2.5 File NDA at FDA 1.5- 2 Test Po p ulation Laboratory & Animal Studies 20 to 100 healthy v olunteers 100 to 500 patient v olunteers 1000 to 5000 patient v olunteers Review & Proposal Process Additional Post- Marketing testing required by FDA Purpose Assess safety, biological activity & formulation Dete r mi n e safety & dosage Evaluate effectiveness, look for side- effects Confirm effectiveness monitor adverse effects from long-time use Success Rate 5000 compounds evaluated 5 Enter Trials 1 A ppro v e d

8. Investigational New Drug Application (IND) An Investigation New Drug Application (IND) is a submission to Food & Drug Administration ( FDA) requesting permission to initiate the study of New drug product In many ways, the investigational new drug (IND) application is the result of a successful preclinical development program. The IND is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials (human trials ). During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. The standard for approval is evidence of safety and efficacy The IND exemption is granted for purposes of clinical investigation ( research)

9. Importance of the IND Affirms a body of knowledge about the manufacturing, pharmacology, and toxicology of the drug to support its use in human testing Requires that the clinical investigation(s) be performed in accordance with Good Clinical Practice (GCP) Provides an additional level of protection through FDA oversight

10. There are three IND types : Investigator IND Emergency Use IND Treatment IND There are two IND categories : Commercial ( Ultimate goal is to achieve marketing approval for new product) Research (non-commercial) TYPES Of IND

11. Investigator/Sponsor IND An Investigator IND is submitted by a physician who both initiates and conducts an investigation , and under whose immediate direction the investigational drug is administered or dispensed . A Research IND is to be submitted for proposed study of Unapproved drug Approved product for New indication New patient population Motivation is not necessarily commercial in nature.

12. Emergency Use IND It  allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with  21CFR , Sec. 312.23 or Sec. 312.34 It is also used for patients: who do not meet the criteria of an existing study protocol or if an approved study protocol does not exist. Reserved for life-threatening situations No standard acceptable treatment is available

13. Treatment IND The treatment IND [21 CFR 312.34 and 312.35] is a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments. Experimental drugs showing promise in clinical testing-safety and efficacy . After completion of Phase I and II Used for the treatment of serious or life threatening conditions No alternate treatments available AIDS, Cancer Made available while final clinical testing is completed and reviewed by the FDA Reduce reluctance of people to participate in expanded drug access programs

14. Who can apply for IND???? Applicant (Drug Sponsor) An applicant, or drug sponsor, is the person or entity who assumes responsibility for the marketing of a new drug , including responsibility for compliance with applicable provisions of the Federal Food, Drug and Cosmetic Act and related regulations. • The "sponsor " I s us u al l y A n indi v idu a l, partnership, corporation , G overnment age n c y , manufacturer or scientific institution .

15. The IND application provides FDA with data necessary to decide whether the new drug & the proposed Clinical trial pose a reasonable risk to human subjects participating in the study. The IND application allows the company to initiate & conduct the clinical studies of their new drug Product . The safety of the Clinical trial Subjects is always the primary concern of FDA . When preparing the IND & throughout the Drug development process the primary goal of the Sponsor should be to demonstrate to the FDA that the new drug proposed trial entire clinical development plan described in the IND is designed to minimize the risk to the trial subjects.

16. When do we need an IND? An IND would be required to conduct a Clinical trial if the drug is – A new ch e m ical entity not a pp r ov e d for th e indication under Investigation in the new dosage form. being administered at the new dosage level . In combination with an o ther drug & the combination is not approved .

17. Content and Format of the IND 21 CFR 312.23 All available information impacting on SAFETY ! Animal studies Pharmacology (ADME)( Absorption, Distribution, Metabolism, Elimination ) Toxicology (Lethal Dose, Short, long, genotoxicity etc) Previous clinical experience Foreign and domestic sources Scientific literature

18. Overall plan of study for next year (minimum) Proposed protocols with justification Patient Inclusion & Exclusion criteria Method of patient selection to prevent bias Identification & qualifications of investigators & sub-investigators Assurances of investigator supervision Assurances sponsor monitor Identification of key responsible individuals

19. GENERAL PRINCILPLE OF IND To assure safety and rights of the subject . T o assure S ci e nti f ic quality of investigation the w i l l yield data C a p able of statutory S ta n dards f or marketing meeting a p p r o v al The ce n tral F ocus shou l d b e on general investigational plan & protocol which should be supported by additional information including animal toxicological studies

20. REQUIREMENTS OF AN IND A sponsor shall submit an IND to FDA who intends to conduct a clinical investigation. I n vestiga t i on is no t s u p p o s e d to beg i n wit h o u t p r i o r written authorization of FDA PHASES OF INVESTIGATION Phase 1 -- ADME (20- 80) healthy subjects P h ase 2 – e f fe c ti v e n ess in parti c ular ind i c a ti o n (several hundred patients) Phase 3 – safety andeffectiveness ( 100- 1000) subjects.

21. FORMAT OF INDA Cover sheet (FORM FDA 1571 ) Table of contents Introductory statement and a general investigational plan Investigators brochure Protocols Chemistry , manufacturing and control information Pharmacology and Toxicology information Previous human experience with the investigational drug Other relevant information like no of IND submissions, N umber of copies to be submitted (1 + 2) Protocol amendments, any changes in the protocol.

22. Name, address, telephone of sponsor Identification of phases Commitment not to begin CT until IND approval Commitment by IRB- Form 56 Commitment for conducting CT- accordance with regulations Name, title – Monitor Name, title – person(s) for reviewing Name, Address of CRO, if any Signature of sponsor Cover sheet (FORM FDA 1571)

23. 2. Table of contents C o mprehe n sive l i sting o f conten t s o f I ND application broken in volumes & page number. TOC should include details of - s e ctio n s, appendices, at t a c hmen t s, r ep o r t s & other reference material A well draft e d T OC wi l l facili t a t e the ta s k of review & decrease the review time .

24. 3. GENERAL INVESTIONAL PLAN a brief 3 to 4 pages note on – the investigational product Sponsors’ Investigational plan Goal of the section is to – to provide brief description of the drug layout development plan of the drug

25. 4.Investigators brochure - key document provided to each Investigator & IRB at each of the Clinical site. - includes- ALL ABOUT THE INVESTIGATIONAL DRUG - IB is a living document & must be updated by the Sponsor .

26. 5. Protocols D e s cr i bes how t he Cl i n i cal tri a l would be conducted . It describes – the objective of the study the trial design how subjects would be selected how the trail is to be conducted. - A L L ABOUT T H AT HO W THE S T UDY WOULD BE CONDUCTED ??

27. 6. Chemistry , manufacturing and control information CMC information- su f ficient d et a il o n QUALIT Y , ID E NIT Y , P URI T Y & POTENCY of the drug product. manufactured in conformance with cGMP. CMC section includes the following – Introduction CMC Summary information of Placebo, if any Proposed clinical label categorical exclusion of any environmental assessment

28. 7. Pharmacology and Toxicology information PHARMACOLOGY & TOXICOLOGY DATA – - N on-clinical safety data that sponsor generated to prove that the IP is safe for clinical study. - T he amount & type of data depends on- class of new drug , duration of proposed , clinical trial patient population that will be exposed during the trial .

29. 8. Previous human experience with the investigational drug integrated summary report of any human studies conducted on the investigational drug Relevant to the safety of the investigations to be done – P harma k okinetic studies, P harmaco d ynamic studies observed adverse event profile

30. 9. Other relevant information like number of IND submissions , No of copies to be submitted (1 + 2) AD D I T IONAL INFO R M A TI O N – sp e cial topics drug dependence & abuse potential Radioactive drugs pediatric population & other information OTHER RELEVANT INFORMATION – Information specifically requested by FDA Financial disclosure information from each Investigator & sub Investigator . Drug master File ( DMF ) Reports or journal articles The IND application is always submitted in 1+ 2 format i.e. 1 original & 2 additional copies of each application.

31. Laws, regulations, Policies, Procedures The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under aseptic conditions ; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.

32. Code Of Federal Regulations (CFR) The final regulations published in the Federal Register (daily published record of proposed rules,final rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the The Federal Food, Drug, and Cosmetic Act and related statutes. Section 21 of the CFR contains most regulations pertaining to food and drugs. 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 316 Orphan Drugs 21CFR Part 58 Good Lab Practice for Nonclinical Laboratory [Animal] Studies 21CFR Part 50 Protection of Human Subjects 21CFR Part 56 Institutional Review Boards 21CFR Part 201 Drug Labeling 21CFR Part 54 Financial Disclosure by Clinical Investigators

33. CDER's Manual of Policies and Procedures (MaPPs) (Center for Drug Evaluation and Research ) MaPPS are approved instructions for internal practices and procedures followed by CDER staff to help standardize the investigational new drug review process and other activities .

34. The Investigational New Drug (IND) Process: Drug developers, or sponsors , must submit an Investigational New Drug (IND) application to FDA before beginning clinical research . In the IND application, developers must include : Animal study data and toxicity (side effects that cause great harm) data Manufacturing information Clinical protocols (study plans) for studies to be conducted Data from any prior human research Information about the investigator

35. fda APPLICATION PROCESS IND contains: sufficient Chemistry, Manufacturing, and other Controls pre-clinical safety information describes the proposed human trial (Phase 1 Multi-disciplinary Review Team 30-Day Deadline for Decision Team Decision Yes? “Okay to Proceed” No? Clinical HOLD Communication to sponsor: What work must sponsor do to get HOLD lifted?

36. FDA Review of The INDA Once the IND stamped as received ,it is sent to the review division within CDER. On arrival at the review division , it is critically evaluated by several reviewers of Chemist Biopharmaceutics Medical Stastistics Microbiology Pharmacology /toxicology sections

37. INDA Review Process overview

38. FDA’s IND REVIEW PROCESS Safety Review: Following review of an initial IND submission, CDER has 30 calendar days in which to decide or if a clinical hold is necessary (i.e., if patients would be at an unacceptable risk or if CDER ( Center for Drug Evaluation and Research ) doesn't have the data to make such a determination). Generally , drug review divisions do not contact the sponsor if no concerns arise with drug safety and the proposed clinical trials. If the sponsor hears nothing from CDER, then on day 3 1 after s u b m is s i on o f t h e I N D, t h e st u dy m ay proceed as submitted .

39. Clinical Hold Decision A clinical hold is the mechanism that CDER uses when it does not believe, or cannot confirm, that the study can be conducted without unreasonable risk to the subjects/patients. If this occurs, the Center will contact the sponsor within the 30-day initial review period to stop the clinical trial . CDER may either delay the start of an early-phase trial on the basis of information submitted in the IND, or stop an ongoing study based on a review of newly submitted clinical protocols, safety reports, protocol amendments, or other information. When a clinical hold is issued, a sponsor must address the issue that is the basis of the hold before the order is removed .

40. CLINICAL HOLD a clinical hold can be – - “ comple t e clinical h o l d ” – a d e lay or S u s p ension o f a l l c l i n ical wo r k reque s t ed under IND submission “ partial c linical hold” - a delay or suspension of only part of clinical work e.g. part of protocol.

41. Notify Sponsor Once a clinical hold is placed on a commercial IND, the sponsor will be notified immediately by telephone by the division director . the division is required to send a letter within five working days following the telephone call . The letter should describe the reasons for the clinical hold, and must bear the signature of the division director (or acting division director). The sponsor may then respond to CDER by sending an " IND CLINICAL HOLD RESPONSE " letter to the division. To expedite processing, the letter must be clearly identified as an " IND CLINICAL HOLD RESPONSE" letter.

42. The division then reviews the sponsor's response and decides within 30 days as to whether the hold should be lifted . If the division does not reply to the clinical hold response within 30 calendar days, the division director will telephone the sponsor and discuss what is being done to facilitate completion of the review. If it is decided that the hold will not be lifted, the hold decision is automatically sent to the office director for review .

43. The o f f i ce director mu s t decide cal e nd a r days wh e t her o r not to within 14 sustain the division's decision to maintain the clinical hold . If the decision is made to lift the hold, the division telephones the sponsor, informs them of the decision, and sends a letter confirming that the hold has been lifted. The letter will be sent within 5 working days of the telephone call. However, the trial may begin once the decision has been relayed to the sponsor by telephone.

44. Sponsor Notified of Deficiencies If other deficiencies are found in an IND that the review division determines are not serious ly enough to justify delaying clinical studies, the division may either telephone or forward a DEFICIENCY LETTER to the sponsor . In either case, the division informs the sponsor that it may proceed with the planned clinical trials, but that additional information is necessary to complete or correct the IND file, or that there are issues that need to be addressed prior to a marketing application (NDA) submission .

45. Study Ongoing Once CDER's 30-day initial review period expires, clinical studies can be initiated , unless a clinical hold has been placed.

46. INDA Annual reports Sponsors should submit an annual report that provides the FDA with a brief update on the progress of all investigations included in the IND. It should contain the following: Individual study information. Summary of the study. Listing of any significant foreign marketing developments with the drug e.g. approval in another country.

47. REFERENCES: www.google.in www.slideshare.net