1. 1 IND Applications for Academic Clinical Investigations John Marler, MD US Food and Drug Administration 10903 New Hampshire Avenue White Oak, MD 20903

2. Disclaimer The views expressed in this presentation are those of the speaker, and are not an official statement of the Food and Drug Administration 2

3. Disclaimer I work for the FDA Center for Drugs and cannot claim to have first-hand knowledge of requirements for devices. I will not be talking about Investigational Device Exemptions (IDEs). My purpose is to minimize the amount of time you spend writing an IND application or request for exemption and more importantly, minimize any delays in getting your clinical investigation started. I will discuss some common problems and avoid using “regulatory” language. Nothing I say or put on these slides supersedes FDA laws or regulations. 3

4. 4 Main Concepts Having an IND is almost all about safety Many studies don’t have to be performed under IND regulations. An IND usually includes only a single trial at the beginning but you can amend the application to add additional studies later for the same drug and indication. You don’t need a new IND for each phase of development. With an IND in effect you have significant responsibilities

5. Who are the FDA Regulatory project manager Clinical reviewers Nonclinical pharmacology and toxicology reviewers who review animal data Clinical pharmacology reviewers who look at pharmacokinetics, pharmacodynamics, and drug interactions in humans. Statistical reviewers Chemistry manufacturing and quality control 5

6. Who is Your FDA What you need to know –In dealing with DNP, your project manager is your point of contact –The project manager can contact the right people, obtain the right answers, and provide the right assistance for any issues that arise –There is NO PROBLEM with you initiating contact with your project manager –Put this person in your list of contacts. 6

7. Purpose of the IND Process #1 Assure the safety and rights of subjects in all phases of development #2 Assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety in Phases 2 and 3. 7

8. Determining the First Step Determine if you have an exempt drug development plan If you do, then you are done. If not exempt (or you don’t know), then apply for an IND unless you don’t have adequate supporting clinical data or animal safety data. In that case you may request a pre-IND meeting to discuss plans for evaluating safety in animals. 8

9. Exemption from IND Requirements The study results won’t be used to support a new label or change of label. The study results won’t support changes in advertising of a marketed drug The study does not create significant new risks of an approved drug because of a new administration route, dosage, or patient population. Requirements for IRB approval are met. The study complies with requirements concerning the promotion and sale of investigational drugs. Not intended to invoke exception from informed consent 9

10. Exemption The decision about whether or not an IND is needed can be made by the investigator. We do understand that IRBs and research sponsors ask investigators to obtain a written opinion from the FDA about whether or not an IND is required. To avoid unnecessary delays we encourage you to submit a letter with some readily available attachments. 10

11. Contents of Request for Exemption A cover letter –Study overview including plan for safety monitoring –Drug name, dosage forms, whether you will make any modifications to the approved formulations, dose, frequency and duration of dose for study drug, and any comparator drugs including a placebo The protocol for the study A copy of the package insert for the drug Forms 1571, 1572, and 3674. Your CV 11

12. Problems Getting Exemptions The description of the study leaves out important information. Protocol doesn’t exclude patients with contraindications listed on the label. Protocol doesn’t require recommended safety monitoring described in the drug label Drug isn’t really an approved drug with a label and prescribing information. For instance, a dietary supplement is not an approved drug. An investigational device is used for selecting patients, administering drug, or is part of the treatment. 12

13. IND Application Content Cover letter 1-Cover sheet (FDA-1571 Form) 2-Table of Contents 3-Introductory statement and investigational plan 4-Investigator’s brochure 5-Protocol 6-Chemistry, manufacturing, and control information. 7-Pharmacology and toxicology information 8-Previous human experience 9-Copies of references and additional information 13

14. 3 Components of Drug Safety Drug product quality safety Animal safety Human safety 14

15. Drug Quality FDA-approved drug –You can usually assume that the drug meets quality standards Investigational drug supplied by another IND sponsor –You can request the IND sponsor to give you a letter that allows you to reference relevant information in the other IND. Investigational drug you make yourself –Must document adherence to FDA quality standards—a complex process beyond the scope of this presentation. Dietary supplement –Subject of a different set of regulations. –A dietary supplement is not an approved drug and does not have an approved safe dose. 15

16. Nonclinical Safety Off the shelf FDA-approved drug –You can usually assume that the drug product meets animal toxicology standards for maximum approved dose and length of exposure on the label. Not necessarily so for higher doses, longer duration of dosing, or a different route of administration. Investigational drug supplied by another sponsor –You can get a letter allowing reference to another IND. Must support the dose you are using. Investigational drug you make yourself –Generally must provide full set of nonclinical pharmacology and toxicology data using you own product. Dietary supplement –No nonclinical toxicology can be assumed. 16

17. Nonclinical Safety If you are using an approved drug or an investigational drug at a dose higher than that tested in existing pharmacologic and toxicological data, then you may need to perform these nonclinical studies. This takes time and usually significant resources. Another example: if you are using drugs in combination with standard treatment, you may be asked for evidence that there is not a drug interaction. –For example, you may be asked to show that a neuroprotectant drug used to treat acute stroke does not interfere with the action of TPA. 17

18. Clinical Safety Off the shelf FDA-approved drug –We usually consider a drug product safe for an investigational use if the dose and condition being treated are described in the label. For higher doses, a different route of administration, or a different indication, there may be published studies, case reports, and series to support the safety of a higher dose. Investigational drug supplied by another sponsor –You can get a letter allowing reference to another IND. Must support the dose you are using and apply to the population you are treating. Investigational drug you make or buy yourself –Published medical literature that shows the safety of the dose you are testing. 18

19. Clinical Safety For a higher dose, different route of administration, dietary supplement, or other use not described on an approved label you may include (as evidence of clinical safety): A summary of previous human experience with the use you propose described in the medical literature at doses as high as you propose for your investigation. It is especially helpful to include a table with numbered rows for each reference and columns showing dose, duration of treatment, number treated, patient population, adverse events, outcomes, author, and reference citation. Include electronic copies of the references if possible. 19

20. Introductory Statement Section 1 of 4 –Name of the drug (active ingredients) –Drug pharmacological class –The structural formula –Formulation (all ingredients) –Dosages (dose, frequency, duration) –The route of administration 20

21. Introductory Statement Section 2 of 4 –Summarize previous human experience All safety experience in humans Experience in humans at maximum dose, route, and duration in protocol If dose is not approved, but there are reports of experience using proposed dose or higher provide a table that includes pertinent information from each published report. 21

22. Introductory Statement Section 3 of 4 –Indicate whether drug has ever been withdrawn from use in the US or another country and if so, describe the circumstances. 22

23. Introductory Statement Section 4 of 4 Describe the overall plan for investigating the drug in the following year. –Rationale for using the drug for the chosen indication –The proposed use: disease to be treated and treatment objective –General approach being followed to evaluate the drug –The types of trials planned for the first year. –Estimated (maximum) number of subjects exposed to drug –Maximum dose –Any risks of particular severity or seriousness on the basis of animal toxicology studies or prior human experience. Explain how protocol(s) will minimize these risks. [Should correlate with safety plan in the protocol] 23

24. Investigator’s Brochure In general, the investigator’s brochure informs physicians using the drug in an investigation about what is known about the drug safety. It may also explain the rationale for using the drug to treat the disease targeted in the clinical investigations. 24

25. Investigator’s Brochure Brief description of the active drug substance, the components formulated with the drug. Summary of pharmacological and toxicological effects of the drug in animals.* Summary of pharmacokinetics and biological disposition of the drug in animals.* Summary of safety and effectiveness in humans A description of the possible risks and side effects.* * Summary of subset of data relevant to the dose and treatment duration you are investigating. 25

26. Investigator’s Brochure If the drug is already FDA-approved, the approved drug label may provide sufficient information to allow it to serve as the investigator’s brochure. You may need to include additional information if the dose, route of administration, or duration of treatment is not within boundaries for use set in the FDA-approved prescribing information. If the investigation is multi-center then a complete investigator’s brochure that places the information in the context of the clinical investigation being performed may be necessary to adequately inform investigators. 26

27. Protocol ≠ Grant Application A protocol is part of GCP, good clinical practice. It serves as the primary source document for the trial methodology and documents study drug, dosage, and procedures to ensure and report patient safety. Our experience is that material from grant applications does not provide sufficient data. 27

28. Terminology FDA “approves” drugs and “licenses” biologicals for specific uses at specific doses. It does not “approve” INDs or protocols. Protocols are “allowed to proceed” or else placed “on clinical hold.” You can withdraw an IND application INDs can be “in effect” Clinical investigations can be “exempt” from premarketing approval requirements, but exemption does not imply approval. 28

29. Results Study is exempt IND allowed to proceed IND placed on clinical hold IND withdrawn Pre-IND meeting scheduled 29

30. After the IND is in effect Read every word of any letter from the FDA. Follow the instructions. Read the 1571, 1572, and 3674 forms. Know what is expected of you. If someone dies or gets sick because of the drug you are testing and you didn’t anticipate this event, then report it to us immediately. (There are more reporting responsibilities) Notify us when you make any changes to the protocol or add or subtract investigators (Form 1572). Send us yearly reports of progress. Keep the research project manager contact information. 30

31. References Guidances for IND applications http://www.fda.gov/Drugs/Development ApprovalProcess/HowDrugsareDevelope dandApproved/ApprovalApplications/In vestigationalNewDrugINDApplication/uc m343349.htmhttp://www.fda.gov/Drugs/Development ApprovalProcess/HowDrugsareDevelope dandApproved/ApprovalApplications/In vestigationalNewDrugINDApplication/uc m343349.htm Or, search for “ucm343349” 31

32. Address for drug product IND application –{Division of [….]} –Food and Drug Administration –Center for Drug Evaluation and Research –Central Document Room –5901-B Ammendale Rd. –Beltsville, Md. 20705-1266 32

33. 33