Sponsor Investigator Responsibilities under an IND Tracy Hysong, MS, CCRP CTSC Clinical Trials Resource Group

Agenda Definitions What is an IND and why do I need one? Sponsor-Investigator Responsibilities under an IND

Definitions Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. 21 CFR 312.3 (b) First establish who we are talking about.. Establish what an Investigator is. Establish what a Sponsor is. Then establish what a Sponsor-Invesitgator is.

Definitions Sponsor means an individual who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator 21 CFR 312.3 (b)

Definitions Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. Does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and sponsor. 21 CFR 312.3 (b)

Quiz Dr. Smith wrote the protocol, submitted the IND, and is the only PI conducting the study. The drug was supplied by a private pharmaceutical company. Dr. Smith is a A) Investigator B) Sponsor C) Sponsor-Investigator

Quiz Dr. Smith is conducting a study for Miracle Pharmaceuticals. They hold the IND and provide the study drug. Dr. Smith provided advice in developing the protocol. Dr. Smith is a(n): A)Investigator B)Sponsor C)Sponsor-investigator

Regulatory vs. Financial Sponsor Regulatory Sponsor the agency, organization, company or person primarily responsible for initiating and overseeing the research and ensuring the study complies with federal regulations For clinical trials (studies involving drugs or biologics) this is typically the IND holder, for device studies, this is the IDE holder For industry-sponsored trials, typically the pharmaceutical/ device/biotechnology company is the regulatory sponsor For non-industry sponsored trials, the regulatory sponsor is typically the PI Financial Sponsor the agency, organization, company, or person that pays for the trial

Quiz Miracle Pharmaceuticals is supplying the drug and holds the IND. A private foundation is paying for the study. Dr. Smith wrote the protocol for Miracle Pharmaceuticals and the company submitted it to the IND. Dr. Smith is conducting the study at his institution. Who is the regulatory sponsor? Who is the financial sponsor? Who is Dr. Smith?

UCDHS 2012 Full IRB Committee Review Of the 66 UC Davis PI led, 9 (14%) were clinical trials. 8 of the 9 were done under IND (1 was granted an exemption) private sponsor 76 UC Davis PI 66 cooperative group 16 PI another inst 17 Of the 66 that were UC Davis PI led, 9 (14 %) were clinical trials and 8 of the 9 were done under an IND. 1 was granted an exemption.

IND Research at UC Davis A Pilot Clinical Trial of the Feasibility and Safety of Intravitreal Autologous Adult Bone Marrow Stem Cells in Treating Eyes with Vision Loss from Retinopathy A Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Allopregnanolone for the Treatment of Traumatic Brain Injury (allo not approved for anything) Randomized Trial of L-arginine in Severe Asthma Patients Grouped by Exhaled Nitric Oxide Levels (L-arginine is a supplement)

Agenda Definitions What is an IND and why do I need one? Sponsor-Investigator Responsibilities under an IND

What is an IND? An IND is a request for FDA authorization to administer an investigational new drug to humans Such authorization must be secured prior to interstate shipment and administration of any unapproved drug

What is an investigational drug? Investigational drug (aka Investigational New Drug): drug or biological drug that is used in a clinical investigation. Clinical Investigation: any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects (an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice).

What is the purpose of an IND? It 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 be performed in accordance with Good Clinical Practice (GCP) Provides an additional level of protection through FDA oversight FDA’s review focuses on safety of human subjects and ensuring that the studies will produce useful information to assess safety and efficacy of the test product

Different types of INDs: Treatment IND (21 CRF 312.320) Investigational New Drugs are used to make promising new drugs available to desperately ill patients as early in the drug development process as possible FDA will permit an investigational drug to be used under a treatment IND if there is: preliminary evidence of drug efficacy, drug is intended to treat a serious or life-threatening disease, or there is no comparable alternative drug or therapy available to treat that stage of the disease in the intended patient population

Different types of INDs: Expanded Access: Single patient INDs sometimes called "compassionate use" use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options

Content & Format of an IND Cover Sheet (Form FDA 1571) Table of Contents Introductory Statement and General Investigational Plan Investigator’s Brochure Clinical Protocol Chemistry, Manufacturing and Control (CMC) Pharmacology and Toxicology Information Previous Human Experience Clinical Trials Certification of Compliance (Form FDA 3674) Additional Information Mention that the content and format pertains to all INDs no matter whether it’s commercial or Sponsor-Investigator ICH-Common Technical Document Format

Introductory Statement and General Investigational Plan (21 CFR 312.23(a)(3)) Information about the drug Brief summary of previous human experience If the drug has been withdrawn from investigation or marketing in any country Brief description of the overall plan for investigating the drug product for the following year These are just my summary bullet points. The text in the CFR is very specific about what needs to be included in this section so if you are writing an IND please reference it.

Investigator’s Brochure (21 CFR 312.23(a)(5)) If required under 312.55, a copy of the investigator's brochure ICH-GCP E6 http://ichgcp.net/7-investigator’s-brochure

Clinical Protocol (21 CFR 312.23(a)(6)) Looking for a good template? http://www.ucdmc.ucdavis.edu/clinicaltrials/StudyTools/StudyTools.html

CMC (21 CFR 312.23(a)(7)) Section describing the composition, manufacture, and control of the drug substance and the drug product Regulations are specific based on what phase of the investigation you are at (i.e., the requirements for a Phase I study are much different than the requirements for a Phase III study)

Pharmacology and toxicology data (21 CFR 312.23(a)(8)) Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations

Previous Human Experience (21 CFR 312.23(a)(9)) For a Phase I study could be none

Additional Information (21 CFR 312.23(a)(10)) (i)Drug dependence and abuse potential (ii)Radioactive drugs (iii)Pediatric studies

Clinical Trials Certification of Compliance (Form FDA 3674)=clinicaltrials.gov

Agenda Definitions What is an IND and why do I need one? Sponsor-Investigator Responsibilities under an IND

Reminder An IND is a request for FDA authorization to administer an investigational new drug to humans

Sponsor Responsibilities Maintain an effective IND Select qualified investigators and monitors Ensure ongoing monitoring of investigations Informing Investigators Partners Human Research Quality Improvement Program www.partners.org/phsqi

Sponsor Responsibilities Maintain an effective IND Select qualified investigators and monitors Ensure ongoing monitoring of investigations Informing Investigators Partners Human Research Quality Improvement Program www.partners.org/phsqi

Select PIs qualified. I might also add that many Sponsors check debarment list on FDA website How might you prove that you have only shipped IP to investigators participating in the trial? IRB approval Form 3455 Financial Disclosures CV of the monitor Documentation of training of the monitor

Sponsor Responsibilities Maintain an effective IND Select qualified investigators and monitors Ensure ongoing monitoring of investigations Informing Investigators Partners Human Research Quality Improvement Program www.partners.org/phsqi

Sponsor Responsibilities Maintain an effective IND Select qualified investigators and monitors Ensure ongoing monitoring of investigations Informing Investigators Partners Human Research Quality Improvement Program www.partners.org/phsqi

Investigator Responsibilities Assure IRB review and approval Maintain adequate and accurate case histories on each subject’s participation in the trial Conduct study according to signed investigator statement, protocol, and applicable regulations Personally conduct and supervise the investigation Protect the rights, safety, and welfare of study subjects The Investigator is responsible for providing Sponsor with reports

Assure IRB review and approval What documentation could we file to indicate that we received IRB review and approval?

Investigator Responsibilities Assure IRB review and approval Maintain adequate and accurate case histories on each subject’s participation in the trial Conduct study according to signed investigator statement, protocol, and applicable regulations Personally conduct and supervise the investigation Protect the rights, safety, and welfare of study subjects The Investigator is responsible for providing Sponsor with reports

Maintain adequate and accurate case histories on each subject’s participation in the trial What documentation can we provide to indicate that we are maintaining adequate and accurate case histories?

Investigator Responsibilities Assure IRB review and approval Maintain adequate and accurate case histories on each subject’s participation in the trial Conduct study according to signed investigator statement, protocol, and applicable regulations Personally conduct and supervise the investigation Protect the rights, safety, and welfare of study subjects The Investigator is responsible for providing Sponsor with reports

Conduct study according to signed investigator statement, protocol, and applicable regulations What documentation can we provide that we are conducting the study according to the 1572, the protocol, applicable regulations?

Investigator Responsibilities Assure IRB review and approval Maintain adequate and accurate case histories on each subject’s participation in the trial Conduct study according to signed investigator statement, protocol, and applicable regulations Personally conduct and supervise the investigation Protect the rights, safety, and welfare of study subjects The Investigator is responsible for providing Sponsor with reports

Personally conduct and supervise the investigation What documentation can PI provide to prove he/she is personally conducting and supervising the trial?

Investigator Responsibilities Assure IRB review and approval Maintain adequate and accurate case histories on each subject’s participation in the trial Conduct study according to signed investigator statement, protocol, and applicable regulations Personally conduct and supervise the investigation Protect the rights, safety, and welfare of study subjects The Investigator is responsible for providing Sponsor with reports

Protect the rights, safety, and welfare of study subjects What documentation can we provide that the Investigator is protecting the rights, safety, and welfare of the subjects?

Investigator Responsibilities Assure IRB review and approval Maintain adequate and accurate case histories on each subject’s participation in the trial Conduct study according to signed investigator statement, protocol, and applicable regulations Personally conduct and supervise the investigation Protect the rights, safety, and welfare of study subjects The Investigator is responsible for providing Sponsor with reports

Drug Accountability The Sponsor is responsible for record of drug disposition The Investigator is required to maintain adequate records of the disposition of the drug The Investigator is responsible to ensure control of investigational drug

Drug Accountability The Sponsor is responsible for record of drug disposition The Investigator is required to maintain adequate records of the disposition of the drug The Investigator is responsible to ensure control of investigational drug

Drug Accountability The Sponsor is responsible for record of drug disposition The Investigator is required to maintain adequate records of the disposition of the drug The Investigator is responsible to ensure control of investigational drug

Record Retention and FDA Inspection

Failure to prepare or maintain [adequate] [accurate] case Top 10 Bioresearch monitoring Observations Used in Turbo EIR (2011-Mar2012) An investigation was not conducted in accordance with the [signed statement of investigator] [investigational plan] Failure to prepare or maintain [adequate] [accurate] case histories with respect to [observations and data pertinent to the investigation] [informed consent]. Drug disposition Informed consent 7562 informed consent: failure to obtain consent before procedures 7227 informed consent: informed consent not properly documented http://swog.org/Visitors/spring12GpMtg/Lanham.pdf

When is an IND necessary? http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/ind_documents/7842dft.pdf Guidance for Industry Investigational New Drug Applications (INDs)— Determining Whether Human Research Studies Can Be Conducted Without an IND

IND exemptions The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of an IND if ALL of the following apply:

#1. There is no intent to report the investigation to FDA as #1 There is no intent to report the investigation to FDA as a well-controlled study in support of a new indication and no intent to use it to support any other significant change in the labeling of the drug #2 In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug #3 The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))

#4. The investigation is conducted in compliance with the #4 The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50) #5 The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product)

Route of Administration #3 The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)) Route of Administration For example, there could be a significant increase in risk if a marketed drug for oral administration is converted to a dosage form that is to be administered by IV Dose Increases in dose, frequency, or duration of administration, compared to labeled dosing regimens, can significantly increase the risk in a study using a marketed drug

#3 (cont’d) The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)) Patient population The acceptability of known and unknown risks can vary considerably across different treatment populations (see § 312.2(b)(1)(iii)) For example, a drug with significant toxicity can be approved for use in a population with life-threatening or severely debilitating disease because the risk of toxicity is acceptable in that population

Does the sponsor intend to (1) report the investigation to FDA as a well-controlled study in support of a new indication, (2) use it to support any other significant change in the labeling of the drug, or (3) use it to support a significant change in the advertising (for prescription drugs only) for the drug? Whether a planned clinical investigation will be used to support a new indication, other significant labeling change, or advertising claim may not always be known or apparent at the outset of the investigation

What if I’m still not sure if I need an IND? Contact CTSC Clinical Trials Resource Group and request a consultation CTSC can help you prepare a request for exemption Content Timelines CTSC can help you prepare an IND http://www.ucdmc.ucdavis.edu/clinicaltrials/Forinvestigators/forinvestigators.html

Quiz Dr. Zang wants to conduct a clinical trial using Zapper (an oral tablet approved for curing the common cold in adults) to treat adults with attention deficit disorder. Does she need an IND? Why or why not?

Quiz Dr. Zang wants to conduct a clinical trial using Zapper (an oral tablet approved for curing the common cold in adults) to treat adults with the common cold. She would like to use 2x the approved dose. Does she need an IND? Why or why not?

Side note: Oncology IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer (the cancer treatment guidance) http://www.fda.gov/downloads/Drugs/Guidances/UCM071717.pdf This guidance is intended to assist sponsors in deciding whether a study of marketed drugs or biological products for treating cancer falls within the exemption under § 312.2(b)(1) (21 CFR312.2(b)(1)) from the general requirement to submit an investigational new drug application(IND).