Questions

The two (2) important goals of ICH E6 are to assure that:

-The rights, well-being, and confidentiality of trial subjects are protected -Trial data are credible

True/ False : In the U.S. compliance with ICH E6 is voluntary, but as with any published FDA guidance, compliance is considered part of GCP

true

The ICH E6 topic falls under which category in the ICH guidelines?

Efficacy

Form FDA 1572, Statement of Investigator, is legally binding between the investigator and the: Sponsor FDA Subjects IRB

FDA The investigator signs the Form FDA 1572 and provides the signed form to the sponsor for filing with the FDA. By signing this form, the investigator agrees to conduct the study according to the protocol and FDA regulations.

Before conducting human clinical trials with an experimental drug, sponsors must file an IND application with the FDA. Which form would this be? 1. Form 3435 2. Form 1572 3. Form 1571 4. Form 3534

FDA Form 1571

The FDA also requires information about the credentials of each investigator and subinvestigator who will use the investigational product as part of the clinical trial. For investigational drugs, this information is submitted on which form?

Form FDA 1572 (Statement of Investigator)

A primary purpose of the ICH is to: Minimize the need for redundant research. Require publication of negative trial results. Develop mandatory worldwide regulations for drug development. Require FDA registration of worldwide clinical trials.

Minimize the need for redundant research.

When sufficient data have been obtained to provide evidence of safety and efficacy, the sponsor submits the results of the trials to the FDA as part of a ____________ that requests permission to market the product in the U.S. The FDA reviews the application.

New Drug Application (NDA)

Dr. Thompson's daughter, who is married and lives with her husband, is a sales representative for DrugCo. His daughter received $132,000 from DrugCo during the past twelve months. Must Dr. Thompson disclose his daughter's income?

No. Investigators must report their own income and financial interests as well as income and financial interests of their spouse and each dependent child. Dr. Thompson's daughter is not a "dependent child."

What is the subject population of a Phase 1 study?

Normal healthy volunteers unless toxicity prevents exposure (for example, cancer drugs). In this case, patients with end-stage disease might be enrolled.

The first step in the drug-development process allows investigators to evaluate the drug using tissue cultures and animal models. This research is referred to as?

Preclinical Trials

What is an Investigator Brochure (IB)?

The Investigator's Brochure (IB) is a compilation of the pre-clinical and clinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures (ICH 2016).

What is the goal for International Council for Harmonisation (ICH)?

The goal of the ICH is to standardize technical guidelines and requirements for drug marketing registrations, so that applications for marketing to various regulatory agencies around the world can occur without redundant testing.

Identify which party is responsible for reporting directly to the FDA the investigator's financial interests with the sponsor: The investigator's institution The IRB The sponsor The investigator

The sponsor The investigator provides the sponsor with a completed form for reporting financial interests to the FDA. The sponsor is responsible for providing the FDA with this information. This includes potential financial interests in the sponsor's company or financial interests that might be influenced positively or negatively by the outcome of the clinical investigation.

In the United States, following the ICH E6 guideline is: Mandatory for studies conducted outside the United States. Mandatory for drug studies. Mandatory for investigational device studies. Voluntary for FDA-regulated drug studies.

Voluntary for FDA-regulated drug studies.

In the guidance, the FDA noted that there are two (2) instances when it is necessary for an investigator to complete and sign a new 1572:

When an investigator is participating in a new protocol that has been added to the IND When a new investigator is added to the study

According to ICH (2016) E6, if the study is terminated prematurely or suspended for any reason, the investigator/institution should:

promptly inform the trial subjects should assure appropriate therapy and follow-up for the subjects where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies).

What are the goals of a Phase 1 Study?

-Assess toxicity -Determine drug's pharmacokinetic and pharmacodynamic profiles -Determine doses resulting in sufficient biological level of drug

What are the goals of a Phase II Study?

-Determine drug's effectiveness (primary goal) -Determine long-term drug safety Confirm Phase II findings

What is the subject population of a Phase III study?

Controlled and uncontrolled studies (but typically placebo-controlled and double-blinded) enrolling larger patient numbers and seeking to confirm results of Phase II trials.

What is the subject population of a Phase II study?

Controlled studies enrolling limited numbers of patients.

True or False: According to ICH E6 Section 4.3.3, if the subject agrees, the investigator does not necessarily need to inform the subject's primary physician about the subject's participation in the trial.

False

How many days does the FDA have to review the IND Application?

30 days

This agreement is a contract that defines both the terms of study conduct and the financial agreements.

Clinical Trial Agreement (CTA)

ICH guidelines cover four (4) main categories and a letter of reference codes each category.

Quality, Safety, Efficacy, and Multidisciplinary Topics

The sponsor organization will generally assess the site first by means of a?

prestudy site visit

Investigators must thoroughly evaluate a clinical trial before agreeing to conduct it. Whether an investigator agrees to conduct the trial depends on many factors, including the investigator's expertise and interest, perceived ability to meet recruitment goals, and whether sufficient support staff and other resources are available. This evaluation is often referred to as

study feasibility

According to 21 CFR 54, the following information must be reported by investigators to the company that submits the new drug application (NDA):

-Compensation made to the investigator in which the value of compensation could be affected by study outcome -A proprietary interest in the tested product, including, but not limited to, a patent, trademark, copyright or licensing agreement -Any equity interest in the sponsor of a covered study (that is, any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices) -Any equity interest in a publicly held company that exceeds $50,000 in value

Development of most new drugs, from discovery to marketing approval, usually takes: 9 years or more Less than 5 months 1-3 years 5 years

9 years or more Development of a new drug requires a detailed and lengthy research process. Preclinical studies can take 3-6 years and Phases I-III clinical trials can take another 6-7 years.

What are the goals of a Phase II Study?

-Determine drug's short-term risks (safety) (primary goal) -Examine preliminary effectiveness of drug

Who are the three (3) industry members of ICH?

-European Federation of Pharmaceutical Industries and Associations (EFPIA from EU) -Pharmaceutical Research and Manufacturers of America (PhRMA from U.S.) -Japan Pharmaceutical Manufacturers Association (JPMA from Japan).

Form FDA 1572 is a binding agreement between the investigator and the FDA. Specifically regarding the investigational product, the investigator agrees to:

-Personally conduct or supervise the investigation according to the protocol. -Inform the subjects that the drugs are being used for investigational purposes and satisfy other requirements for obtaining informed consent. -Maintain complete and accurate records and make the records available for inspection.

True or False: If the thirty (30) day review period passes without notification from the FDA, the sponsor may proceed with the research as described in the IND application.

True

True or False: Once the study has been terminated, the investigator is required to notify the IRB/IEC and provide a summary (final) report.

True

The investigator must maintain study records for how many years after the drug has been granted marketing approval in the U.S. for the indication tested in the study?

Two years

The FDA regulations require the label for investigational drugs to contain specific information. Labels on investigational drugs may differ in design but all such labels should contain the following minimum primary information:

-Name of the study -Name of the study drug (even the placebo is labeled with the study drug code) -Subject study number -How supplied (for example, the number of tablets per container) -Dose per unit (mg per tablet, mg/mL, etc.) -Lot number -Batch number -A federal statement limiting use to experimental studies: "Caution: New Drug - Limited by Federal Law to Investigational Use" (Investigational New Drug Application 2014)

The IRB approves Dr. Brazier's study and DrugCo sends the first shipment of exludimab to Dr. Brazier. Courtney is the research coordinator for this clinical trial, and Dr. Brazier delegated Courtney to manage the study drug supplies. The first shipment of exludimab arrives. The package includes twenty boxes and each box includes seven syringes filled with exludimab. What actions should Courtney take after she receives the first shipment? Courtney should:

1. Verify that the correct product was received, the shipment is correct and that the contents match the description in the protocol. 2. Inspect the packaging to see if the packaging has been damaged. Record receipt of the investigational product according to the sponsor's requirements. 3. Ensure that the date and amount received, and the lot numbers of the product are recorded on the drug accountability log. 4. Store the drug according to the instructions in the protocol and on the packaging. 5. Ensure that access to the product is controlled.

If the sponsor and the investigator agree that the study should be placed at the investigator's site, the sponsor representative will request that the investigator review and sign this FDA Form.

1572, Statement of Investigator By signing this form, the investigator enters into a legally binding contract with the FDA. The sponsor is the conduit for transmitting this information to the FDA. By signing this form, the investigator assumes full responsibility for the study, attests that he/she has read the IB, and agrees to conduct the study according to the protocol and FDA regulations.

Sara instructs Courtney to dispose of the product because Dr. Brazier does not have evidence that the product was maintained at the correct temperature. What actions must Courtney take to account for the first shipment of exludimab?

Courtney should: (1) ensure she receives the instructions to dispose of the product in writing; (2) follow local and OSHA requirements for drug disposal; and (3) record the disposition of the product.

In completing Form FDA 1572, Statement of Investigator, the investigator agrees to: -Conduct or supervise the investigation personally -Maintain a contract with the sponsor -Maintain records indefinitely -Report to the FDA any adverse events that occur

Conduct or supervise the investigation personally All investigators agree to personally conduct or supervise the investigation when they sign the Form FDA 1572. They must report adverse events to the sponsor, not the FDA. Records must be retained for two (2) years after drug approval, disapproval, or study termination. Maintaining a contract is not a requirement.

Which countries fall under International Council for Harmonisation (ICH) E6 guideline?

European Union, Canada, Japan, Switzerland and the U.S.

Dr. Thompson agrees to serve as Principal Investigator for this new study. What documentation must Dr. Thompson provide to DrugCo before he can start enrolling subjects?

Dr. Thompson must provide an updated curriculum vitae (CV), a completed and signed FDA Form 1572, and financial disclosure forms for every member of the research team who is directly involved in the treatment and evaluation of research subjects. He must also provide the sponsor with evidence of IRB approval.

Myra submits the IRB application, protocol, consent form, advertisements and investigator brochure to the IRB for review and approval. The IRB reviews the documents and has some concerns that some of the subjects will be on placebo and may experience increasing asthma symptoms. The IRB requires a revision to the protocol to include provision of an inhaler for all subjects to use if their symptoms increase. What should Dr. Thompson do?

Dr. Thompson should contact the sponsor to discuss the IRB's requirements. If the sponsor agrees to provide the inhaler, the sponsor will also need to revise the protocol and consent form to describe the procedures associated with use of the inhaler and any foreseeable risks associated with the inhaler. If the sponsor disagrees with the IRB's requirement, the sponsor should help Dr. Thompson respond. In any event, Dr. Thompson cannot start the study at his site until the IRB's requirements are met and IRB approval is obtained.

When must the investigator update the IRB about the progress of a trial? -Never -At study termination only -During the conduct of the study only -During the conduct of the study and at termination

During the conduct of the study and at termination Investigators must provide periodic updates to the IRB in accordance with its policies. This typically occurs at least once per year, but may be required more often by the individual IRB.

True or False: The sponsor is required to obtain financial disclosures before an investigator can participate in the trial and is required to receive updated information for two years following completion of the trial.

False: Up to one year

Who is include in a financial disclosure?

For purposes of financial disclosures, the term "investigator" includes anyone who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse and each dependent child of the investigator (21 CFR 54).

Before an investigational product can be shipped to an investigator, the research sponsor must file which FDA Form?

Form 1571 Investigational New Drug [IND] application

How should deviations be reported? (Planned, unplanned, and to eliminate immediate hazard)

If an investigator plans to deviate from the protocol for a purpose other than to eliminate an immediate hazard, the investigator must obtain prior approval from the sponsor and the IRB/IEC. If a deviation was needed to eliminate a hazard, the deviation must be documented and rationale submitted to the sponsor, IRB/IEC, and regulatory authorities. In some instances, an investigator inadvertently deviates from the protocol. When such unplanned deviations are discovered, the investigator should explain the deviation in writing. In addition, the investigator should take appropriate corrective actions and will follow the steps necessary to ensure that similar deviations do not occur in the future.

ICH E6 describes standards that apply to: -Research sponsors only -Investigators only -Investigators, sponsors, and IRBs -IRBs only

Investigators, sponsors, and IRBs

The ICH GCP guidelines: Require certification of clinical research sites and investigators Guarantee that a submission in any ICH region will be approved for marketing. Set standards for the design, conduct, monitoring and reporting of clinical research. Replace FDA regulations for internationally conducted studies of drugs that will be marketed in the U.S.

Set standards for the design, conduct, monitoring and reporting of clinical research.

Once IRB/IEC approval is obtained and other institutional prerequisites have been satisfied, the study can begin at the investigator's site. The sponsor organization will have a?

Site Initiation Visit At this initiation stage, the protocol, data-collection instructions, and regulatory obligations will be reviewed. Once a site is initiated, study product may be shipped to the site and subject recruitment may begin.

There are several reasons for conducting post approval, or Phase IV, clinical trials. What is one of them?

Some of the trials are conducted voluntarily by drug companies for various reasons such as collecting long-term safety and efficacy data or comparing the drug with other drugs on the market. Other Phase IV trials are required by regulatory authorities such as the FDA. For example, the FDA might require a Phase IV trial as a means of collecting more information on efficacy and long-term safety after a drug is approved through an accelerated approval process.

Which of the following is an investigator's commitment to the sponsor? -Provide the financial disclosure document directly to FDA -Retain study documents for three (3) years after study completion at the site -Submit documents to sponsor for yearly approval to continue the study -Submit a new Form FDA 1572 to the sponsor as needed

Submit a new Form FDA 1572 to the sponsor as needed The investigator must submit a new Form FDA 1572 to the sponsor when an investigator is participating in a new protocol that has been added to the IND or when a new investigator is added to the study. The IRB, not the sponsor, provides ongoing approval for study continuation at the site. The investigator submits the financial disclosure document to the sponsor and the sponsor submits financial disclosure information to FDA. Study record retention is two (2) years after drug approval, disapproval, or study termination.

While the study is ongoing, DrugCo asks Dr. Thompson to present information about the study drug and the trial at an international conference on asthma. Dr. Thompson agrees. He receives a $30,000 honorarium from DrugCo for the presentation. What must Dr. Thompson do to remain compliant?

This income represents a financial conflict of interest and Dr. Thompson must update the financial disclosure that he made to the sponsor so that it includes this income. He must also comply with the IRB's requirements for reporting conflicts of interest. When the IRB considers the conflict, it might require Dr. Thompson to take some additional actions such as informing potential subjects about the conflict during the consent process.