CITI training

What is the timeline of drug development?

Preclinical trials, IND Submission, Clinical Development (Phase I-III), NDA submission, Marketing (Phase IV)

FDA or ICH: Treatment alternatives only need to be listed in the consent form

FDA

Who addresses the role of "Sponsor-investigators?"

FDA

Form: contractual agreement between the sponsor and FDA.

FDA 1571

T/F: FDA requires Investigator to inform the subject's primary physician about the subject's participation in the trial if subject has a PCP and if the subject agrees to the primary physician being informed.

False, this is a requirement of ICH E6 guidelines.

Who provides the ICH secretariat?

The International Federation of Pharmaceutical Manufacturers Association (IFPMA)

Define Assent

The agreement of someone who cannot consent for his or herself.

Which of the following reports must be filed using an FDA Form 1572? A. Annual Reports B. Addition of a new investigator C. Protocol amendments

B. Addition of a new investigator.

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

Voluntary for FDA-regulated drug studies

Usually, the intent of the sponsor-investigator/investigator-initiated trial is to

gain scientific knowledge without seeking market approval for the drug.

What ethical principles stem from the Declaration of Helsinki?

in notes....

When do Annual Reports need to be submitted to the FDA?

within sixty (60) days of the anniversary date that the IND went into effect.

What are the expert working groups responsible for?

developing specific guidelines. * The ICH then provides an efficient process and format to standardize the new requirements across agencies and countries.

What are the 6 regulatory and pharmaceutical industry groups that have representatives working for ICH?

-European Commission (EC) -European Federation of -Pharmaceutical Industries' Association (EFPIA) -Ministry of Health, Labor, and Welfare, Japan (MHLW) - Japan Pharmaceutical Manufacturers Association (JPMA) - US Food and Drug Administration (FDA) - Pharmaceutical Research and Manufacturing of America (PhRMA)

what are the three types of protocol amendments?

-new sponsor protocol -a change in an existing protocol when the entire sponsor protocol is not revised - identifying and adding new investigator to a study

Form FDA ____: Investigational New Drug Application, NDA

1571

Form FDA ______: Statement of the Invesitgator

1572

How many seats on the Committee does each of the 6 working groups of ICH have?

2

detailed requirements for the content and format of an IND can be found in

21 CFR 312

What regulation must a PI comply with in order to use an edc system for a clinical trial?

21 CFR Part 11

the regulation stating: exception from informed consent for emergency research

21CFR 50

How long does FDA have to review IND submission?

30 days

How long does the NDA submission take?

6 months - 2 years.

How long is the clinical development phase (Phase 1-III) in process for IND?

6-7 years.

Development of most new drugs from discovery to marketing approval usually takes:

9 years or more

If following ICH guidelines who all should sign the consent form between the subject, witness, and person obtaining consent.

All of them.

How do the World Health Organization (WHO) and the European Free Trade Association (EFTA) [represented by Swissmedic, and Health Canada participate with ICH?

As observers.

Regarding subject signature on consent forms, which is true about dates?

Both the FDA and ICH require

When the sponsor-investigator holds the IND for an investigational drug he or she is responsible for annual reporting of which one of the following to FDA? A. IND renewal application B. Adverse Event Summary Report, but only from unblinded portions of studies ("open-label IND safety report") C. IND report D. Marketing plan (i.e. annual updated projection of sales and profits)

C. IND report

Which of the following is a criterion for determining if a study of an approved drug is exempt from the require of an IND? A. The study intends to invoke an exception from informed consent. B. The study involves a route of administration that significantly increases the risks to the patient. C. The study is not intended to be reported to FDA to support a new indication or support a labeling change. D. The study intends to involve more than 100 patients in a study.

C. The study is not intended to be reported to FDA to support a new indication or support a labeling change.

what can be cross-referenced when the manufacturer of an IND already has an active IND for the drug being studied?

Chemistry, manufacturing, and controls (CMC) information Pharmacology and toxicology information Previous human experience with the drug

Is the ICH GCP regulation or guideline?

Depends, several countries adopted it as law, but the U.S FDA adopted it only as guidance. (Federal Register, Vol. 62, MAY 9, 1997)

What does the ICH E6 guidelines require in a consent form for treatment arms.

Description of each arm, the likelihood of being assigned to each of the study arms, and an explanation of " the subject's responsibilities"

means in addition to producing the drug, the company also supplies the investigator with the drug for use in the study

Drug Supplier/Manufacturer

this document notifies FDA of relevant changes in investigators conducting clinical trials under the IND.

Form FDA 1572

FDA or ICH: requires that the potential benefits and risks of the alternatives should also be included in the consent form.

ICH

ICH or FDA: Only subjects who are able to consent for themselves are allowed to enroll in non-therapeutic research studies (a trial in which there is no anticipated direct clinical benefit to the subject.

ICH

If planning to market drugs outside the US, what guidance must a PI follow while conducting the clinical trial?

ICH E-6 Good Clinical Practice.

FDA or ICH requirement: IRB/IEC is required to review -written ICF and updates - trial protocols/amendments - subject recruitment procedures (advertisements) - written information to be provided to subjects - IBs Safety information Info about payments and compensation to subjects - CVs and qualifications - any other docs IRB/IEC may require to fulfill its responsibilities

ICH E6 Guideline. FDA not clear in requirements for IRB/IEC review of documents.

Provides a unified standard for designing, conducting, recording, and reporting research involving human subjects.

ICH E6 guideline for good clinical practice.

FDA vs. ICH when enrolling an adult who is unable to consent for him or herself.

ICH E6 requires assent along with permission from their LARs. Not required by FDA.

FDA or ICH: requires the consent form to include a statement that "monitors, auditors, the IRB/IEC, and the regulatory authorities will be granted access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject is authorizing such access

ICH GCP

What must you file before conducting human clinical trials with an experimental drug?

IND application (Form FDA 1571)

What can Investigators reference when unsure if an IND is required for a study of an approved drug?

IND exemptions for studies of lawfully marketed drug or biological products for the treatment of cancer OR seek opinion from FDA.

21 CFR 56

IRBs

Define: Oversee research involving human subjects to assure the protection of their rights, safety, and welfare.

IRBs/IECs

What does ICH require in terms of benefits in the ICF?

If there is no intended clinical benefit to the subject, Section 4.8.10(h) requires that the subject be made aware. Consent form should describe the anticipated prorated payments to subjects (recommended for FDA as well)

submitted when new toxicology, chemistry, or other technical information is available. Study discontinuation is also submitted as this.

Information amendments

What is ICH's more specific name?

International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use.

When is there "Sponsor-investigators"

Investigator-initiated trials of investigational drugs.

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

Investigators, sponsors, and IRBs.

What is the legal status of ICH in the U.S.?

It is a guideline

Define the term: an individual, or judicial or other body, authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedures involved in the research

Legally Authorized Representative (LAR)

During the clinical development phase of the IND process, what must sponsors do?

Maintain current IND application by amending IND with new Form FDA 1571 and providing FDA with: safety updates copies of new protocols FDA 1572 Annual Progress reports

A primary purpose of the ICH is to: - 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

Minimize the need for redundant research.

What is the NDA?

New Drug Application, submitted prior to Phase IV marketing phase.

Does FDA require description in consent if research provides no expected benefit?

No, only an explanation of expected benefits of the research?

Can an employee at the research site be witness to a patient's consent?

No, they are involved in the trial. Witness must be "a person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial"

Regarding probability of assignment to trial arms in consent forms, which is true?

Only ICH recommends.

What is determined for a drug in the preclinical phase

Pharmacokinetics and bioavailability Outcome shows promise of safety and efficacy warranting additional studying.

Pharmacokinetics and pharmacodynamics of a new formulation of an investigational drug most likely refers to which clinical phase of a study in humans?

Phase 1

The first randomized, controlled study of an experimental drug versus aspirin for postoperative pain control will enroll 55 patients in each arm. Which of the following best describes the clinical phase of this study?

Phase 2

Adults with more than a 12-month history of migraines were assigned randomly in a double-blinded study to receive treatment with experimental drug X (10 or 20 mg/day) or placebo. The primary efficacy measure was the reduction in severity of the migraine attacks. Enrollment was 1200 subjects. Which of the following best describes the clinical phase of this study?

Phase 3

Determine the trial phase from the subject population: Normal healthy volunteers unless toxicity prevents exposure (e.g, cancer drugs). In this, case patients with end-stage disease might be enrolled.

Phase I

Determine the trial phase: - Assess toxicity - Determine drug's PK and PD profiles - Determine doses resulting in sufficient biological level of drug

Phase I

Determine the trial phase from the subject population: Controlled studies enrolling limited numbers of patients

Phase II

Determine the trial phase: - Determine drug's short-term risk (safety) (primary goal) - Examine preliminary effectiveness of drug

Phase II

For a Phase 1 new drug study in humans, what is the primary source of the data included in the initial Investigator's Brochure?

Preclinical data

Determine the trial phase from the subject population: Controlled and uncontrolled studies (but typically placebo-controlled and double-blinded) enrolling larger patient numbers.

Phase III

Determine the trial phase: - Determine drug's effectiveness (primary goal) - Determine long-term drug safety - Confirm findings

Phase III

Long-term toxicology of an experimental drug in animals most likely refers to which part of drug development?

Preclinical

When does a sponsor submit the IND?

Prior to clinical development phases (human trials). *30 day process.

an unplanned excursion from the requirements of the protocol that is not implemented or intended as a systematic change.

Protocol Deviation (or Violation)

What must be provided to investigators before they beginning conducting trials at their site?

Protocol and Investigator's Brochure

What are the four main categories covered by ICH guidelines?

Q: Quality topics (chemical and pharmaceutical assurance) S: Safety topics: in vitro and in vivo preclinical research E: Efficacy topics: relating to research in human subjects M: Multidisciplinary topics: those that do not fit uniquely into one of the above categories. (QSEM)

What must a witness do before the consent process starts?

Read the consent form and other written information provided to the participant. They must also determine whether the participant has any other questions and should sign the impartial witness signature block on the consent document.

The ICH GCP guidelines: - set standards for the design, conduct, monitoring and reporting of clinical research. - guarantee that a submission in any ICH region will be approved for marketing. - require certification of clinical research sites and investigators - 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.

means the entity who takes responsibility for and initiates a clinical investigation. The sponsor can be any legal entity, including a company, an academic organization, or an individual. The intent of the sponsor's IND is to allow testing for marketing approval of the drug. These are generally considered commercial or corporate INDs. Note: the sponsor is often but not always the entity that funds the clinical research.

Sponsor

means an individual who both initiates and conducts the clinical investigation and under whose immediate direction the investigational drug is being administered, used, or dispensed. The sponsor-investigator assumes all of the responsibilities of the sponsor as well as all the responsibilities of an investigator as outlined in the Form FDA 1572 (see the module, Investigator Obligations in FDA-Regulated Research). Usually, the intent of the sponsor-investigator trial is to gain scientific knowledge without seeking market approval for the drug. These are considered investigator-initiated or sponsor-investigator trials.

Sponsor-investigator

The FDA will apply: - The ICH E6 GCP standards - The Code of Federal Regulations - Local IRB requirements - State law where the sponsor's headquarters are located.

The code of federal regulations

who nominates other nonvoting participants to attend ICH steering Committee meetings?

The observer groups (WHO, Health Canada, and EFTA)

What are the two important goals of the ICH E6 standard?

To assure that 1: The rights, well-being, and confidentiality of trial subjects are protected. 2: Trial data are credible.

The following are purposes of what: -The rights and well-being of human subjects are protected. -The reported trial data are accurate, complete and verifiable from source documents. -The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirements.

Trial monitoring

ICH requires a witness when enrolling illiterate subjects, true or false?

True

Is assent required for both FDA and ICH?

Yes, and the consent of the parents.

If an IND application is submitted and the FDA has not contacted the physician within 30 days after acknowledging receipt, can the trial start?

Yes, one of two conditions must be met. 1. 30 days elapsed since FDA received IND application and no hold as been placed. 2. Correspondence has ben received from FDA allowing the trial to start.

How is the ICH governed?

a Steering Committee

The content for an IND for studies of marketed products is the same as the content for studies of new drugs, with the following exception:

a copy of the approved labeling (including the package insert) can be provided in lieu of the Investigator's Brochure.

When can ICH allow subjects to be enrolled that cannot consent for themselves? (Exceptions)

studies where: - the objectives cannot be met without including these subjects. the foreseeable risks to the subject are low as is the negative impact. - the study is not illegal AND The IRB/IEC has specifically agreed to include these subjects.

Where do the ethical principles followed by ICH GCP guidelines originate from?

the Declaration of Helsinki

Who supports the ICH?

the ICH Secretariat

ICH E6 guideline pertains specifically to what

the conduct of clinical research to support marketing applications for drugs.

what is the goal of the ICH?

to minimize redundant research. and standardize technical guidelines and requirements.

Per FDA requirements, what is required of the IRB/IEC?

to review the consent form (21 CFR 56.109) and to keep "copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents.

What happened because of the concern and confusion regarding interpretation of Part 11in 2003.

FDA withdrew all the guidance documents related to Part 11, while re-examining. They then issued: Guidance for Industry: Part 11, Electronic Records; Electronic Signatures-Scope and Application (2003) and Guidance for Industry: Computerized Systems Used in Clinical Investigations (2007). ** The 2007 guidance "supplements the 2003 guidance"