investigational new drug application

51
INVESTIGATIONAL NEW DRUG (IND) Department of Pharmaceutical Sciences, Maharshi Dayanand University , Rohtak PRESENTED BY:- Bindu Xtreiy Regn. No. : 12 utdpr 0040

Upload: bindu-xtreiy

Post on 21-Apr-2017

45 views

Category:

Education


3 download

TRANSCRIPT

1

INVESTIGATIONAL NEW DRUG (IND)

Department of Pharmaceutical Sciences,

Maharshi Dayanand University , Rohtak

PRESENTED BY:-Bindu Xtreiy

Regn. No. : 12 utdpr 0040

WHAT IS A DRUG? A drug is, among other things, an article (other than food) that:

• is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease.

• is intended to affect the structure or any function of the body.

• achieves its primary intended purpose through chemical action in the body or by being metabolized.

What is an IND?• An Investigational New Drug (IND) application allows a

sponsor to lawfully use an investigational drug for the purpose of conducting a clinical investigation of that drug.

• An investigational drug can be an unapproved drug or an approved product being studied for a new indication or in a new patient population.

After completing preclinical testing, the company files an IND with FDA Act to begin to test the drug in people. The IND becomes effective if FDA does not disapprove it within 30 days.

The IND shows results of previous experiments, how, where and by whom the new studies will be conducted;

1. Chemical structure of the compound.2. How it is work in the body.3. Toxic effects found in the animal studies.4. How the compound is manufactured.

What is the purpose of an IND?The FDA’s objectives are to assure data quality and study subject safety. In an initial IND submission, the sponsor provides:

• Pharmacology, toxicology, and manufacturing information used to assess whether the product is reasonably safe for initial testing in humans.

• A clinical protocol and, if applicable, an Investigator Brochure.

• A signed agreement to adhere to informed consent, IRB review, and general IND regulations

Once approved, an IND grants the sponsor an exemption from the federal statute that prohibits shipping an unapproved drug in interstate commerce.

What is a clinical investigation?

•A clinical investigation is any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects.

Who must apply for an IND?

The sponsor of a clinical investigation that is not otherwise exempt from the IND requirements is responsible for submitting an IND application to FDA and obtaining Institutional Review Board (IRB) approval before the study can begin.

Which clinical investigations are exempt from the IND requirements?

A clinical investigation of a drug is exempt from the IND requirements if all of the following criteria are met:

• The drug product is lawfully marketed in the United States.

• The investigation is not intended to be reported to the FDA in support of a new indication for use or any other significant change in the labelling for the drug.

• The investigation is not intended to support a significant change in the advertising for a prescription drug product.

• The investigation does not involve a change in route of administration, dosage level, or patient population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with use of the drug product.

• The investigation is conducted in compliance with the requirements for IRB review (21 CFR 56) and informed consent (21 CFR 50).

• The drug may not be represented as safe or effective for the purposes for which it is under investigation, nor may it be commercially distributed or sold.

Who is a sponsor?An individual or pharmaceutical company, governmental agency, academic institution, private organization or other organization who takes responsibility for and initiates a clinical investigation. The sponsor submits and maintains the IND.

Who is an investigator?

An investigator is 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 of an investigation being conducted by a team of individuals, “investigator” refers to the responsible leader of the team.

Who is an sponsor-investigator?

A sponsor-investigator is an individual who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed. For administrative reasons, only one individual should be designated as sponsor.

What are the phases of an investigation?

An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap.

Phase 1 - Phase 1 includes the initial introduction of an investigational new drug into humans. These studies are usually conducted in healthy volunteer subjects. These studies are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Phase 1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. The total number of subjects included in Phase 1 studies is generally in the range of twenty to eighty.

Phase 2 - Phase 2 includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase 2 studies usually involve several hundred people.

Phase 3 - Phase 3 studies are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labelling. Phase 3 studies usually include several hundred to several thousand people.

What are the types of INDs?There are two IND categories:Commercial: An IND for which the sponsor is usually either a corporate entity or one of the institutes of the National Institutes of Health (NIH). In addition, CDER may designate other INDs as commercial if it is clear the sponsor intends the product to be commercialized at later date.

Research (non-commercial): An IND for which the sponsor is usually either a corporate entity or one of the institutes of the National Institutes of Health (NIH). In addition, CDER may designate other INDs as commercial if it is clear the sponsor intends the product to be commercialized at a later date.

There are three non-commercial IND types: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 physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.

Emergency Use IND  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.

Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

The IND application must contain information in three broad areas :

Animal Pharmacology and

Toxicology Studies – Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. It also includes any previous experiences with the drug in humans (often foreign use).

Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.  This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.

Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.  Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfil their clinical trial duties.  Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.

Criteria for applicationA clinical study is required for an IND if it is intended to support a :

• New indication

• Change in the approved route of administration or dosage level

• Change in the approved patient population (e.g. pediatric) or a population at greater or increase of risk (elderly, HIV)

• Significant change in the promotion of an approved drug.

Application submission: Most INDs are paper submissions. While only 12% of INDs are submitted electronically, 28% of IND Amendments are submitted electronically a result of maintaining a growing number of INDs submitted electronically to date.

Additional regulations: Experimental drugs under an IND must be labeled, "Caution: New Drug--Limited by

Federal (or United States) law to investigational use."

Guidance documents for INDs

Guidance documents to help prepare INDs include

• Guidance for Industry: CGMP's for Phase 1 Investigational Drugs.

• Guidance for Industry: Exploratory IND Studies. • Content and Format of Investigational New Drug Applications (INDs)

for Phase 1 Studies of Drugs Including Well Characterized, Therapeutic, Biotechnology-Derived Products.

• Q & A - Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products. This guidance is intended to clarify when sponsors should submit final, quality-assured toxicology reports and/or update the Agency on any changes in findings since submission of non-quality-assured reports or reports based on non-quality-assured data.

• Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. This guidance should be useful for applicants planning to conduct bioavailability (BA) and bioequivalence (BE) studies during the IND period for an NDA, BE studies intended for submission in an ANDA, and BE studies conducted in the post approval period for certain changes in both NDAs and ANDAs.

• IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer.

• Drug Master Files: A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

Immunotoxicology Evaluation of Investigational New Drugs. This guidance makes recommendations to sponsors of investigational new drugs (INDs) on

• The parameters that should be routinely assessed in toxicology studies to determine effects of a drug on immune function.

• When additional immunotoxicity studies should be conducted, and

• When additional mechanistic information could help characterize the significance of a given drug’s effect on the immune system.

Laws, Regulations, Policies and Procedures

Code of Federal Regulations (CFR): The regulations apply to the IND application process are shown in Table. Table: Code of Federal Regulations (CFR) for different application

21CFR Part 312 Investigational New Drug Application

21CFR Part 314 New INDA and NDA Applications for FDA Approval to Market a Drug (New Drug Approval)

21CFR Part 316 Orphan Drugs24

21CFR Part 58 Studies

Good Lab Practice for Nonclinical Laboratory [Animal]

21CFR Part 50 Protection of Human Subjects21CFR Part 56 Institutional Review Board21CFR Part 201 Drug Labelling21CFR Part 54 Financial Disclosure by Clinical Investigators

Format & Content of an Investigational New Drug

Following sections are contained in an IND:1. Cover Sheet (Form FDA 1571)2. Table of Contents3. Introductory Statement & General investigational plan(a) Name of the drug, pharmacological class drug, structural

formula, dosage form, formulation, route of administration, objective and planned duration of the proposed clinical investigation.

(b) Identification of countries where drug has been withdrawn from investigation or marketing for any reasons related to safety and reasons for withdrawal.

4. General Investigational Plan- brief description of the overall plan for investigating the drug product for the following:(a) Rationale for drug study.(b) Indication for the study.(c) General approach to be followed in evaluating the drug. (d) Kinds of clinical trials to be conducted in the first year (indicate if plans not developed for full drug).(e) Safety risks anticipated- any risks of particular severity or seriousness anticipated based on toxicology data or prior human experience with the drug.

5. Investigator’s Brochure- contain the following information(a) Brief description of the drug (include structural formula) and the formulation.(b) Summary of the pharmacological and toxicological effects of the drug in the animals and to the extent known, in man.(c) Summary of pharmacokinetics and biological disposition of

the drug in animals and if known, in man.(d) Summary of information relating to safety and effectiveness in

humans from prior clinical studies. Precaution or special monitoring to be done as part of investigation.

6. Clinical Investigation(a)Protocol for each planned study.(b) Investigators Name, Address and CV of each Investigator. Name and address of each sub- investigator. Name and address of research facilities. Name and address of IRB.(c) Monitor- name, title and CV (The person responsible for monitoring the conduct and progress of the clinical investigation). Safety monitor- name, title and CV (The person or persons responsible for review and evaluation of information relevant to safety off the drug.(d) Labeling for clinical supplies.

7. Chemistry, Manufacturing and Controls Information(a) Drug substances Description of physical and chemical characteristics Name and address of the manufacturer Method of preparation Reference standard Specifications Method of analysis Stability(b) Drug product Components (reasonable alternatives) Inactive components- Test and specifications Components (reasonable variations)

Name and address of manufacturer Manufacturing and packaging procedure Specifications Method of analysis Stability Labeling for clinical supplies Placebo- composition, manufacture and control Environmental analysis- claim for categorical exclusion

8. Pharmacology and toxicology(a) Pharmacology and drug dispositionSection describing the pharmacological effects and mechanism(s) of action of the drug in animals.

(b) Toxicology ID and qualifications of persons conducting and evaluating results of studies concluding reasonably safe to being proposed investigation.9. Previous human experience- Summary of known prior human experience with the investigational drug to include(a) If previously investigated or marketed detailed information about such experience relevant to safety of proposed investigation or rationale.(b) For combination of drugs- part 9a information for each drug.(c) Foreign marketing- List of countries where marketed list of

countries where drug has been withdrawn from marketing for reasons related to safety.

The IND Development Process in United States

An investigator may be required to submit an IND application to FDA in order to study a marketed medical product in a new (i.e. unapproved) clinical indication. An investigator is always required to hold an IND to study an un-marketed (i.e. unapproved) medical product. In both situations, FDA considers the products “investigational”.

1. Determine Whether You Need an IND

Review the five requirements below to determine if your study qualifies for exemption from an IND (21 CFR 312.2). The FDA Draft Guidance Investigational New Drug Applications (INDs) – Determining whether human research studies can be conducted without an IND provides more detail on a range of issues,including the process for consulting with FDA if unsure.Exemptions: As we discussed it in previous slides.

2. Complete the study protocol: An IND requires a fully developed protocol.A fully developed clinical protocol is the basis for both the IRB Application and the initial IND submission. Review the study application https://eric.ora.georgetown.edu/eric for required content. A completed protocol must be included in the IND application.1. You may start with a protocol synopsis;2. Compile a reference list - include all published articles andunpublished reports or manuscripts cited. Collect a copy of each article or report listed.3. For approved medications that are part of the study, read thePrescribing Information. The safety plan should acknowledge known safety risks from the prescribing information and incorporate relevant.safety monitoring into the protocol.

Prepare the Initial IND Submission.

The IND Sponsor-Investigator compiles information in three broad areas:

o Animal Pharmacology and Toxicology Studies: Preclinical data used to assess whether the product is reasonably safe for studies in humans. For studies of marketed drugs in new indications, this section might contain data from animal models supporting the utility of the drug in the new indication

o Manufacturing Information: The composition, stability, and controls used for manufacturing the drug substance and the drug product.

1. For marketed drugs, the FDA already has this information on file in the manufacturer’s Drug Master File (DMF). An Investigator-Sponsor can request a Letter of Authorization

(LOA) from the manufacturer to refer to the information, although it is not required. Consult the PRDC for more information if necessary.2. For legally marketed drugs, the information in the product label might suffice for the manufacturing information.

o Clinical Protocols and Investigator Brochures: A detailed clinical study protocol, and Investigator Brochure are required sections of an IND application. The Investigator Brochure is primarily needed for multi-center studies and is a summary of information needed by participating investigators to assess the safety of the investigational product. For approved medications, a copy of the Prescribing Information may be used in place of an Investigator Brochure.

File the Initial IND & Receive an IND Number

1. The initial IND submission should be accompanied by a cover letter, a Form FDA1571 and a Certification Form 3674. All must be submitted in triplicate (an original and two photocopies):

The IND Sponsor-Investigator completes, signs, and dates the Form FDA 1571.

The IND Sponsor-Investigator assembles the signed submission and makes three photocopies and one .PDF of the original documents.

For an initial submission, the IND Sponsor-Investigator sends the original and two photocopies to the following address, via overnight courier:

For a Therapeutic Biological Product:Food and Drug Administration

Center for Drug Evaluation and ResearchTherapeutic Biological Products

Document Room5901-B Ammendale Road

Beltsville, MD 20705-12669

For a Drug:Food and Drug Administration

Center for Drug Evaluation and ResearchCentral Document Room5901-B Ammendale Rd.

Beltsville, Md. 20705-1266

2. Keep a photocopy of the courier Airbill. On the delivery date, track the shipment on the courier website for confirmation of delivery. Print and file a copy of the delivery confirmation.

3. The IND Sponsor-Investigator files the .PDF and the third photocopy of the signed submission. The IND Sponsor-Investigator’s photocopy is kept in an IND Binder.

The FDA responds to the initial submission of a new IND with a letter, acknowledging receipt of the submission and assigning the IND number. An IND generally goes into effect 30 days after the Date of Receipt shown in this letter.

The IND Acknowledgement letter also provides the mailing address for all subsequent submissions to the IND.

Maintain the IND: Amendments, Safety Reports, and Annual Reports

To maintain an IND, the Sponsor-Investigator must submit Protocol Amendments, Safety Reports and Annual Reports to the FDA. Each type of report is time-sensitive and has a specific structure. The first two, Protocol Amendments and Safety Reports, are submitted when needed to report updated or unforeseen circumstances. The third type, the Annual Report, is submitted every year, even when no studies are in progress under the IND. Send all submissions to the address provided in the IND Acknowledgement letter received in response to the initial submission.

• IND Protocol AmendmentsOnce an IND is in effect, the IND Sponsor-Investigator is responsible to amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. An IND Protocol Amendment is a submission to an existing IND notifying the FDA of one or more of the following:

a. A new study protocolb. A change in an existing study protocolc. A new investigator

• IND Safety ReportsAn IND Safety Report is expedited, written notification to the FDA of an adverse experience associated with the use of a study drug that is both serious and unexpected. “Associated with the use of the drug” is a Code of

Federal Regulations term meaning, “There is a reasonable possibility that the experience may have been caused by the drug.” An IND Safety Report consists of a MedWatch Form and a cover letter. It is due to the FDA within 15 calendar days of initial receipt of the SAE Report.

• IND Annual ReportsAn IND Annual Report is a brief report of the progress of studies conducted under an IND, due annually to the FDA within 60 days of the anniversary of the date that the IND went into effect.

Withdrawal off an IND• At any time a sponsor may withdraw an effective IND without

prejudice.• If an IND is withdrawn, FDA shall be so notified, all clinical

investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or otherwise disposed of at the request of the sponsor in accordance with 312.59.

• If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all participating investigators, and all reviewing Institutional Review Boards, together with the reasons for such withdrawal.

After approval of IND application then clinical trial will be started on formulation of new molecule. Clinical trials are mainly use of drug on human beings.