New Drug Approval Process and Investigational New Drug (IND)

Application

The FDA Drug Approval Process

New Drug Approval

• It takes 12-15 years and hundreds of million dollars to get a new drug from the laboratory onto the pharmacy shelf.

• Once a company develops a drug, it undergoes 3 ½ of laboratory testing,

• Then an application is made to the U.S. Food and Drug Administration (FDA) to begin testing the drug in humans.

• Only 1 in 1000 of the compounds that enter laboratory testing ever make it to human testing.

Probability of Success and Duration of Drug Development

New Drug Approval Timeline

New Drug Approval Process• : Abandoned Investigational

New Drug ApplicationsCase 1• Advisory Committee

MaterialsCase 2• FDA Advisory Committee

Member Conflict-of-Interest StatementsCase 3

• Data about Disapproved UsesCase 4

• Abandoned NDAsCase 5• Phase IV ProtocolsCase 6

Pre-clinical testing

• When new drugs show promise in lab testing, studies are designed to evaluate them further.

• These studies in animals are referred to as “pre-clinical studies.”

Pre-clinical testing

• Pre-clinical studies help establish boundaries for safe use of the treatment if/when human studies begin. (Animal Models :- to test drugs & side effects)

• Many new drugs and treatments are abandoned at this step because they are proven unsafe.

Clinical research and development

• The application to the FDA to request permission to begin human testing is called an Investigational New Drug application, or IND.

• The IND permits the use of an investigational new drug for the sole purpose of conducting clinical trials.

What is an IND ?

• IND is not a marketing application• An exemption from the law which otherwise

requires that a drug (biologic, device) be approved before it can be transported across state lines

• The standard for approval is evidence of safety and efficacy

• The IND exemption is granted for purposes of clinical investigation (research)

Importance of the IND

• 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(s) be performed in accordance with Good Clinical Practice (GCP)

• Provides an additional level of protection through FDA oversight

Investigational New Drug (IND)• There are three IND types:Investigator INDEmergency Use INDTreatment IND

• There are two IND categories:Commercial(Ultimate goal is to achieve marketing

approval for new product)Research (non-commercial)

Investigator/Sponsor IND• 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 Research IND is to be submitted for proposed study of Unapproved drugApproved product for

» New indication» New patient population

• Motivation is not necessarily commercial in nature

Emergency Use IND21 CFR 312.36

• It 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.

Reserved for life-threatening situations No standard acceptable treatment is available

Treatment IND

• Experimental drugs showing promise in clinical testing-safety and efficacy.

• After completion of Phase I and IIUsed for the treatment of serious or life threatening

conditions• No alternate treatments available• AIDS, Cancer

Made available while final clinical testing is completed and reviewed by the FDA

Reduce reluctance of people to participate in expanded drug access programs

Content and Format of the IND21 CFR 312.23

• All available information impacting on SAFETY!

Animal studies Pharmacology (ADME) Toxicology (LD, Short, long, genotoxicity etc)

Previous clinical experience Foreign and domestic sources Scientific literature

Content and Format of the IND21 CFR 312.23

• Test article information and proposed dosage form

– Chemical structure– Manufacturing and purification techniques– Analytical testing methods– Physical characteristics– Stability

Content and Format of the IND21 CFR 312.23

• Overall plan of study for next year (minimum)• Proposed protocols with justification• Patient Inclusion & Exclusion criteria• Method of patient selection to prevent bias• Identification & qualifications of investigators &

sub-investigators• Assurances of investigator supervision• Assurances sponsor monitor• Identification of key responsible individuals

Content and Format of the IND21 CFR 312.23

• Requirements

Form FDA 1571Table of contentsIntroductory statementGeneral investigational planInvestigators brochureClinical protocolsChemistry, manufacturing and control dataPharmacology and toxicology dataPrevious human experience

IND APPLICATION PROCESS• IND contains:

– sufficient Chemistry, Manufacturing, and Control– pre-clinical safety information and describes the proposed human trial

(Phase 1)

• Multi-disciplinary Review Team• 30-Day Deadline for Decision

• Team Decision– Yes? “Okay to Proceed” No? Clinical HOLD

• Communication to sponsor: What work must sponsor do to get HOLD lifted?

30-Day Safety

• Studies shall not be initiated until 30 days after the date of receipt of the IND by the FDA unless you receive earlier notification by the FDA that studies may begin.

WHAT NEXT AFTER FILING IND?????

CLINICAL TRIALS

Phase 1 trials• Drug is tested for its interaction

with the human body.

• Trials are conducted to determine the appropriate dose range with regard to safety and toxicity (NOT efficacy).

• Trials are conducted on a limited number (20-80) of normal volunteers or patients (such as patients with cancer or AIDS).

Phase 1 trials

• Phase 1 trials often takes 9 to 18 months to complete.

• Many drugs are abandoned in Phase 1 testing because of problems with safety or toxicity.

Phase 2 trials

• Small-scale, well-controlled trials evaluate the preliminary safety & efficacy in 100 to 300 patients with the disease or condition to be treated.

• May focus on dose-response, dosing schedule or other issues related to preliminary safety and efficacy.

Phase 2 trials (IIa, IIb)

• Often takes 1 to 3 years to complete.

• Additional animal testing may be conducted at the same time to obtain long-term safety data.

• If studies show drug to be safe and useful, testing may proceed to Phase 3.

Phase 3 trials

The most extensive (and expensive) testing of a drug.

• These trials fully assess safety, efficacy and drug dosage in a large group of patients with the specific disease to be tested.

Phase 3 trials

• Conducted on larger (100s to 1000s) and more diverse groups of patients with the condition.

• Make comparisons between the new treatment and a placebo and/or the standard treatment.

Phase 3 trials

• Trials help to better understand the drug’s safety and uncover any adverse effects.

• Trials often take 2 to 5 years to complete.

PHASE 2 PHASE 3PHASE 1

WHAT AFTER PHASE 3 ????

NDA Review

FDA Approval

Phase 4 Clinical Trials

Phase 4 trials (Post-marketing surveillance)

• Companies continue clinical trials of a drug after it has been approved for marketing.

• Phase 4 trials may be performed to learn more about side effects and long-term risks and benefits.

• Companies may also evaluate different formulations of a drug (like sustained-release) or test the drug for a different indication.

Phase 4 trials (Post-marketing surveillance)

• The company must continue to report information about new findings and problems after drug approval.

• Health care providers can report new findings to the company or directly to the FDA (consumers can report information to the FDA as well).

New Drug Approval Process (Overview)