# Presentation: 497911

## FDA MEDICAL REVIEW of the IND

- Robert Kane, MD
- Medical Officer, DODP, CDER

## Review Activities - 1

- Meetings and Review of commercial/research protocols
- Pre-IND
- IND (phase 1)
- Phase 2 and 3,  SPAs
- Pre-NDA
- NDA
- Post Marketing (phase 4)

## IND Review Process

- Prescribed by Law and Regs
- Content and Format of IND (guidances)
- _[http://www.fda.gov/cder/guidance/index.htm](http://www.fda.gov/cder/guidance/index.htm)__ _
- _[http://www.fda.gov/cder/guidance/clin2.pdf](http://www.fda.gov/cder/guidance/clin2.pdf)_
- CFR 312

## Phase 1 IND Review 

- Initial dose and schedule selection
- Safety – IRB, Consent, monitoring
- Patient population selected
- Process for determining MTD and RP2D

## Phase 1 Clinical Protocol

- Regulatory requirements
- (21 C.F.R. § 312.23(a)(6))
- Statement of objectives and purpose
- Investigator information
- Patient inclusion/exclusion criteria
- Study design
- Dosage and administration
- Data collection – what and when
- Adverse event procedures

## Sponsor and Investigator Obligations

- Obligations of sponsors and investigators
- Sponsor obligations (21 C.F.R. § 312.50)
- Management of IND
- Safety reports
- Transportation/shipment of drug
- Collection of unused drug
- Records: maintenance and retention
- Investigators obligations (21 C.F.R. § 312.60)
- Assure IRB review and informed consent
- Adherence to protocol
- Adverse event reporting
- Trial supervision
- Records: maintenance and retention

## IND Safety Reports 21 C.F.R. § 312.32

- Reasonable possibility that the experience may have been caused by the drug
- Disability
- Life-threatening adverse drug experience
-  SAE
- Unexpected AE

## Subpart E: Drugs Intended to Treat Life-threatening and Severely- debilitating Illnesses 21 C.F.R. § 312.81)

- Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted
- diseases or conditions that cause major irreversible morbidity
- Sponsors are encouraged to consult with FDA on the applicability of these procedures to specific products.
- Created: Fast Track and Priority Review

## IND Exemptions

- Drug product is marketed in the US
- Investigation is not intended to support a new indication or labeling change
- No change in advertising
- Administration - route or dose level or patient population or other factor that significantly increases the risks of use?

## Clinical Hold of Studies not Designed to be Adequate and Well-controlled21 C.F.R. § 312.42 

- Safety/Investigator Qualification
- Reasonable evidence that this trial (that is not adequate and well-controlled) is impeding enrollment to a study that is
- Insufficient quantities of drug to conduct a well-controlled trial as well
- One or more other adequate and well-controlled investigations strongly suggest lack of efficacy

## Overview of Therapeutic Development

*Pre-IND.*

**1**

**2**

**3**

**4**

**Pre-clinical**

- Consultation

- IND Filing

- NDA Filing

- Comprehensive multidisciplinary* *review often with Advisory Committee discussion

- Monitor safety, review new protocols, annual reports, approve exceptions

- Safety and Phase 4 monitoring

- Standard

- Accelerated

- NDA Filing

## NDA

## Basis for New Drug  Approval - NDA

- Demonstration of efficacy with acceptable safety in adequate and well-controlled studies    CFR 314 = NDA Regulations
- Ability to generate product labeling that
- Defines an appropriate patient population for treatment with the drug
- Provides adequate information to enable safe and effective use – prescribing of the drug
- Analogous rules for Biologics - BLA

## “Adequate and Well-controlledClinical Investigations”

- Required by FDA Regulations
- Defined in CFR 314.126:  (NDA regs)
- Clear statement of objectives
- Methods of assessment are well-defined and reliable
- Clearly-described analysis plan
- Valid comparison with control to allow a quantitative assessment of drug effect
- Adequate measures to minimize bias

##  Types of Approval

- Regular approval: Clinical benefit
- Accelerated approval: Surrogate endpoint  (PDUFA 1992)
- Endpoint reasonably likely to predict-
- Serious or Life Threatening disease
- Better than existing therapy (if any)
**See Johnson, Williams, Pazdur JCO 2003;21:1404-11**.

## Regular Approval Requires Efficacy Endpoints of Clinical Benefit

- Longer Survival (quantity)
- Easy to measure
- Better Survival (quality)
- Hard to measure
- Effective _and_ Safe  in context -
-           (Risk / Benefit)

## Quantitative Assessment of Drug Effect

- Adequate sample size/power
- Magnitude of statistically persuasive treatment effect (effect size)
- Internal consistency between centers and between subgroups
- Consistency of secondary endpoints
- Independent substantiation of results

## Time in Development - Days