Drug Development Process

Types of CDER Approvals

• novel drugs

• new/expanded uses of already approved drugs

• biosimilars

• new formulations

• new dosage forms

Fast track

• serious condition

• unmet medical need

• based on promising animal or human data

Breakthrough therapy

substantial improvement over standard therapy

Priority review

• significantly improve treatment, diagnosis, or prevention

• shorten to 6 month review

Emergency Use Authorization

• during public health emergencies

• must have adequate manufacturing info to ensure quality/consistency

• all safety data from phase 1 and 2

• Ongoing phase 3 data eval

• potential benefits outweigh known/potential risks

Types of clinical trials

• prevention

• screening

• diagnostic

• quality of life

• treatment

  • phases I-IV

• health services/outcomes trial

Pre-clinical study

• evaluate drug in tissue cultures and animal models

• obtain LD

• define organ-specific toxicity and reversibility of toxic effect

• define initial safe dosage for Phase I

LD

• lethal dose

• cause acute toxicity in 10% of animals tested

IND Exemptions

• not seeking to support new FDA approved indication

• not seeking to support a change in the marketing of a drug

• ex. phase 2 studies of marketed drugs, new routes/schedules of marketed drugs

Phase I

• healthy or patient volunteers

• small number (20-80)

• open label, dose escalation, randomized to different dose level

• goal: SAFETY

  • define appropriate dose, interval, route, safety, and toxicity

• starting dose: 1/10th of LD from pre-clinical study

• endpoints:

  • dose-limiting toxicity

  • maximum administered dose

  • maximum tolerated dose

  • optimal biologic dose

Dose-limiting toxicity

• set of unacceptable ADRs related to study drug

• pre-determined

• graded on scale of 1-5 (higher=worse outcome)

Maximum administered dose

highest dose which certain % patients develop DLT

Maximum tolerated dose

• dose level below MAD

• recommended phase 2 dose

Optimal Biologic Dose

• dose where maximal immunologic effect is observed in the absence of DLTs that define the MTD

  • in readily available tissue

  • with reliable measuring assay

  • optimal target inhibition must be pre-defined

Dose escalation methods

• sub-therapeutic doses, quickly enroll while maintaining safety

• rule based

  • no prior assumptions

  • up/down depending on toxicity

  • traditional: 3+3 rule (modified fibonacci design)

• model based (adaptive dose finding model)

  • establishes dose-tox curve prior to enrollment

  • utilizes statistical models. to find dose level based on toxicity data

  • requires real-time biostat support

3+3 design

• at dose 1, if no one has dose-limiting toxicity, move up to dose 2

• at dose 2 if no one has dose-limiting toxicity, move up to dose 3

• at dose 3, if one person has a dose-limiting toxicity, add 3 more people

• if dose 3 is tolerated by the 3 extra people, move 3 patients up to dose 4

• if 2/3 at dose 4 develop DLT → max admin dose; dose 3 → max tolerated dose

  • MTD decided when 6 pts treated at dose level with less than 2 DLTs

Limitations of Phase I

• potential risks without benefits

• small samples, inter-patient variability

• toxicity influenced by extensive prior therapy

Phase II

• patient volunteers

• large number of subjects (100-300)

• open label, randomized to single or double arms

• purpose: SAFETY and EFFICACY at fixed dose in specific indication

• starting dose: max tolerated dose from phase 1

• Endpoints:

  • response efficacy (labs)

    • commonly single arm

  • non-response (patient reported outcome tools)

    • randomization is required, blinding encouraged

    • prospective crossover encouraged

Phase II Two Stage Design

• accrue specific number of patients

• stop accrual and perform interim analysis

• stage II: obtain more patients and assess results

Simon’s Two Stage Design

assess treatment response

Bryant and Day Design

• toxicity and efficacy simultaneously monitored

• study drug is promising if response rate is greater than standard and less toxic

Population Enrichment Design

• target population that would benefit the most

• ex. targeted therapies with biomarker associations

2004 Critical Path White Paper

• modernized drug development

• comments, consultation with stakeholders

2006 Critical Path Report and List

• biomarker development

• streamlining clinical trials

Interim Analysis

• analysis of accumulating data

• pre-specified time points and decision rules

• allow design adaptations

• require statistical analysis

Data Monitoring Committee

• enhance safety of trial participants and scientific integrity

• randomized and interim analysis

• independent members (don’t work for investigators/manufacturers)

• clinical experts

Master Protocol

overarching protocol which evaluates one or more interventions in one or more diseases in the same trials

Adaptive Clinical Trial Designs

• model based phase I

• two stage design phase II

• Phase I/II seamless

• Phase II: adaptive randomization, drop the lose

• umbrella

• basket

• platform

Umbrella design

tests multiple targeted therapies in a single disease

Basket design

tests single targeted therapy in multiple diseases/subtypes

Platform design

• tests multiple targeted therapies in a single disease continuously

• experimental arms are added to trial anytime

• if arms show high positive complete response, graduate to phase 3 and revise randomization probability

Phase IV

• patient volunteers

• large number of volunteers (~1000)

• post marketing surveillance study

• goal: long-term safety/effectiveness

Types of Phase 4 studies

• non-interventional

  • treated with med and per standard of care

• large simple trial

  • combination of RCT and observational

  • routine practice along with randomization to diff tx

  • minimal monitoring

Investigational Drug Services Responsibilities

• study initiation

• drug accountability documentation

• investigational medication acquisition

• receipt/storage

• temp monitoring

• prep/dispensing

• transport

• destruction

• monitor visits

• staff training

• delegated responsibilities from PI