How to Run A Clinical Trial Overview of Phase 1-3 · 2020. 4. 28. · How to Run A Clinical Trial Overview of Phase 1-3 Anita DiFrancesco VP of Clinical Operations. Samumed, LLC •

How to Run A Clinical Trial

Overview of Phase 1-3

Anita DiFrancesco

VP of Clinical Operations

Samumed, LLC• Samumed started operations in 2008 with headquarters in San Diego, CA

• Samumed is currently conducting clinical trials with several potential disease-modifying drug

candidates across a range of therapeutic areas with high unmet need including knee osteoarthritis,

oncology, and Alzheimer’s disease

Disclaimer

The views, thoughts, and opinions expressed in this presentation belong

solely to me, and not necessarily to my employer, Samumed.

3

Drug Development Timeline

Source: http://www.tech-res.com/TRIbune/Winter-2015/IssueImages/FDA-Expedited-Review-timeline-FINAL-crop.png

5,000 – 10,000

Compounds

250 5

AD clinical trials landscape

Universe of drugs

in development

J. Cummings et al. Alz & Dem 2019. 5: 272-293 5

Drug Development:

From IND to NDA

• Out of every 10,000 new compounds only 5 are consider safe for

testing in human subjects. One of these 5 will be approved for

marketing.

• Current cost of bringing a drug to market is ~$2.6 billion.

• Timeline from synthesis to approval = 10.5

‒ Entry into clinical to approval = 8 years

2014 Tufts University -Tufts Center for the Study of Drug Development.

Regulatory permission to proceed to human testing

• In US, Investigational New Drug (IND)

• In EU, Investigational Medicinal Products Dossier (IMPD)

• Other regions-

‒ Australia - Movement to Phase 1 is governed by Ethics Committees.

‒ Japan, China, Singapore, Taiwan- submission and process similar to US

‒ Latin America- similar but some countries have 2 levels of regulatory review

• Also allows for shipment of investigational drug

Investigational New Drug (IND) Submission

• Cover Letter

• Form FDA 1571: Investigational New Drug Application

(Instructions)

• Form FDA 3674: Certification of Compliance with Requirements

of ClinicalTrials.gov

• Table of Contents

• Introductory Statement/General Investigational Plan

• Investigator’s Brochure

Phase 1


5,000 – 10,000

Compounds

250 5

Phase 1 Objective

‒ Safety, Safety, Safety (MTD)

‒ Develop pharmacokinetics profile, pharmacodynamics

‒ Further understand pharmacodynamics

*Approximately 70% move to the next phase‒ https://www.fda.gov/ForPatients/Approvals/Drugs/

Sufficient information about the drug's

pharmacokinetics and pharmacological effects

should be obtained to permit the design of well-

controlled, scientifically valid, Phase 2 studies.

First in Man Phase 1-Study Design

• Single Ascending Dose

• Randomized, double blind, open label

• Locked overnight facility, commonly single site

• Healthy volunteers, usually compensated

• Continuous safety monitoring- kidney, liver, heart, signs and symptoms

• May have food restrictions

• PK sampling (pre drug and hourly after dose)

• Several cohorts of 6-8, total N 16-60

• Multiple Ascending Dose

First in Man Phase 1, Operations

• Site Selection

• Database Creation

• Plan Creation‒ Monitoring, Safety, eTMF

• Vendor Selection and Specification Development‒ May have very few or no vendors in this Phase

• Regulatory Document Collection

• Monitoring

• Database Lock

• Clinical Study Report

**If it wasn’t documented it didn’t happen

Phase 1 results

• Emerging side effect profile

‒ Maximum Tolerated Dose (MTD)

• PK characteristics – variability, linearity, dose proportionality.

• Steady state characteristics- accumulation and time-dependency

• Early understanding of drug elimination

Additional studies

• Which studies and when conducted depends on drug under study

‒ Populations – pediatric and elderly

‒ Kidney or Liver impaired Subjects

‒ Drug-Drug Interactions- How drug behaves when certain concomitant meds on

board

‒ Thorough QT Study (TQT)- To identify drugs that prolong QT interval which will

need monitoring in later stages of development

Phase 2


5,000 – 10,000

Compounds

250 5

Phase 2

• Originally, most drugs were developed with a two step Ph 2 program-

‒ 2a- Exploratory Proof of Concept – is it safe and does it do what we thought it

would do?...Biomarkers

‒ 2b – Confirmatory through larger population, additional doses…Biomarkers and

PROs

• Recently companies may try to conduct a single larger trial with multiple doses in a

effort to save time.

• Cost implications, adaptive design, biomarkers to PRO/long term outcome

• *Approximately 33% of drugs move to the next phase

Phase 2 – Study Design

• Issues to consider‒ Defining patient population

o Restrictive?

‒ Length of treatment-

o How long before it shows the effect and how long must it be sustained?

‒ Dose selection

o Comparator or placebo?

‒ How many patients do you need?

o Statistical sample size calculations

‒ How will you monitor safety?

o Are there AEs of interest?

‒ How will you measure effect? (biomarkers/imaging/PROs)

o Biomarkers are surrogates markers for how a patient feels, functions or survives

Phase 2, Operations

• Site Selection, multiple sites



• Vendor Selection and Specification Development‒ More vendors in this phase

‒ Vendors are becoming partners

‒ Specifications may be more exploratory


• Monitoring

• Database Lock





5,000 – 10,000

Compounds

250 5

Back to the FDA

• End of Phase 2 meeting

‒ Review results of Phase 2 studies

‒ Update on ongoing toxicology studies

‒ Update on CMC

‒ Seek agreement on studies needed for approval, additional CMC, and any other

potential obstacles to approval.

Agreement on Clinical Trial Design (Example)

• The proposed co-primary endpoints of the pivotal Phase 3 study consist of;

‒ a) Change from Baseline on the ADAS-cog

‒ b) Change in Severity on the ADCS-CGI

Phase 3

• Expand the population to acquire additional safety

• Ultimate test of Efficacy

• Label information

‒Approximately 25-30% of drugs move to the next phase

Phase 3, Design

‒ Prospective – protocol define objectives, hypotheses, measurement, analyses

‒ Control group- placebo, no treatment, active comparator, dose comparison, historical control

‒ Design – parallel, sequential or cross over.

‒ Subject selection – clear entrance criteria that assures subjects have condition or symptom or evidence of susceptibility to condition under study

‒ Bias - Minimize potential bias via randomization and blinding, assure active and control groups are comparable in characteristics.

‒ Measurement – outcome variables prospectively defined and measures reliable and valid (improves how a patient feels/functions/survives)

‒ Analysis – clearly stated statistical method including any planned interim analyses

‒ Must have statistically significant and clinically meaningful effectiveness

Phase 3, Operations

• Site Selection, multiple sites



• Vendor Selection‒ Vendor Partners-collaborate on study design

‒ Specifications are exact and well defined


• Monitoring

• Database Lock





5,000 – 10,000

Compounds

250 5

New Drug Application (NDA)

• All inclusive submission

‒ All human trials, integrated summaries of safety and efficacy

‒ Additional animal/laboratory testing

‒ Detailed CMC

The NDA documentation is the narrative story of the drug’s development including what happened in the clinical trials, what the ingredients of the drug are, the results of the nonclinical (animal) studies, how the drug behaves in the body, how it is manufactured, processed and packaged, plans for label.

Result of NDA Review

• 50% gain approval with first submission. Another 20% eventually gain approval

with additional work.

• Common reasons for failure -

‒ Efficacy more often than safety

ostudy endpoints, conflicting results, with dosage selection

‒ Safety – newly uncovered safety signals

‒ Issues with trial conduct which cause concern about data integrity

‒ CMC issues – methods, validation, API

•

Questions?

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Documents

How to Run A Clinical Trial Overview of Phase 1-3 · 2020. 4. 28. · How to Run A Clinical Trial Overview of Phase 1-3 Anita DiFrancesco VP of Clinical Operations. Samumed, LLC •