Clinical Trial Optimization:Making Every Patient Count

CAPT E. Dennis Bashaw, Pharm.D. Dir. Division of Clinical Pharmacology-3

Office of Clinical PharmacologyOffice of Translational Sciences

US Food and Drug Administration

Session 905:HOW TO IMPROVE DEVELOPMENT EFFICIENCY AND SAVE CLINICAL RESOURCE

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• The presentation today should not beconsidered, in whole or in part as beingstatements of policy or recommendationby the US Food and Drug Administration.

• Throughout the talk, representativeexamples of commercial products will bementioned. No commercial endorsementis either implied or intended.

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Outline

• The Cost of Drug Development

• Why Replicate Trials?

• Personalized Medicine

• Maximizing Value-Enrichment Approaches in Clinical Trials

• Communicate, Communicate, COLLABORATE!

• Conclusions and Closing Thoughts

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THE COST OF DRUG DEVELOPMENT

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Current Snapshot

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM536693.pdf

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Lengthy Process to Reach Market

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Updated Drug Development Cost Figures

J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012

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Need to Optimize Development is NOT a New Concern

Equivalent to 5.03 Billion Dollars

https://futureboy.us/fsp/dollar.fsp

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WHY REPLICATE TRIALS?

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Definition of “Substantial Evidence”

• Guidance for Industry-Providing Clinical Evidence

of Effectiveness for Human Drugs and Biological

Products

– Congress adopted the 1962 Drug Amendments, Section 505(d) of the Actuses the plural form in defining “substantial evidence” as “adequate andwell- controlled investigations, including clinical investigations.” See alsouse of “investigations” in section 505(b) of the Act, which lists thecontents of a new drug application. which included a provision requiringmanufacturers of drug products to establish a drug’s effectiveness by"substantial evidence." Substantial evidence was defined in section505(d)of the Act as “evidence consisting of adequate and well-controlledinvestigations, including clinical investigations, by experts qualified byscientific training and experience to evaluate the effectiveness of thedrug involved, on the basis of which it could fairly and responsibly beconcluded by such experts that the drug will have the effect it purports oris represented to have under the conditions of use prescribed,recommended, or suggested in the labeling or proposed labelingthereof.”

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The Cost of Research vs Ease of Conduct

High

Low

Single Center Randomized Trials

Low

Single Case

Reports

Cohort Studies

Case-Control Studies

Case Series

HighEase of conduct

Multi-Center Randomized Trials

Cost

This has been the traditional view, but can we develop new paradigms

of drug research to slow this trend (unlikely to reverse costs)

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Making Every Patient Count

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Linear vs. Iterative Process

http://www.irnd3.org/presentations/ASPCT_rare_diseases_March_11_2016.pdf

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PERSONALIZED MEDICINE

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Heterogeneity in Response to Medicines In Clinical Trials

Benefit

Harm

Adapted from presentation by Dr. Barbara Evans, ASCPT Annual Meeting (2010)

Frequency of various responses in the RCT treated population

Neither harm or benefit --Nonresponders(50%)

Mixed Benefit and Harm (30%). Small benefit for most.

Harm Without Benefit (10%)

Large Benefit with little harm (10%)

Magnitude

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Personalized Medicine & Personalized Genomics

• Personalized medicine uses traditional, as well as emergingconcepts of the genetic and environmental basis of disease toindividualize prevention, diagnosis and treatment.

• Personalized genomics builds on principles established by theintegration of genetics into medical practice.

• Principles shared by genetic and genomic aspects of medicine,include the use of variants as markers for diagnosis, prognosis,prevention, as well as targets for treatment.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128266/

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Quantitative Tools During Drug Development

Basic Research

Non-Clinical

ClinicalPost-

Marketing

Tools

Decisions Target IDADME, Biomarkers, POC, Dose,

Efficacy, Safety, Approval, Labeling

Safety, New

Indication

Process Pre-INDEOP2A

EOP2NDA/BLA

Quantitative ModelsMechanistic Empirical

Innovative Designs

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Personalized Medicine in the Age of Biomarkers

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Decreased Development Time

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=10588&pubmed-linkout=1

A net decrease in

development time of 34

months or almost 3yrs

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MAXIMIZING VALUE ENRICHMENT APPROACHES IN CLINICAL TRIALS

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Average Efficacy and Safety of Drugs in Clinical Trial Participants

% of patients achieving a clinically significant response

Source: Steven Paul, CEO, Lilly

Leading causes of deaths in the United States for 2006

Source: Centers for Disease Control

BENEFIT RISK

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Enrichment Trial Design

Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413

• Can be viewed as a modification of a

standard trial design where patients

screened for trial enrollment are

evaluated for a specific mutation prior

to treatment randomization

• Those with the mutation are then

randomized to therapy

• Those without the mutation are

removed from the trial

• Following screening the population

remaining in the trial is “enriched”

towards responding rather than a

naive randomization without screening

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Umbrella Trials

Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413

• An umbrella trial is restricted to patients

with a single primary site or histologic type

of cancer.

• Those with “actionable” mutations are

grouped together by mutation and are

randomly assigned to therapy that is

mutation “specific”.

• Those without actionable mutations are

removed from the trial.

• The leverage here is that more than one

drug or treatment regimen can be

evaluated based on the observed

mutations.

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Basket Trials

Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413

• Patient eligibility is based on a defined

genomic alteration rather than on primary

site.

• They can be nonrandomized or

randomized and can include more than

one drug

• In a multi-drug basket study, for each

drug studied, all of the patients share a

common mutation but have different

primary disease sites. The primary

disease site deter-mines the cell type of

the tumor, and this may influence

responsiveness to a drug in addition to

mutations present in the tumor.

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Adaptive Trial Designs

• Adaptive aspects can be incorporated into most trial designs, including the standard cross-over and parallel designs.

• It incorporates intermediate looks at the defined times during the trial and then re-adusting the trial by:

– Enrolling more patients

– Re-evaluating dosing levels

– Changing treatments

– Evalutaing multiple biomarkers

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REGULATORY APPROACHES

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Fast Track Designation

• Drug intended to treat a serious condition

• Nonclinical or clinical data needed to

demonstrate the potential to meet an

unmet medical need.

Breakthrough

• Drug intended to treat a serious condition

• Must be preliminary clinical evidence to

indicate the drug may substantially improve a

clinically significant endpoint compared to

available therapies

Priority Review

• Drug must treat a serious condition and, if

approved, offer a significant improvement in

safety or effectiveness

• Designation assigned only at the time of the

original NDA or efficacy filing

Accelerated Approval

• Drug must treat a serious condition and

generally provide a meaningful advantage over

available therapies

• Must demonstrate an effect on a surrogate

endpoint that is likely to predict a clinical

benefit or on a clinical endpoint

FDA’s “Accelerated” Pathways

Entering Drug

Development cycleTo Market

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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Accelerated Pathways Under PDUFA-V

https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm552923.pdf

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Use of Special Programs 2016

• Total NME’s Approved - 22

• Priority – 15

• Orphan Drugs – 9

• Fast Track – 8

• Breakthrough – 7

• Accelerated – 6

• Two - 5

• Three - 4

• Four - 4

• Five - 1

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM536693.pdf

73% of all NME Approvals Used One or More Designation

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COMMUNICATE, COMMUNICATE, COLLABORATE!

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Why Communicate?

• Based on my 30yr experience in drug development I can saywithout hesitation that early and competent communicationwith a regulatory Agency is key to a proper decision-making.

– Competent in that the questions asked must be based onscience and not “hypothetical”

– Proper decision-making in that sometimes “killing” a drugin development IS the right answer

• The FDA is open to discussion with individual sponsors andconsortia and there are many mechanisms to accomplish that

– InFY2015, FDA received over 3,000 formal PDUFA meetingrequests from sponsors

• From a regulatory standpoint the FDA has identified and hadcodified key time points for meetings with industry.

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Communication: The A, B, C’s

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A-B-C Meetings

• Type A Meeting – is a meeting that is "immediatelynecessary for an otherwise stalled drug developmentprogram to proceed." This type of meeting refers tomeetings to resolve disputes, talk about clinical holds,special protocol assessments.

• Type B Meeting – these are listed as (1) pre-IND meetings,(2) certain end of Phase I meetings, (3) end of Phase 2/pre-Phase 3 meetings and (4) pre-NDA/BLA meetings.

• Type C Meeting – can you guess? Yes, a Type C meeting isany other kind of meeting.– This includes “Discipline specific meetings” when you only have

issues for one review discipline such as Chemistry or ClinicalPharmacology and the other review disciplines are not required

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Clinical Pharmacology Advice on the Development of Personalized Medicines

• AD, assay development; BCS, biospecimen collection/storage; DA, data analysis; ED, exposure/dosing; FDA, US Food and Drug Administration; IND, investigational new drug application; PS, patient selection; Saf, safety; TD, trial design.

Key Milestones in Development

http://onlinelibrary.wiley.com/doi/10.1038/clpt.2013.32/full

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www.fda.gov/downloads/scienceresearch/specialtopics/regulatoryscience/ucm268225.pdf

Regulatory ScienceScience of developing new tools,standards, and approaches to assess thesafety, efficacy, quality, and performanceof FDA- regulated products

VisionFDA will advance regulatory science tospeed innovation, improve regulatorydecision- making, and get products topeople in need. 21st Century regulatoryscience will be a driving force as FDAworks with diverse partners to protectand promote the health of our nation andthe global community

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2. Stimulate Innovation in Clinical Evaluations & Personalized

Medicine to Improve Product Development and Patient Outcomes

4. Ensure FDA Readiness to Evaluate Innovative Emerging

Technologies

6. Implement a New Prevention-Focused food Safety System to

Protect Public Health

5. Harness Diverse Data Through Information Sciences to Improve

Health Outcomes

7. Facilitate Development of medical Countermeasures to Protect

Against Threats to U.S. and Global Health and Security

8. Strengthen Social and Behavorial Science to Help Consumers

and Professionals Make Informed Decisions about Regulated

Products

1. Modernize Toxicology to Enhance Product

Safety

3. Support New Approaches to Improve Product Manufacturing

and Quality

Science Priority Areas

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Partnership Matrix

Ramsey BW et al. N Engl J Med 2017;376:1762-1769

Partnership roles vary formany reasons includingthe state of knowledge ofthe disease, the existenceof biomarkers, and thedevelopment of matureacademic research centersfor a particular disease.

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CONCLUSIONS AND CLOSING THOUGHTS

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The Future

• It is easy to say that we are on the edge of a revolution in drug development

– We have ALWAYS been on the EDGE!

– Only the tools and our perspective of them have changed

• Patient factors are being recognized more and more as the key to individualizing not only drug therapy but expectations of therapy.

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Missing Patients

• Clinical trials still have an underrepresentation of all affected populations

• Genetic, social, patient care, and drug delivery factors are often missed with serious consequences

• It was only 24yrs ago that the FDA started requiring the enrollment of women in clinical trials.

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Linkage of Patient Factors to PK and PD

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Communicating the Future

• As new advances are made, they must be reflected both in regulatory policy and in patient care

• While we rightly focus on the population, we must not lose sight of the individual patient and the individual physician, nurse, and pharmacist as well

• Clinical Pharmacology can help identify populations and broaden patient utility and safety

• Only by selecting the right biomarkers and identifying the proper dose for the patient population can we make “every patient count” as every patient is a teaching opportunity for us

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Collaborative Efforts to Strengthen Regulatory Science

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Combining the Workstreams

Biomarker SelectionUtilize in vitro and in

vivo systems to probe

and qualify biomarkers

PBPK ModelingBuild models based on

observed knowledge with a

“learn and confirm” strategy.

Classical PK/PDSynthesize the

available PK/PD data

on Drug Metabolism

Develop

Actionable

InformationInformed labeling for the

prescriber

PharmacogenomicsUtilize in vitro systems

to identify relevant

genetic factors to

enhance patient safety

and selection

Patient SelectionUnderstand the pathology

of the disease to select

the needed diversity in the

affected population

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Concluding Thought

“If I had five minutes to

chop down a tree, I’d spend

the first three minutes

sharpening my axe.”

Abraham Lincoln

Rigorous preparation is the key to success

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Contact Information

CAPT Edward D. Bashaw, PharmD.Director, Div. of Clinical Pharmacology-3US FDA10903 New Hampshire AveBuilding 51, Rm 3134Edward.Bashaw@fda.hhs.gov

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Acknowledgements

• The Staff of the Division of Clinical Pharmacology-3

• The Office of Clinical Pharmacology

• The Office of Translational Sciences

• The Drug Information Association-China