Presentation on drug development challenges and clinical trial optimization. Originally presented at DIA China May 2017. The companion slide set is here as well-Optimizing Clinical Trials with Advanced Tools

1. Clinical Trial Optimization:
Making Every Patient Count
CAPT E. Dennis Bashaw, Pharm.D.
Dir. Division of Clinical Pharmacology-3
Office of Clinical Pharmacology
Office 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 be
considered, in whole or in part as being
statements of policy or recommendation
by the US Food and Drug Administration.
• Throughout the talk, representative
examples of commercial products will be
mentioned. No commercial endorsement
is 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 Act
uses the plural form in defining “substantial evidence” as “adequate and
well- controlled investigations, including clinical investigations.” See also
use of “investigations” in section 505(b) of the Act, which lists the
contents of a new drug application. which included a provision requiring
manufacturers 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-controlled
investigations, including clinical investigations, by experts qualified by
scientific training and experience to evaluate the effectiveness of the
drug involved, on the basis of which it could fairly and responsibly be
concluded by such experts that the drug will have the effect it purports or
is represented to have under the conditions of use prescribed,
recommended, or suggested in the labeling or proposed labeling
thereof.”

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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 emerging
concepts of the genetic and environmental basis of disease to
individualize prevention, diagnosis and treatment.
• Personalized genomics builds on principles established by the
integration 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
Clinical
Post-
Marketing
Tools
Decisions Target ID
ADME, Biomarkers, POC, Dose,
Efficacy, Safety, Approval, Labeling
Safety, New
Indication
Process Pre-IND
EOP2A
EOP2
NDA/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 cycle
To 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 say
without hesitation that early and competent communication
with a regulatory Agency is key to a proper decision-making.
– Competent in that the questions asked must be based on
science and not “hypothetical”
– Proper decision-making in that sometimes “killing” a drug
in development IS the right answer
• The FDA is open to discussion with individual sponsors and
consortia and there are many mechanisms to accomplish that
– InFY2015, FDA received over 3,000 formal PDUFA meeting
requests from sponsors
• From a regulatory standpoint the FDA has identified and had
codified 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 "immediately
necessary for an otherwise stalled drug development
program to proceed." This type of meeting refers to
meetings 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 is
any other kind of meeting.
– This includes “Discipline specific meetings” when you only have
issues for one review discipline such as Chemistry or Clinical
Pharmacology 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 Science
Science of developing new tools,
standards, and approaches to assess the
safety, efficacy, quality, and performance
of FDA- regulated products
Vision
FDA will advance regulatory science to
speed innovation, improve regulatory
decision- making, and get products to
people in need. 21st Century regulatory
science will be a driving force as FDA
works with diverse partners to protect
and promote the health of our nation and
the 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 for
many reasons including
the state of knowledge of
the disease, the existence
of biomarkers, and the
development of mature
academic research centers
for 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 Selection
Utilize in vitro and in
vivo systems to probe
and qualify biomarkers
PBPK Modeling
Build models based on
observed knowledge with a
“learn and confirm” strategy.
Classical PK/PD
Synthesize the
available PK/PD data
on Drug Metabolism
Develop
Actionable
Information
Informed labeling for the
prescriber
Pharmacogenomics
Utilize in vitro systems
to identify relevant
genetic factors to
enhance patient safety
and selection
Patient Selection
Understand 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-3
US FDA
10903 New Hampshire Ave
Building 51, Rm 3134
Edward.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