the changing drug development and regulatory landscape...the changing drug development –and drug...
TRANSCRIPT
The Changing Drug Development and Regulatory Landscape
Peter P. Stein, M.D.Deputy Director
Office of New Drugs
Center for Drug Evaluation and Research
November 2018
Disclaimers
• Views expressed in this presentation are those of the speaker and do not necessarily represent an official FDA position
• I do not have any financial disclosures regarding products regulated by FDA
•3
The Changing Landscape….
• An overview of changes
• New targets, new approaches
• The (potential) role of real world evidence: a regulatory viewpoint
• Summary
•4
The changing drug development – and drug regulatory landscape
Changing scienceoIncreasing genomic/genetic characterization of
diseases – providing new targets
oIncrease molecular subtyping of diseases--targeting disease or subtype specific targets
oRecognition of molecular drivers in cancer
oNew platforms for “undruggable” targets: e.g., ASOs, siRNA , dual targeted MAbs
Changing development and regulatory approaches (PDUFA VI, Cures, SUPPORT)o Increasing role of patients and caregivers: patient-
focused drug development
o Focus on biomarkers: Biomarker Qualification Program, standardizing approach to surrogate endpoints for AA
o New approval pathways (e.g., LPAD) and rising requests for BTD, FT
o Changing nosology: tissue agnostic drug approvals
o Master protocols / platform trials / basket trials
o Rising efforts on decentralized trials, use of mobile technologies for trial endpoints and monitoring
o Efforts to integrate clinical research into practice (EHR to eCRF) to support pragmatic trials and RWE generation and focus on use of RWE in a wider range of regulatory decisions
o Adaptive trial designs and of other novel trial designs: Bayesian approaches, model-informed drug development
o Development of a common protocol template
Changing the types & targets of drugsoFewer drugs targeting common diseases with
more drugs targeting rare diseases
oFocus on disease subtypes: late stage disease or phenotypic or genetic subgroups
oDramatic increase in targeted cancer drugs
oRise in biosimilar and complex generics
oFocus on drug cost: FDA role - Drug Competition Action Plan, Biosimilar Action Plan
•5
The changing drug development – and drug regulatory landscape
Changing scienceo Increasing genomic/genetic characterization of diseases – providing new targets
o Increase molecular subtyping of diseases--targeting disease or subtype specific targets
o Recognition of molecular drivers in cancer
oNew platforms for “undruggable” targets: e.g., ASOs, siRNA , dual targeted MAbs
Changing the types & targets of drugso Fewer drugs targeting common diseases with more drugs targeting rare diseases
o Focus on disease subtypes: late stage disease or phenotypic or genetic subgroups
oDramatic increase in targeted cancer drugs
o Rise in biosimilar and complex generics
o Focus on drug cost: FDA role - Drug Competition Action Plan, Biosimilar Action Plan
•6
The evolution of drug targets over 10 years
16
2
18
10
60
11
32
17
49
6
30
15
0
10
20
30
40
50
60
70
Rare Disease Uncommon Cancer / Targeted Therapy
Targeted Therapy Non-rare Cancer Non-rare, Chronic Disease
Common Infectious Disease
2007-2008 2018
%
+ =
Preliminary, not validated
•Increased proportion of targeted therapies
•Increased proportion are drugs for rare diseases
•Among drugs for common, chronic diseases – most targeting late stage / failing other therapies, subgroups or subtypes of disease
•7
Development phase work continued to grow in 2017
•7
Data are from the PDUFA Workload Adjuster and represent a 12 month period of July 1st - June 30th
•8
Targeted therapy: identifying and targeting specific molecular defects
• Dramatic progress in cancer therapeutics based upon
identification and targeting of specific driving mutations
– First in 1998 (HER2), now many approved targeted therapies,
particularly for cancer
• Mutations in cystic fibrosis responsive to ivacaftor (enhances
chloride transport) to expand indications for use
New Guidance (2017):
•9
Effect of ivacaftor on lung function in patients with cystic fibrosis in a responsive mutation
Patients with a functional loss mutation (G551D) treated with ivacaftor vs pbo
Mutations causing absence of CFTR transporter protein
Mutations causing decrease in CFTR transporter function
From S Rowe et al NEJM 2005
From Ivacaftor prescribing information
•10
Using in vitro data to expand indicated use of ivacaftor in cystic fibrosis
In vitro sweat chloride assay –testing drug effect on Cl- transport in cell line expressing different CF mutations
Previously studied responsive mutation
Mutations showing response – increase in chloride transport
No response
Specific mutations added to labeled indication
Not indicated
From Ivacaftor prescribing information
•11
The changing drug development – and drug regulatory landscape
Changing development and regulatory approaches (PDUFA VI, Cures, SUPPORT)o Increasing role of patients and caregivers: patient-focused drug development
o Focus on biomarkers: Biomarker Qualification Program, creating a framework for the approach to surrogate endpoints for AA
oNew approval pathways (e.g., LPAD) and rising requests for BTD, FT
o Changing nosology: tissue agnostic drug approvals
oMaster protocols / platform trials / basket trials
o Rising efforts on decentralized trials, use of mobile technologies for trial endpoints and monitoring
o Efforts to integrate clinical research into practice (EHR to eCRF) to support pragmatic trials and RWE generation and focus on use of RWE in a wider range of regulatory decisions
oAdaptive trial designs and of other novel trial designs: Bayesian approaches, model-informed drug development
oDevelopment of a common protocol template
•12
Changes in drug and drug regulatory landscape
Approved Orphan Indications for all NDAs and BLAs† (including efficacy supplements) by CY
•Orphan indication: < 200,000 patients in US (or limited financial value)
•Orphan subset: subset of common disease (with < 200,000), and drug would not be appropriate for broader disease (MOA/efficacy/safety)
•If same as already approved drug, must be superior
•Benefits: tax credits, waiver of filing fees, 7-year exclusivity for indication
•13
Utilization of expedited development and review programs remained high in 2017
• Almost two – thirds (61%) of the
drugs approved in 2017 were
approved under Priority Review
• Over a third (37%) of the drugs
approved in 2017 received
Breakthrough Therapy
designation
• About four out of ten (39%) of
the drugs approved in 2017
received Fast Track designation
•13
•14
Increasing the role of the patient in regulatory decision making: patient-focused drug development
Pre-ClinicalDevelopment
Clinical Development
DiscoveryPost-
Approval
FDAReview
What are important therapeutic targets for the disease?
Developing trial endpoints (COAs)
What extent of improvement in the endpoint is clinically meaningful?
What benefit risk “ratio” is acceptable?
What is the experience post-approval?
Key areas of input from patients can include:
•Impact of disease on patient: important goals and targets for therapy
•Developing appropriate “tools” (e.g., patient-reported outcome endpoints)
•Progression of disease over time: understanding “natural history”
•Impact and burden of treatments and unmet needs
•How clinical trials can be improved, facilitating participation
•What benefits do patients seek and what risks are they willing to accept?
•15
Mobile devices: enhancing trial conduct and data collection
• Patient reported outcome tools-(dedicated devices or “BYOD”)
• Cell phones-videos, photographs
• Pedometers, accelerometers, electrocardiographs, thermometers, electroencephalographs, movement sensors, GPS, glucometers, spirometers
•16
Use of phone app to track drug ingestion: recent abilify “MyCite” approval
An application pairs with a patch that communicates with a device that marks when a pill has been ingested
FDA developing experience with programs for drug-device (software) combinations
•17
RWD/RWE: The potential and value of expanding regulatory use
• Much broader and diverse patient experience vs traditional Phase 3 clinical studies
– Includes settings and patients who will use drug post-approval
– Patients with broader age, racial/ethnic, co-morbid disease, disease severity, concomitant medication
• Very large sample sizes – potential for detection of infrequent events, drug-drug interactions
• Lower resource intensity
– Observational database studies: utilizing data from routine interactions of patients with their health care system
– Pragmatic clinical trials: usually non-blinded (low cost of drug supply), data emerging from patient’s usual health care - data extracted from EHR/claims, more limited eCRFs
•18
Wide spectrum of potential uses of RWD / RWE in clinical studies
Randomized InterventionalNon-randomized / non-interventional
Interventional non-rand’ized
Case – Control
Prospective Cohort Study
eCRF + selected outcomes identified using EHR/claims data
RWE to support site selection
RWE to assess enrollment criteria / trial feasibility
Mobile technology used to capture supportive endpoints (e.g., to assess ambulation)
Registry trials/study
Traditional Randomized Trial Using RWD Elements
Observational Studies
Trials in Clinical Practice Settings
Pragmatic RCT using eCRF (+/-EHR data)
Pragmatic RCT using claims and EHR data
Single arm study using external control
Retrospective Cohort Study (HC)
Prospective data collection
Using existing databases
Pragmatic RCTs
Increasing reliance on RWD
Traditional RCT RWE / pragmatic RCTs Observational cohort
•19
Many potential uses of RWE: beyond supporting regulatory decisions
+ having utility in regulatory decisions
• Assessing drug uptake and utilization, patterns of drug use
• Post-approval safety assessment: signal detection, signal evaluation using observational analyses or pragmatic RCTs
• Detection / evaluation of drug-drug interactions, medication errors
• Prospective observational studies (e.g., registries) to support initial approval or label expansion (e.g., in cancer, rare diseases)
• Pragmatic RCTs for new uses: new indications, populations, endpoints
• RWE observational database analyses to support label expansion
• Comparative effectiveness research: effectiveness / safety of approved drugs in broader populations in different practice settings – using observational database analyses or pragmatic RCTs
• Treatment strategy assessments using observational analyses or pragmatic RCTs, including a wide range of interventions and treatment approaches
• Measuring quality of care in health care delivery
• Assess alternative dosing regimens for established medications (e.g., ASA in the ADAPTABLE trial) in clinical practices
Relevant for physician practice and relevant for payors
•20
RWE in regulatory decision-making for drugs in US: current status
• RWE used for evaluation of safety of marketed products
– Sentinel provides access to large claims database to assess potential safety signals
• RWE used in regulatory decisions for oncology and rare diseases
– Define natural history, provides historical (external) control for interventional single arm trials
• Registry data: prospectively collected
• External control database using observational clinical dataset
– Regs (21 CFR 314.126): use of “historical control” for substantial evidence
• Otherwise, to date, limited use of RWE in drug regulatory decisions to support expanding indications
•21
Regulatory approach to rare disease approvals: the example of Brineura for CLN2
Brineura single arm clinical study / extension (n=22)
Natural history cohort (n=42)
•CLN2 (a neuronal ceroid lipofuscinoses) - rare inherited disorder of CNS (~2 to 4 of every 100,000 live births in US)
•Deficiency tripeptidyl peptidase-1 enzyme
•Late infantile form onset 2 - 4 yrs - language delay, seizures, ataxia; progressive, fatal disease
•Brineura (cerliponase alfa) - a recombinant human TPP1
Division worked closely with applicant; clinical evidence from single arm study, comparison to natural history cohort (nonconcurrent)
Estimated Time to Sustained 2-category decline or Zero scoreCox proportional hazards model
Analysis Day
Delivered into CSF through port
•22
The effectiveness requirement: the statutory standard for approval
• Requirement to demonstrate substantial evidence
• As defined in Section 505(d), substantial evidence is:
o “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.”
• FDAMA (1997) added flexibility: one A&WC trial and confirmatory evidence, if considered appropriate
• 21 CFR 314: defines characteristics of an adequate and well controlled study
22
•The FDA standardrequirement for two A&WC studies
•Reduces risk of false positive findings, bias or confounding in a single trial
•23
Application of the effectiveness requirement
• The statutory and regulatory framework for approval is notchanging (FDCA 505, 21 CFR 314)
• But, application will be tailored to the characteristics of individual programs
• One size does not fit all– Common, chronic diseases vs small population programs
– Serious and life-threatening illness with substantial unmet need vs drugs for less severe symptomatic disorders
– Feasibility and ethics of study conduct
• The application of our frameworks will change as the types of programs change
• And, will change as the reliability of new sources of effectiveness data – e.g., RWE, mobile technology, decentralized trials – becomes clearer
•24
Issues to consider: non-interventional RWE observational studies to support regulatory decisions
Key Parameters in Feasibility and Adequacy of Non-interventional Studies
The Research Question
Patient and Group Selection
The EndpointDatabase Quality and Traceability
• What “type” of research question
• Can the question be answered using RWD: are there sufficient patients
• Is the endpoint assessable –available in RWD
• Is patient selection appropriate
• Are comparison groups balanced
• Is patient management comparable
• Can the endpoint be assessed in RWD
• Are the outcomes accurately evaluated
• Is duration in RW database sufficient
• Database quality: accuracy, completeness
• Is data traceable to source
• Is source data available for inspection
And study integrity: pre-specification, posting, no data “dredging”
•25
Challenges and limitations of RWD/RWE for regulatory decisions: patient population / comparison group selection
• Assuring accurate patient selection
– Algorithms for case identification: validation that appropriate patients identified
– Selection of timepoint for starting study period to provide comparable exposure / comparable outcome risk between groups
• Assuring “study drug” and comparison groups balanced for risks for outcome
– Therapeutic equipoise - equal risk for outcome event (vs. randomization)
– Comparable disease status, patient risk factors so that study drug and comparator selection both reasonable alternatives
– Channeling biases related to known covariates and unknown covariates
• Assuring comparable patient management: co-interventions, testing
– Co-intervention use comparable between comparison groups: treatment selected, or patient status / risk factors may lead to differential co-interventions
– Patient’s disease status / risk factors or drug selected may lead to differential diagnostic intensity
•26
Drawing causal inference: RCT vs Observational analyses
Treatment selected
Patient’s risk of event
Outcome
Observational database analysis: Retrospective
Treatment decision (drug selected) not independent of patient’s risk of outcome of interest – so patient risk factors and treatment bothaffect event rate
Identify patients on specific treatments: drug to be studied and comparators
Meet
enrollment criteria
Enter trial
Study drug
Comparator
R
Large population of patients with target disease and status
Enrollment criteria restricts population
Access to sites, interest, time, willingness to participate
All factors influencing risk of outcome event balanced by randomization
Randomized clinical trial: prospective
Patients with target disease and disease status – in intended indicated
population
•27
Why expand use of RWD/RWE?
• Much broader and diverse patient experience vs traditional Phase 3 clinical studies
– Includes settings and patients who will use drug post-approval
– Patients with broader age, racial/ethnic, co-morbid disease, disease severity, concomitant medication
• Very large sample sizes – potential for detection of infrequent events, drug-drug interactions
• Lower resource intensity
– Observational database studies: utilizing data from routine interactions of patients with their health care system
– Pragmatic clinical trials: usually non-blinded (low cost of drug supply), data emerging from patient’s usual health care - data extracted from EHR/claims, more limited eCRFs
•28
But….reasons not to expand use of RWD/RWE
• However….many improvements in analytic and design
methodologies may overcome limitations of observational
analyses
– New user designs and new methods for matching to balance outcomes risks in drug and comparator groups
– Improving database quality (and quantity)
– “Hardening” of EHR; claims, EHR, and pharmacy database linkages
– Experience with pragmatic clinical trials and observational database analyses
• Risk of falsely concluding effectiveness from observational dataset analyses –
unclear if strong basis for causal inferences
• Double-blind RCTs “gold standard”: robust determination of efficacy (drug
works or doesn’t) and safety of primary importance in regulatory decision-
making
– Broader understanding of treatment effect estimate in indicated population highly
desirable – but not critical to regulatory decision
Can these solutions now allow us to draw robust causal inferences?
•29
The changing drug development – and drug regulatory landscape
Changing scienceoIncreasing genomic/genetic characterization of
diseases – providing new targets
oIncrease molecular subtyping of diseases--targeting disease or subtype specific targets
oRise in drugs targeting molecular drivers in cancer
oNew platforms for “undruggable” targets: e.g., ASOs, siRNA , dual targeted MAbs
Changing development and regulatory approaches (PDUFA VI, Cures, SUPPORT)o Increasing role of patients and caregivers: patient-
focused drug development
o Focus on biomarkers: Biomarker Qualification Program, standardizing approach to surrogate endpoints for AA
o New approval pathways (e.g., LPAD) and rising requests for BTD, FT
o Changing nosology: tissue agnostic drug approvals
o Master protocols / platform trials / basket trials
o Rising efforts on decentralized trials, use of mobile technologies for trial endpoints and monitoring
o Efforts to integrate clinical research into practice (EHR to eCRF) to support pragmatic trials and RWE generation and focus on use of RWE in a wider range of regulatory decisions
o Adaptive trial designs and of other novel trial designs: Bayesian approaches, model-informed drug development
o Development of a common protocol template
Changing the types & targets of drugsoFewer drugs targeting common diseases with
more drugs targeting rare diseases
oFocus on disease subtypes: late stage disease or phenotypic or genetic subgroups
oRise in biosimilar and complex generics
oFocus on drug cost: FDA role - Drug Competition Action Plan, Biosimilar Action Plan
•30
Thank You!