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

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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

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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

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Development phase work continued to grow in 2017

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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):

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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

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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

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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

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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

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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

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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?

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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”

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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

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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

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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

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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?

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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

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Thank You!