Transcript Thierry Le Chevalier, MD

How do International Regulatory
Groups View Clinical Trials and
Outcomes Measures?
Thierry Le Chevalier, MD
Outline
• Brief overview of regulatory authorities and their approval processes
• Discuss their perspectives on clinical trial endpoints in drug approval
What Is the Issue?
• A clinical trial is designed to evaluate (Phase II) and compare (Phase III) a
drug/drug combination/therapeutic modality with existing standard treatments
• A registration-driven study will mainly focus on the drug activity on the
disease, while an academic-driven study will mainly focus on the overall
effect of the treatment on the patient’s life (duration and QoL)
QoL = quality of life.
General Introduction and Background
• How has the field of drug use, manufacture and development evolved over the
centuries?
• To understand the current landscape of all aspects of medicine regulation, we
need to know how the story has developed, and country-specific issues
• To understand how to build a registration-driven study, we need to know the
rules
• To be the patients’ defenders, we need to evaluate the impact of the protocol
constraints on the patients
• This is not essentially “new” but has really come into its own in the past few
decades
Regulatory Mission
To protect and promote public health
• Quality, safety and efficacy
• Protection for users of medicines
• Adequate and appropriate information for patients and physicians
Harmonisation
The International Conference on Harmonisation
of Technical Requirements for Registration of
Pharmaceuticals for Human Use is unique in
bringing together the regulatory authorities and
pharmaceutical industries of Europe, Japan and the
US to discuss scientific and technical aspects
of drug registration
Brief Overview of Regulatory Authorities and Their
Approval Processes:
FDA, EMA, and MHLW/PMDA
FDA: Drivers for Regulation in the 20th Century
• The Pure Food and Drug Act of 1906 in the US, driven fundamentally by
concerns in food industry
• Harrison Narcotics Tax Act in 1914
• Elixir sulfanilamide 1937
• Thalidomide 1961
This followed on from a public health mission
that began in 1862
FDA Organisation
http://www.fda.gov/AboutFDA/CentersOffices/OrganisationCharts/ucm393155.htm. Accessed March 04, 2015.
FDA: Scope of Products Regulated
• Drugs (prescription and over-the-counter)
• Biologics
– Vaccines
– Blood products
– Biotechnology products and gene therapy
• Medical devices
• Veterinary products
• Food
• Consumer and medical radiation products
• Cosmetics
Seeking Approval: “Menu” of Choice
• Depending on the drug, disease, and business decision, consider:
Filing/review
type
Type of
approval
“Regular”
approval
Accelerated
approval
Orphan drug
(accelerated
vs. regular
approval)
Fast-track
designation
Priority
review
Standard
review
New
molecular
entity
“Me too”/
generics
Licensing Approval Scenarios
Regular approval on completion of Phase III clinical studies
• Full data package with sufficient data to demonstrate
– Safety and efficacy
– Clinical benefit
Accelerated approval
• Intended to make promising products for life-threatening diseases available on
the basis of preliminary evidence prior to formal demonstration of patient
benefit
• Approval based on a surrogate endpoint
• Considered provisional approval with a written commitment to complete
clinical studies
Filing Types
Fast track
• A process designed to facilitate the development and expedite the
review of new drugs that are intended to treat serious or
life-threatening conditions to fill an unmet medical need
• Benefits include:
– “Rolling submission” for a marketing application
– More-frequent meetings with the FDA to discuss development plans and ensure collection of appropriate
data needed to support approval
Priority review
• Offers major advances in treatment or provides a treatment where
no adequate therapy exists
• Goal for completing a priority review is 6 months (vs standard
of 10 months)
• Request for priority review is made by the sponsor at the time of
the new drug application filing
FDA’s Process Overview
Center for Drug Evaluation and Research
Courtesy of Thierry Le Chevalier, MD
Directives Shaped Regulatory Processes in EU
• In the UK the whole system was reshaped
– Committee on Safety of Medicines in 1963
– Yellow Card scheme in 1964
– EEC Directive 65/65/EEC – law, regulation and administrative action relating to
medicinal products
• Harmonisation took 10 years to develop
– Two directives in 1975 (75/318/EEC and 75/319/EEC)
– 87/22/EEC – introduced a centralised procedure and paved the way for Council
Regulation (EEC/2309/93 EMEA) and re-established CHMP to formulate opinion for
the agency
EEC = European Economic Community Clinical Trial Directive; EMA = European Medicines Agency;
CHMP = Committee for Medicinal Products for Human Use.
EMA
Coordination of drug licensing in the EU
Committees including:
• CHMP
• Committee for Orphan Medicinal Products
• Committee for Oncology Developments, Advanced Therapies and Paediatrics
Centralised vs decentralised (or mutual recognition) systems of approval
Proposed legal basis of applications (full or full-mixed)
Generic, hybrid or similar biological applications
Approval under exceptional circumstances
Conditional marketing authorisation
The role of the Scientific Advisory Committee
EMA = European Medicines Agency; CHMP = Committee for Medicinal Products for Human Use.
EMA/CHMP Organisation
Paediatric WP
•
•
•
•
•
•
•
Safety WP
Joint quality WP
Pharmacovigilance WP
Biological WP
Scientific advice WP
CHMP
HIV/viral disease
Anti-infectives (not HIV)
Cardiovascular
Central nervous system
Diabetes and endocrinology
Diagnostics
Oncology
Pharmacogenetics WP
Gene therapy WP –
Cell-based therapy WP
Blood products WP
Vaccines WP
Cell-therapy WP
WP on similar biological
medicinal products
EMA = European Medicines Agency; CHMP = Committee for Medicinal Products for Human Use; WP = working party
Quality Review of Documents.
EMA: Centralised Approval Procedure
Company files
application
Comments from member states
28 days
EMA
CPMP
Rapporteurs
210 days
Positive
opinion
issued
EU commission
EPAR and
marketing
authorisation
Launch
EMA = European Medicines Agency; CPMP = Committee for Proprietary Medicinal Products; EPAR = European
Public Assessment Report.
EMA: Licensing Approval Scenarios
Regular approval on completion of Phase III clinical studies
• Full data package with sufficient data to demonstrate
– Safety and efficacy
– Clinical benefit
Accelerated assessment procedure
• Rarely used by EMA
Drug Approval Process: EMA vs FDA
EMA
FDA
Source: CDER 21st Century Review Process (www.fda.gov); User Guide for Micro, Small and Medium-sized Enterprises
(www.ema.europa.eu). Accessed March 04, 2015.
Regulatory History in Japan*
• First regulation in Japan for the clinical development of
anticancer drugs issued in 1991
• Results from phase 2 trials using RR were accepted
• Phase 3 trials needed to be conducted post-approval
– Required only the protocol to be submitted at the time of approval
• However, almost no phase 3 trials were conducted after approval
• Guidelines revised in 2006
• Results from phase 3 studies with survival data are mandatory for
major cancers (NSCLC, GC, CRC, BC)
• Japanese regulatory authorities believe clinical data from
foreign patients to be of limited applicability to Japanese
patients and require a stand-alone development program
*Specific to oncology.
Maeda H et al. Ann Oncol. 2015;26:211-6.
Regulatory Authorities in Japan
Ministry of Health, Labour
and Welfare (MHLW)
Pharmaceuticals and
Medical Devices Agency
(PMDA)
National Institute of
Biomedical Innovation
(NIBIO)
MHLW Official: http://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/orphan_drug.html. Accessed March 04, 2015.
Regulatory Authority in Japan:
Functions of PMDA
Pmda
Its Key
Services
PMDA Official: http://www.pmda.go.jp/english/service/outline_s.html. Accessed March 04, 2015.
MHLW/PMDA: Approval Process
PMDA Official: http://www.pmda.go.jp/english/service/outline_s.html. Accessed March 04, 2015.
Duration of PMDA Review Process
PMDA Official: http://www.pmda.go.jp/english/service/outline_s.html. Accessed March 04, 2015.
Regulation in Japan:
Accelerated Approval and Surrogate Endpoints
Accelerated approval
• No formal regulation for accelerated approval program in Japan
Expedited programs
•
•
•
•
Priority review for orphan drug in patients with life-threatening disease
Orphan-drug designations
Public knowledge-based application
Special committee on unapproved drugs
Surrogate endpoints
•
The regulatory agencies in Japan accept surrogate endpoints as
endpoints supporting approval besides survival, but there are no
specific guidelines
Maeda H et al. Ann Oncol. 2015;26:211-6.
Tanimoto T et al. Invest New Drugs. 2013;31:473-8.
PMDA Official: http://www.pmda.go.jp/english/service/outline_s.html. Accessed March 04, 2015.
Drug Approvals: EMA vs FDA vs PMDA
Application characteristics
EU (EMA)
USA (FDA)
Japan (PMDA)
28
27
24
NBE rate
14%
19%
12.5%
OD rateb
62%
52%
37.5%
Expedited review rate
7%
81%
42%
Expedited approval rate
31%
33%
na
‘First-at-all-approved’ rate
18c
96%d
4%e
‘First-at-all-submitted’ rate
18%f
89%g
8%h
Median approval time
13.3 mts (95% CI: 12.5–14.4 mts)
6.0 mts (95% CI: 5.9–8.8 mts)
15.0 mts (95% CI: 12.0–18.3 mts)
Median active review time
6.6 mts (95% CI: 6.5–6.7 mts)
6.0 mts (95% CI: 6.0–8.9 mts)
nd
Median clock-stop time
4.2 mts (95% CI: 2.9–4.9 mts)
na
nd
Median administrative time
2.1 mts (95% CI: 2.0–2.7 mts)
na
na
Median ‘Time-to-submission’
delayj
–1.7 mts (95% CI: –0.9– –3.2 mts)
14.9 mts (95% CI: 6.29–24.1 mts)
Median ‘Time-to-market’ delayj
–7.2 mts (95% CI: –4.7– –15.0 mts)
25.1 mts (95% CI: 6.2–34.1 mts)
Number approvals
NMEa
Approval and review times
Expedited approval/review times
Expedited vs normal
Expedited vs normal
Expedited vs normal
Median approval time EA
14.6 mts vs 12.8 mts  = -1.8 mts
6.0 mts vs 7.7 mts  = -1.7 mts
na
Median approval time ER
9.0 mts vs 13.6 mts  = 4.6 mts
6.0 mts vs 9.8 mts  = 3.8 mts
14.2 mts vs 15.2 mts  = 1.0 mts
na
na
 (delta) = time difference; EA = expedited approval (EU: approval under exceptional circumstances and conditional marketing authorization; USA: accelerated approval); ER = expedited review
(EU: accelerated assessment; USA: priority review; Japan: priority review and/or expedited review); mts = months; na = not applicable; NBE = new biological entity; nd = no data; NME = new
molecular entities; OD = orphan designation.
aEight NME were simultaneously approved between January 2006 and December 2011 in all three regions. NME are defined as active ingredients, never before been marketed in the respective
territory in any form; bOD prevalence criteria (cases/inhabitants): EU <5/10,000, US <7.5/10,000, Japan <4/10,000; cFirst approved in EU: catumaxumab, histamine, mifarmutide, trabectidin,
vinflunine;dOnly bendamustine had been previously approved elsewhere (EU); eMiriplatin, approved in Japan only so far; fCatumaxumab, histamine, ipilimumab, trabectidin, vinflunine; gOnly
bendamustine, decitabine, and ipilimumab had been submitted first in the EU; hMiriplatin and eribulin; iFirst review cycle only; jIn comparison to EU based on paired observations, ie, calculated
from dossier submission and marketing authorization dates of those drugs which were approved in both regions.
Maeda H et al. Ann Oncol. 2015;26:211-216.
27
Differences in Drug Approval:
FDA vs EMA vs MHLW/PMDA
Example: Gemtuzumab ozogamicin in AML
Tanimoto T et al. Invest New Drugs. 2013;31:473-8.
Regulatory Authorities’ Perspectives on Clinical Trial
Endpoints
Clinical Trial Endpoint Selection in Last Two Decades
• Strict legal requirements to demonstrate benefit
– Randomised controlled trials (how many are necessary?)
– Primary endpoint: Valid and reliable measure that provides the most clinically
relevant and convincing evidence
– Wrong design or lack of efficacy the most important reason
for rejection
• The commonly used endpoints are based on
– Survival: OS then PFS
– Tumour response
– Symptom assessment
OS = overall survival; PFS = progression-free survival.
Clinical Trial Endpoint Selection in Last Two Decades (cont’d)
• Advantages and disadvantages
– OS: Historically viewed as the most effective way, as it addresses biology of tumour
and the natural history of the disease
– PFS: Progression is associated with tumour growth, assesses tumour shrinkage
and stabilisation of disease
Clinical Trial Endpoint Selection: EMA
Design of Pivotal Trials (N=47 approved indications)
RR: 22 (47%)
PFS: 16 (34%)
OS: 9 (19%)
Design
Endpoint
n
Reason for Accepting Design
Phase II
RR
18
PFS
2
Outstanding activity
AND
No established treatments
RR
PFS
OS
4*
14
9
Phase III
RCT
Rejected/Withdrawn Indications (N=13)
Design
Endpoint
n
Reason for Rejection
Phase II
RR
5
Non randomised
AND
No outstanding activity
Phase III
RR
6
•
•
•
•
OS
2
• No effect
• Wrong comparator
• Dose justification
Low level of response
Inadequate control
Target/size of population
Dose justification
*Variation of established drugs.
Eur J Clin Pharmacol. 2002;58(9):573-580.
32
Clinical Trial Endpoint Selection: FDA
Primary endpoints for new molecular entities
Proportion of clinical studies used to support approval using
various endpoints
Accelerated
Regular
Response rate
93%
53%
Survival
0%
12%
Time to progression
7%
20%
Symptom benefit
0%
12%
Other
7%
32%
Note: Totals are not 100% due to multiple endpoints.
S. Hirschfeld, presentation to the CBER Office of Cellular Tissue and Gene Therapy seminar on
November 16.
Talarico et al. ASCO 2005.
Clinical Trial Endpoint Selection: Japan
Changes in endpoints supporting approval for
oncology drugs before and after the revision of
the guideline for oncology drugs in Japan in 2006
Before the
guideline
revisiona
After the
guideline
revisionb
N
%
N
%
Survival
2
6.3
29
34.9
Response rate
26
81.3
28
33.7
Progression-free survival
0
0.0
15
18.1
Time to progression
2
6.3
5
6.0
Disease-free survival
1
3.1
2
2.4
Quality of life
0
0.0
0
0.0
Patient-reported outcomes
0
0.0
0
0.0
Other end points
1
3.1
4
4.8
Total
32
100.0
83
100.0
Endpoint
aBetween
bBetween
• Evolution in approval endpoints:
– ↑ OS and PFS
– ↓ RR
– ↓ Surrogate endpoints, except
PFS
the approval of drugs from Arpil 2001 and new drug application by March 2006.
new drug application from April 2006 and the approval of drugs by April 2014.
Maeda H et al. Ann Oncol. 2015;26:211-216.
34
Clinical Trial Endpoint Selection
• Phase III, confirmatory studies (Revision 3)
– Interim analyses/data maturity
– OS as primary endpoint, not response rate
– Possible: PFS when clinically relevant, symptom control
• Surrogate endpoints
– For accelerated approval: must predict clinical benefit over available therapy
• Overall response rate has been the most commonly used surrogate endpoint in
accelerated approval
Evolving Landscape in NSCLC
Requires a broader and more balanced view
• Issues:
– Pros and cons of OS vs PFS
– Patient-related outcomes
• How do you evaluate clinical benefit?
Use of biomarkers in targeting treatment
• Inclusion of biomarkers/companion diagnostics in the label
– Erlotinib
– Gefitinib
– Afatinib
NSCLC = non–small cell lung cancer.
Some General Rules and Observations
• No one size fits all solution
– The applicability of PFS is a case-by-case assessment
– It varies from health authority to health authority, according to tumour type and even
the line of therapy
• Regulatory authorities increasingly conservative on use of surrogate markers
in oncology
Q: Has there been a paradigm shift at the FDA on employing surrogates
for regulatory approval?
A: (Reviewer, Division Hematology Products, FDA): There is an
increasing reluctance to rely on surrogates as they often fail to capture
significant safety issues, which might impact the ultimate clinical outcome
Some Factors Determining Acceptance of PFS
Acceptance determined by:
Degree of validation of
PFS as surrogate for
clinical benefit, or, extent of
understanding that PFS
represents a clinical benefit
in itself
Tumour type
Stage of disease
and/or line of therapy
(including availability
of subsequent
therapies)
Trial design (e.g. blinded vs
open-label)
Data quality
(including independent
review)
Proven benefits of
comparator therapy
Magnitude of effect
Toxicity of treatment
Some Recent Observations and Future Trends
• PFS is proving more challenging to employ as a regulatory endpoint
– However, it will continue to have a future potential role in oncology drug registration
if rigorous acceptance criteria and standards are met
• There will be increasing regulatory pressure to link or associate PFS benefits
with other clinical trial outcomes that show direct clinical benefit (e.g. QoL
benefits, disease-related symptom benefits, OS positive trends)
– PFS may have its best future applications in symptomatic disease settings and/or
where delay in disease progression correlates with delay in symptom onset
– Benefit of delay of progression may also be measured by assessing QoL benefits
pre- vs post-progression, independent of study arm
What Are the Differences Between the FDA and EMA Regarding PFS as Primary
Endpoint for Registration?
• FDA is typically more stringent and critical of PFS than EMA in first-line or
early metastatic disease settings
– Various examples of products in first-/early line settings with easier EU registration,
but more difficult US registration
• Conversely, the FDA is often more accepting of PFS in later-line settings
– Delay of disease progression, particularly in symptomatic settings, often seen as a
direct clinical benefit in itself
– Refractory patients are "a more symptomatic patient population. Hence, a delay in
progression in a symptomatic population probably has a little more clinical meaning
than simply a radiographic delay in an asymptomatic patient population." R. Pazdur,
AVASTIN ODAC Dec 2007
– Various examples of products in later-line settings with easier US registration but
more difficult EU registration
Metastatic Breast Cancer (mBC) Example: Bevacizumab in the First-line Setting
Substance
and indication
Bevacizumab in
first-line mBC
(E2100; add-on to
paclitaxel vs
paclitaxel, PFS
primary endpoint,
open-label,
cooperative study)
FDA
EMA
Highly complex and difficult
regulatory background in US:
Relatively easily registered
in EU (Mar 2007) for
HER2+ and HER2–
• Docetaxel combination
registered in Jul 2009
• EMA reconfirmed
registration of paclitaxel
combination in Dec 2010
(but revoked docetaxel,
and refused capecitabine
combinations)
• sBLA withdrawn Sept 2006
• Resubmitted Aug 2007
• Negative ODAC Dec 2007
• Accelerated (provisional)
approval Feb 2008 for HER2–
• AVADO and RIBBON-1
confirmatory studies failed to
replicate PFS finding of E2100
• Negative ODAC Jul 2010
• FDA decision to withdraw mBC
indication Dec 2010
• Roche currently appealing
decision and proposing new
biomarker-based study
mBC = metastatic breast cancer; sBLA= supplementary biological license application.
Further Examples in mBC: Lapatinib and Ixabepilone in the Third-/Fourth-line
Setting
Substance
and indication
FDA
EMA
Lapatinib for treatment of
HER2+ mBC patients after
previous anthracycline,
taxane and trastuzumab
therapy
6-month priority review
(full approval Mar 2007)
Initial CHMP
recommendation after
14-month review. EU
Commission requested
reassessment. CHMP
re-evaluation, with
increased liver toxicity
warnings. EU Conditional
Approval Jul 2008
Ixabepilone for treatment,
either as monotherapy or
capecitabine combination
therapy, in patients failing
taxane and anthracycline
therapy
6-month priority
review
(full approval Oct 2007)
Marketing authorisation
approval withdrawn Jan
2009 after initial rejection by
CHMP; "very small increase
in survival did not outweigh
the concerns over the
medicine's safety"
mBC Example: Lapatinib in the First-line Setting
In contrast to third-line setting, first-line approval was easier in the EU
Substance
and indication
Lapatinib for
combination
therapy with
letrozole in
HER2+ breast
cancer
FDA
EMA
Jan 2010 accelerated
approval (provisional)
Apr 2010 full authorisation
• Significant post-approval
commitments, including OS
study of lapatinib/letrozole/
trastuzumab vs letrozole/
trastuzumab
Sometimes OS Does Not Suffice…Cetuximab in
NSCLC (FLEX Study)
• Rejected by CHMP in Nov 2009 (after appeal against initial rejection)
– Small OS benefit not balanced by significant increase in toxicity, plus negative
impact on PFS
– Company tried to identify positive subgroup of patients aged <65 years but rejected
by CHMP (retrospective analysis, concerns over multiplicity)
Can We Observe Any Trends?
EMA Example: mBC
PFS benefits in pivotal studies in mBC: All lines of therapy (CHMP)
PFS primary endpoint unless stated otherwise
Courtesy of Thierry Le Chevalier, MD.
Can We Observe Any Trends?
FDA Example: mBC
PFS benefits in pivotal studies in mBC: All lines of therapy (FDA)
PFS primary endpoint unless stated otherwise
Courtesy of Thierry Le Chevalier, MD.
What Did the Previous Slides Conclude?
Efficacy Conclusions: CHMP
PFS differences of 5–6 months and/or an improvement of PFS by factor
of two appear to be good determinants of a full approval
PFS benefits of 2 months or less very unlikely to receive approval (see revoked
bevacizumab indication based on 1.9 months in AVADO study)
The failure of RIBBON-1 with a PFS delta of a robust 2.9 months may
suggest that:
• The hurdle to gain approval via PFS has increased (compare 2.9 vs1.9 months of original full
approval of bevacizumab + docetaxel in AVADO in Q3 2009)
• It is not only necessary to have a significant absolute PFS delta, but it is also important to show a
significant relative improvement vs active comparator; fold-improvement in RIBBON-1 only 1.51,
compared with two for trastuzumab + anastrozole in TAnDEM or bevacizumab + paclitaxel in
E2100
Conditional approval of lapatinib + capecitabine in second-line setting with similar
data to ixabepilone may reflect more favourable safety profile of lapatinib/biomarkerselected population
• Lapatinib might have been rejected in current climate
What Did the Previous Slides Conclude?
Efficacy Conclusions: FDA
PFS differences of 5–6 months and/or an improvement of PFS by a
factor of two appear to be good determinants of an accelerated
approval unless statistically significant OS differences can be shown
(see eribulin)
The failure of RIBBON-1 with a PFS delta of 2.9 months shows that:
• Gaining approval in a first-line setting is more difficult compared with
second- or third-line (compare with ixabepilone and lapatinib in thirdline mBC)
• Not only necessary to have significant absolute PFS delta, but also
important to demonstrate significant relative improvement vs active
comparator; improvement in RIBBON-1 was only 1.51-fold
• Safety profile of test therapy, plus demonstration of other measures of
clinical benefit, have crucial role to play in overall assessment
Regulatory Perspective on Symptom Assessment Endpoints
• Symptomatic improvement is considered a clinical benefit
• However, measures of global health-related QoL have not served as primary
efficacy endpoints in oncology drug approvals
• For the improvement of signs and symptoms or QoL assessments to be used
as primary endpoints to support cancer drug approval, there must be a clear
distinction between improvement in tumour symptoms and lack of drug toxicity
– An apparent effectiveness advantage based on a global health-related QoL
instrument can simply indicate less toxicity rather than effectiveness
Problems With Symptom Data
Missing data and infrequent assessments
• Withdrawing treatment because of drug toxicity or tumour progression is one
cause of missing symptom data
• Ideally, when patients stop treatment, data collection forms should continue to
gather information to inform the analysis
• In fact, patients are often lost to follow-up when the treatment is discontinued
Biomarkers
• Predictive biomarkers do not serve as primary endpoints for drug approval
• Further research is required to establish the validity
of available tests and determine which biomarkers may predict clinical benefit
• May serve as elements of a composite endpoint
in the future
Summary
• The function of the regulatory authority is to protect and promote public health
• There are variations among the regulatory authorities’ organisations, approval
processes, as well as their prospective/preferences for approvable clinical
study endpoints
• In order to expedite the process of bringing novel and effective drugs to
patients and minimising suboptimal resource utilisation, these idiosyncrasies
must be taken into consideration when designing registrational trials and
applying for drug approval