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INSTITUTE OF CLINICAL TRIALS & METHODOLOGY
Future-Proofing Academic Clinical Trials To Adapt
For Regulatory Use
Andrew Embleton15-Feb-2019
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2
Outline
ICON6 regulatory submission
Rationale
EMA submission review
Draft recommendations
Outline
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INSTITUTE OF CLINICAL TRIALS AND METHODOLOGY
THE ICON6 EXPERIENCE1
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Six cycles of platinum-basedchemotherapy Carboplatin/paclitaxel Carboplatin/gemcitabine Single agent platinum
Maintenance phase
Treatment continued to 18 months or until progression
(>18 for patients continuing to benefit)
Continueplacebo
Switch toplacebo
Maintenance cediranib
Chemotherapy + cediranib
Chemotherapy + placebo
Arm A(Placebo)
Arm B (Concurrent)
Arm C (Maintenance)
Chemotherapy + cediranib
Relapse >6 months after completion of first line
platinum-based chemotherapy
Randomise2 : 3 : 3
ICON6
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5ICON6
Hazard Ratio 0.57 (0.45–0.74)Log-rank p=0.00001
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Source Data Verification Quality Checking
ICON6
Blinded Independent Central Review
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7ICON6
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8ICON6
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9ICON6
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10ICON6
Submission
EMA following retrospective verification
Opinion within 210 days
With a couple of opportunities for pauses where AZ answer questions
Opinion was negative at interim
GCP inspection was requested
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GCP inspection
ICON6
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12ICON6
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INSTITUTE OF CLINICAL TRIALS AND METHODOLOGY
RATIONALE2
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Academic research needed because industry…
1. Cannot explore all options
2. Rarely investigate less common diseases
3. Prefers short-term outcomes
The most obvious differences to me are in terms of purpose and cost
Motivation
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INSTITUTE OF CLINICAL TRIALS AND METHODOLOGY
LITERATURE REVIEW3
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Looking for the interaction of two broad themes
Literature review
Academic-led trials Regulatory submission
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Regional regulatory approval (1)
Industry-academia interactions (4)
Academic drug discovery (2)
Trial conduct (2)
Data standards (2)
Literature review
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INSTITUTE OF CLINICAL TRIALS AND METHODOLOGY
REVIEW OF EMA LICENCE SUBMISSIONS
4
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20EMA review
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EPAR review
Understand the problem
Retrieval
Search process
EMA review
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22EMA review
Results
1141 medicines processed > 386 results > 109 relevant
Categorised as major, minor or micro involvement
25 (23%) major examples of academic involvement, 42 (39%) minor and also 42 (39%) micro
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23EMA review
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Name INN Status Indication Therapeutic area Trial use Main issueZometa zoledronic acid Withdrawn Extension Breast cancer Pivotal Lack of activity
Choice of reference armTrial conduct
Firazyr icatibant acetate Withdrawn Extension Hereditary Angioedemas Pivotal Trial conductStrimvelis autologous CD34+ enriched
cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence
Approved Initial Severe Combined Immunodeficiency
Pivotal -
Zemfirza cediranib maleate Withdrawn Initial Ovarian cancer Pivotal Size of effectTrial conduct
Lutathera lutetium (177Lu) oxodotreotide
Approved Initial Neuroendocrine tumors Supportive -
EMA review
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25EMA review
Approved
Majority
Approval rate comparable
Larger proportion that anticipated initial applications
Rare diseases – much more common, commercial interest?
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26EMA review
Withdrawn
Split initial/extensions
Majority not rare
All had major objections due to GCP
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27EMA review
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28EMA review
Mylotarg (gemtuzumab ozogamicin, EMEA/H/C/004204)
ALFA-0701, conducted and sponsored by the Acute Leukemia French Association (ALFA) group Also 5 non-commercial trials in supporting meta-analysis
– ALFA-0701– SWOG-S0106– MRC AML15– NCRI AML16– GOELAMS AML2006IR
For the treatment of acute myeloid leukaemia in patients above 15 years of age
Some retrospective safety data collection needed
Approved
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INSTITUTE OF CLINICAL TRIALS AND METHODOLOGY
DRAFT RECOMMENDATIONS5
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30Draft recommendations
ICON6
Regional, co-operative sponsors
Lead group oversight
Versioning of scales
Only enrol patients with Ethic’s approved, fully translated, consent forms
Formal IB communication
Whether these can be generalised to most trials or not is yet to be determined
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31Draft recommendations
More broadly
Academic-led trial use is possible
Gain more experience in collaboration on complex matters
Engage with the EMA – Scientific Advice
Awareness of potential issues – GCP inspection
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32Draft recommendations
Goal
Illustrate it is possible for successful submission of academic-led trials
Ultimately aiming to create a CONSORT-style framework of points to consider
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INSTITUTE OF CLINICAL TRIALS & METHODOLOGY
Future-Proofing Academic Clinical Trials To Adapt
For Regulatory Use
Andrew Embleton15-Feb-2019