sme's in clinical trials
TRANSCRIPT
An agency of the European Union
Presented by: Melanie CarrHead of SME Office
SME’s in Clinical Trials
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Experience with SMEs to date….
Chemicals42%
Biologicals15%
Advanced therapy medicinal products
11%
Medical devices11%
Vaccines6%
Foods5%
Other10%
Categories relate to distinct products in the pipelines or ‘combined’ substances/products
520 companies assigned SME status currently
Product pipeline:
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SMEs registered with EMA
Research/Discovery15%
Pharmaceutical development
16%
Preclinical17%
Clinical exploratory16%
Clinical confirmatory12%
(Pre) Registration12%
Marketing12%
Phase of development:
Status of SME Applications for Marketing Authorisation for Human Medicines
Dec 2005- Dec 2010
1
-
4
13
2010
6
-
8
4
2009
6
2
5
12
2008
3
1
1
11
2007
3-Negative
1
-
10
2006
17Withdrawals
18Positive
50No. of applications
submitted
Total
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MAA outcomes over time for SMEs
0123456789
2006 2007 2008 2009 2010
positive opinions negative/withdrawals
For medicines for human use
Overall success rate for SMEs 47% vs 75% for all companies
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Questions raised & response timeAverage number of major objections:
§ 4 for positive MAAs (from 0 to 10)
§ 10 for negative/withdrawn MAAs (from 1 to 34)
Clincal efficay30%
Clinical safety12%
Preclinical10%
Quality43%
Clincal efficacy Preclinical Clinical safety Quality
Response time on average: 7 months
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Examples of Major Objections “Clinical”
• Discrepancy between studied patients & proposed indications
• Insufficient clinical package – one pivotal study
• Inadequate trial design
• Efficacy not demonstrated to significantly robust level
• Primary endpoint is not statistically significant
• Choice of dose not sufficiently justified
• Predefined criteria for clinical relevance not met
• Inconsistency in statistical methods between protocol & report
• Multiplicity issues
• Data do not allow comprehensive evaluation of safety profile
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Distribution of major objections relating to clinical efficacy for SME applications
Other15%
Marginal/No clinically relevant efficacy
20%
Analysis/robustness of pivotal data
15%
Validity of clinical trial data7%
General issue on study design
7%
Dose regimen justification relating to clinical efficacy
15%
Pharmacokinetics13%
Inadequate duration of treatment or insufficient long
term f/u8%
e.g.- “lack of evidence in single pivotal trial”- “primary analysis failed to show efficacy”- “no beneficial effects seen in ITT population, results based on post-hoc analysis in a sub-group…..”
- “Description & analysis of pivotal studies insufficient”-“Exclusion of patients from evaluation not acceptable & put overall results in question”-“Sensitivity analysis of primary outcome imputing discontinuations to worst category demonstrated non-robustness..”-“Switch of primary analysis of efficacy from superiority to non-inferiority not justified…”
- “quality of PK data extremely poor & does not allow assessment of PK parameters”- “data on biodistribution inconclusive due to methodological flaws….”
e.g. - major protocol violations - GCP issues
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Distribution of major objections relating to clinical safety for SME applications
Safety profile24%
Other4%
Lack of interaction studies relating to
safety12%
Safety database (size/quality/duration)
48%
RMP/PhVig system12%
- “safety population database was v. limited to enable less common measurement of adverse events”- “long term safety data lacking”- “safety database limited, especially in proposed indication & inconsistent”- “proper assessment hampered by small number of patients and fact pivotal study was an uncontrolled study…”
In terms of frequency and severity of adverse events
Scientific advice at the EMA
Drug development strategies
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Scientific Advice
•Scientific Advice can be given on ANY scientific question (pharmaceutical, non-clinical and clinical)
•No guideline available OR when not adhering to guidelines
•Product specific or Broad advice
•Confidential
•Fee incentives
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FAQs SA: Clinical
•Clinical pharmacology plan?
– PK/PD, dose-finding, interaction studies •Design key features exploratory/pivotal studies?
– endpoints (e.g. composite primary, QoL secondary…)– statistical plan– blinding– definition of patient population (inclusion and exclusion
criteria)?– comparator?– placebo-controlled study design acceptable in this indication?– proposed ‘standard of care’?
•Single pivotal study as basis for approval?
•Size of safety database at the time of marketing application?
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Closing Remarks
With increasing experience can identify areas where SMEs encounter problemsMajor objections run high particularly in area of quality and clinical efficacyObjections raised highlight need for scientific advice in specific areas
Observations:
Recommendations:Early Scientific advice is strongly encouragedMaximise dialogue with regulatory authorities as development proceeds
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Thank you for your attentionThank you for your attention
Contact SME Office:Tel +44 207 418 [email protected]
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