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§ 10 for negative/withdrawn MAAs (from 1 to 34)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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Contact SME Office:Tel +44 207 418 8575smeoffice@ema.europa.eu

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