zwiers onco database findings - az-regulatory.com...ich s6 and s9 17 ich s9 nonclinical evaluation...

Registration of

oncology productsZwiers onco database findings

Why a database?

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Methodology

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Obtain data from the European Public Assessment Report

(EPAR; EMA website) in the period 2010-2017

Overall ~70 fields per product

Determine which data to collect and how, for example:

literature or safety pharmacology part of main studies;

which products are for treatment of advance cancer;

exclude hormone-sensitive cancers from reproductive

toxicology analysis

Example of EPAR

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Characteristics of database

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In total 71 drugs:

Small molecules 52 (73%), Biotech 19 (27%)

Non-advanced 29 (41%), Advanced 42 (59%)

Small Molecules Biotech

Non-advanced 20 (38%) 9 (47%)

Advanced 32 (62%) 10 (53%)

Total 52 19

What to expect?

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1. Procedures & timelines

2. Preclinical

3. Clinical

1. Procedures and timelines

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Is there an impact of conditional approval on time to

positive CHMP opinion?

Is there a difference for orphan drugs?

Are there products with no special status at all?

Small molecules versus biotech?

Does it hurt if you do not have scientific advice?

Does company size matter?

Procedural timelines

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Without Spec Status Conditional

approval

Accelerated

Assess

Small Mol (n=52) 358 (n=30) 400 (n=12) 212 (n=10)

Biotech (n=19) 417 (n=11) 330 (n=4) 197 (n=4)

Timelines ‘Without Special Status’

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Orphan Status

yes no

Small Mol (n=28) 348 (n=12) 351 (n=16)

Biotech (n=11) 486 (n=5) 359 (n=6)

Time required to answer first round of questions

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(in months)

> 3 months

15 Small mol ( 30%)

7 Biotech ( 40%)

Time required to answer first round of questions

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Small mol :212 (n=10)

Biotech :197 (n=4)

Scientific Advice meetings

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For 20% of the small molecule products no SA meetings!

Effect of scientific advice on review

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Small molecules

Effect of scientific advice on review

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Biotech

Timelines and company size

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Conclusions

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Is there a positive impact of conditional approval

on time to positive CHMP opinion?

No, only

for

biotech

Is there a difference for orphan drugs? No

Are there products with no special status at all? Yes – 30%

Small molecules versus biotech? Yes

Does it hurt if you do not have scientific advice? No

Does company size matter? Yes

2. Preclinical

ICH S6 and S9

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ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals

“In the development of anticancer drugs, clinical studies often involve cancer patients whose

disease condition is progressive and fatal.

In addition, the dose levels in these clinical studies often are close to or at the adverse effect

dose levels.

For these reasons, the type, timing and flexibility called for in the design of non-clinical studies

of anticancer pharmaceuticals can differ from those elements in non-clinical studies for other

pharmaceuticals.”

ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

“Regulatory standards for biotechnology-derived pharmaceuticals have generally been

comparable among the European Union, Japan and United States. All the regions have

adopted a flexible, case-by case, science-based approach to preclinical safety evaluation

needed to support clinical development and marketing authorisation. In this rapidly evolving

scientific area, there is a need for common understanding. “

Results - safety pharmacology

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Results - Genotoxicity

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Small molecules: if in vitro is positive, in vivo might not be warranted (S9)

Biotech: studies are not needed (S6).

For 50 compounds genotoxicity studies – 21 compounds were positive

Preclinical findings in general

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Small molecules:

• Development is comparable to typical small molecule;

• Often studies are conducted in 2 species (rodent/non-

rodent).

Biotech:

• Often studies were not conducted or only for 1 species,

as suggested by the S6 guideline.

• Effect of S9 guideline limited?

3. Clinical – what to expect?

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Are volunteers participating in studies for oncology

products?

Would you give a compound which is positive in genotox

studies to volunteers?

What is the typical size of the database?

How often do companies submit with only phase I/II data?

Are dedicated studies done for: pediatrics/QTc/ drug

interactions?

Healthy volunteers studied

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% of products (N of N)

Small Molecules 67 (35 of 52)

Biotech 5 (1 of 19)

Positive genotoxicity 19 (7 of 36)

Patient exposure

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Around 55% less than 1.000 subjects

Exposure categories

1: <500

2: 500-1000

3: 1000-1500

4: 1500-2500

5: 2500-3500

6: >3500

No Phase III

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N % Advanced Orphan Conditional

approval

Accelerated

Assessment

Small Mol 11 21 6 5 5 2

Biotech 5 26 2 5 5 2

Dedicated DDI and QT studies

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Special populations: pediatrics

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Products without pediatric studies (67) have:

- Class waiver (n=42)

- Product specific waiver (n=4)

- Deferred measures (n=20)

- Literature studied (n=1)

Pediatric study

N 4

% 6%

Type 3 small molecules, 1 biotech

Conclusions

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Are volunteers participating in studies for oncology

products?

Yes

Would you give a compound which is positive in genotox

studies to volunteers?

Yes

What is the typical size of the database? <1.000 in ~ 55%

How often do companies submit with only phase I/II

data?

20-25%

Are dedicated studies done for special populations/

pediatrics/QTc/ drug interaction?

Yes

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