Key Study Concept

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Key Study Concept
Seminar for Biocides Authorities, Sofia, 19 April
2006 Elisabeth Fassold Expert Centre Biocides
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Background

• TNsG on Dossier Preparation and Study Evaluation
  Part I Dossier Preparation,
  Chapter 4.2
• Core data requirements
• for the endpoints in BPD Annexes IIA and IIB at
  least one acceptable study or a justification for
  non-submission of data
• Additional data required?
• studies for the endpoints in BPD Annexes IIIA
  and IIIB may also be relevant
• In addition
• submission of any additional available data
  relevant to the risk assessment i.e. all valid
  studies per endpoint!
• key study definition
• a study regarded as sufficient and adequate to
  use for the risk assessment
• If no key study can be identified, an additional
  study has to be performed (if no satisfactory
  justification for waiving)

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Purpose of Selection of key studies

• common for existing substances several reports
  available on a specific endpoint
• each studys value to the risk assessment has to
  be judged individually
• detailed study summaries for all studies are
  laboursome and not necessary
• for risk assessment normally only GLP-compliant
  studies, where relevant, and test guideline
  studies are taken into account
• other studies serve to confirm the assessment or
  are not used because they are not relevant or
  adequate
• key study concept useful to distinguish the
  studies that need summarising in detail from
  those that do not

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Key study criteria and selection

• a key study
• is in accordance with principles laid down in the
  
• relevant Test-Guidelines, incl. GLP wherever
  possible,
• the TNsG DR, and
• the TGD on risk assessment
• is a tiered, transparent approach that ensures
  that at least one reliable study is defined as
  key study for each relevant endpoint
• has a certain flexibility to allow for special
  data conditions and risk assessment requirements
  following consultations with a Competent
  Authority.
• procedure for selection
• all study reports available for an endpoint are
  pre-evaluated,
• the most critical one is chosen,
• if not meeting the key study criteria, the next
  critical one, etc.

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Decision tree for defining level of detail for
studies
Pre-evaluate available study reports (starting
with most critical study)
Detailed study summary
NO
Yes
Key Study?
Other adequate studies
Less adequate study/ Inadequate study
Acc. to EC/ OECD Guidelines?
Detailed study summary with full description of
methods
Results more critical than in key study?
Yes
NO
NO
Study summary with IUCLID screening level of
detail.
Detailed study summary with description of
methods if deviating from guideline
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(Eco)toxicological studies (I)

• The key study for a specific endpoint is normally
  defined as the study, which results in
• the lowest no-effect value (below which no
  effects were seen for that endpoint in that or
  any other similar study) and/or
• the lowest effect dose (e.g. LD50 or LC50
  indicating highest toxicity)
• except where scientific evidence and the
  characteristic signs of toxicity for the
  substance in the relevant species indicates the
  contrary.
• The most sensitive species, among the relevant
  species, should normally be used

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(Eco)toxicological studies (II)

• IUCLID short summary of all studies performed
  (incl. the key results and the validity rating)
• from IUCLID study summaries the key study should
  be selected, justified and summarised in greater
  detail
• In case of several reliable studies based on
  different test guidelines on the same endpoint,
  the key study should be selected from the method
  with the highest sensitivity
• Several studies can be considered as key studies
  for the same endpoint (for example, when data is
  available on several species or different routes
  of exposure or if different results are observed
  in valid tests).
• Detailled summaries of all studies with
  positive findings for mutagenicity,
  carcinogenicity and teratogenicity!

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(Eco)toxicological studies (III)

• All data for key studies should be of an
  acceptable quality
• flexibility is necessary for studies with
  deficiencies, if they are crucial or support
  special risk assessment aspects
• this could apply
• to non-guideline studies
• to studies on endpoints not specifically required
  by the BPD
• to literature data if their result is crucial for
  risk assessm.
• this would apply
• to all carcinogenicity, mutagenicity and
  reproductive toxicity studies with positive
  results,
• this could also be relevant
• for studies on sensitive sub-populations or
• on mechanisms of action.

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Ecotoxicological studies

• For further details see Chapter 4.2.4,
  Ecotoxicological studies in
• TNsG on Dossier Preparation and Study Evaluation,
  Part I Dossier Preparation