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GLP, quality assurance and some international guidelines

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  Introducing international guidelines – OECD, FDA,

 More details about GLP

  If you want to review a set of SOPs, look up our SOPs at

  http://labanimals.no/ADFDsop/index.html

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  Describe what you do, and how you do it   Then you should do what you have described

–  Must be documented   Minimum standards are introduced when

possible –  Instruments –  Animals –  Environment

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 Better quality to increase competitiveness  Avoid competition bias   Safer products

 Note: Animal welfare is not a main motivation, but has become more important

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 Laws - general and are enforced by legal system

 Regulations, provisions

 Recommendations  Guidelines

 ALL documents can be used in legal action – National authorities – WTO

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 Animal welfare act, Forskrift om forsøk med dyr

 Occupational health regulations –  Internkontrollforskriften, Arbeidsmiljølovcn

 Rules of competition – OECD – CFR USA – …and similar in all countries

  If OECD has guidelines, then these are de-facto standards

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 Arbeidsmiljøloven – Forskrift om internkontroll – Forskrift om kreftfremkallende stoffer – Forskrift om arbeid med biologiske faktorer

  detaljer om arbeid med mikroorganismer   Etc.

 Occopational health and safety

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  international standardization is closely related to: –  ISO 9001

  Part of a family of quality systems: – Good manufacturing practise – Good clinical practice – Good documentation practise

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  “GLP” - an international standard –  better science through standardization –  standardization -> reproducibility –  standardization - > avoid competitive edges

internationally, and product control – Scientific gains are obvious

 GLP is about PRE-CLINICAL STUDIES – But could (should?) be implemented for all

activity in the animal unit

OECDs GLP guidelines 1

•  Organization and personnel – Responsivbillities: Director, principal

investigator, all involved persons •  Facilities

–  buildings, •  4. Instruments, Materials,

Reagents

OECDs GLP 2

•  5 og 6 Test Systems, test objects – animals and animal products, other

organisms

•  7. Standard Operating Procedures = SOP – SOP, manuals, control, calibration – Forms to fill in to document the process

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GLP: Work flow that must be documented:   Ordering of animals, bedding, feed   Reception of animals   Acclimatization - quarantine & release from it   Start of experiment   Observations: Weight, inspection, clinical symptoms,

environmental parameters   End of study - autopsy, histology   Reporting   Archives   Inspections - internal & external

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GLP differs from…   AAALAC accreditation, that is primary concerned

about animal welfare (in a wide perspective)   And has more specific demands

  ISO 9001, that is a documenting system   Very comprehensive system

  -----------------------------------------------------------   GLP includes internal Quality Assessment

  You must have a QA unit with a master schedule for three kinds of inspections

  GLP is compulsory for a test site (def)

•  US standards •  More details than OECD

– Code of Federal Regulations – Guidelines for industry

•  detaljer -

•  US Food and Drug Administration will check if you follow the CFRs

[Code of Federal Regulations] [Title 21, Volume 7] [Revised as of April 1, 2001]

  From the U.S. Government Printing Office via GPO Access [CITE: 21CFR601.41]

[Page 38]

TITLE 21--FOOD AND DRUGS

DEPARTMENT OF HEALTH AND HUMAN SERVICES--(Continued)

PART 601--LICENSING--Table of Contents

Subpart E--Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses

Sec. 601.41 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.

FDA may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.

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Application Avvik - when things go wrong

Inspections OECD

guidelines & development

•  LD50 •  Humane end points

– NB: Very similar to FELASA recommendations (www.lal.org.uk)

OECD and LD50

•  Controversy over the procedure for 20 years (or more)

•  LD50 = the dose that kills 50% of the animals in a toxicity test –  Death = end point –  Nominal variable = statistical problem

•  PROBIT model

•  GHS stepwise procedure

Classical LD50 (and still required by

some)

Dose # anim #dead

50 7 0 100 7 0 500 7 0 1000 7 3

2000 7 7

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GHS stepwise procedure

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Bottom line: The importance of training

•  from –  researchers and lawmakers

•  FELASA guidelines

•  to – Caretakers