planning a be study n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Planning a BE Study PowerPoint Presentation
Download Presentation
Planning a BE Study

Loading in 2 Seconds...

play fullscreen
1 / 62

Planning a BE Study - PowerPoint PPT Presentation


  • 212 Views
  • Uploaded on

Planning a BE Study. Training Program on Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence Jiaxing, Zhejiang, China 5 – 9 November 2007 Dr. Henrike Potthast (h.potthast@bfarm.de) temporary advisor to WHO. Guidance Documents.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

Planning a BE Study


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
planning a be study
Planning a BE Study

Training Program on Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence

Jiaxing, Zhejiang, China

5 – 9 November 2007

Dr. Henrike Potthast (h.potthast@bfarm.de)

temporary advisor to WHO

guidance documents
Guidance Documents
  • WHO Working Document Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability

November 2005

  • EU “Note for Guidance on the Investigation of

Bioavailability and Bioequivalence”

CPMP/EWP/QWP/1401/98 and related guidances and documents (www.emea.eu.int/pdfs/human/ewp )

  • FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000)
  • Canadian Guidance for Industry: “Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations used for systemic effects.” (1992)……………………….an related/others
some background information
Some Background Information

CTD

5.3 Clinical Study Reports

5.3.1 Biopharmaceutic Studies

(bioavailability and bioequivalence; “what does the product do to the drug substance”)

5.3.2. + 5.3.3 Human Pharmacokinetic Studies

(in situ and in vivo; „what does the body do to the drug substance”)

5.3.4 Human Pharmacodynamic Studies

(„what does the drug substance do to the body“)

5.3.5 Efficacy and Safety Studies

planning a be study some background information
Planning a BE Study Some Background Information
  • drugs are usually administered as dosage forms
  • the dosage form can affect drug bioavailability
  • differences in the pharmaceutical formulation can lead to different bioavailabilities
  • effects of formulation differences apply particularly to oral dosage forms and may be manifest at all stages of the absorption process
  • in vitro tests provide valuable information but are not necessarily a reliable guide to the bioavailability or therapeutic performance of the product
  • therapeutic equivalence between like formulations should not be assumed, unless therapeutic equivalence (bioequivalence) has been demonstrated in man; nor should therapeutic equivalence be assumed simply because therapeutic non-equivalence has not been reported

(nach D.N. Wade aus ‚Drug Treatment‘, Graeme S. Avery, 1980, Adis Press, Sydney))

planning a be study definitions
Planning a BE Study Definitions
  • Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!)
  • Bioequivalence – equivalent bioavailability within pre-set acceptance ranges
  • Pharmaceutical equivalence Bioequivalence
  • Bioequivalence Therapeutic equivalence
planning a be study definitions1
Planning a BE StudyDefinitions

♦„Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives AND if their bioavailabilities after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same.“

[section 2.4 of the EU guidance on BA and BE]

 possible surrogate for full clinical/toxicological documentation

planning a be study definitions2
Planning a BE StudyDefinitions

♦Bioequivalence is „…the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.“

[FDA Guidance for Industry Bioavailability and Bioequivalence Studies for orally administered Drug Products-General Considerations March 2003]

planning a be study definitions3
Planning a BE StudyDefinitions

♦„…Bioequivalence focuses on the equivalence of release of the active pharmaceutical ingredient from the pharmaceutical product and its subsequent absorption into the systemic circulation.“

[WHO Working Document Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability November 2005]

planning a be study definitions4
Planning a BE StudyDefinitions

♦„….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.“

[Faassen et al. Clin Pharmacokinet 43 (2004)1117]

 what does the product do to the drug substance?

planning a be study1
Planning a BE study
  • Bioequivalence Studies
  • in vivo comparison by means of volunteers serving as “in vivo dissolution model”
  • ‘biological quality control’

 comparison of product characteristics in order to ensure therapeutic equivalence

planning a be study ethical considerations
Planning a BE StudyEthical Considerations

IEC / IRB: ICH Definition

  • An independent body of medical, scientific and non-scientific members
  • Responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial
  • Among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects;
  • Independent “Risk-benefit” evalution
planning a be study ethical considerations1
Planning a BE StudyEthical Considerations

Composition requirementsICH GCP

  • At least 5 members
  • At least one member whose primary area of interest is a non-scientific area
  • At least one member who is independent of the trial site
  • Members without conflicting interest

Only those members independent of the investigator and the sponsor should review on a trial-related matter

planning a be study ethical considerations2
Planning a BE StudyEthical considerations

e.g. additional US FDA requirement for IRB composition:

  • Diverse backgrounds (race, gender, cultural, qualification)
  • Not entirely one gender
  • Special expertise may be invited but without voting rights
planning a be study ethical considerations3
Planning a BE StudyEthical Considerations

Required documents

  • Protocol (signed at least by the principal investigator)
  • Patient Information Sheet/Consent Form
  • Investigator´s Brochure
  • Subject recruitement procedures (e. g. advertisements)
planning a be study ethical considerations4
Planning a BE StudyEthical Considerations

Approval notification to Investigator as part of study report

  • Timely written approval
    • Identification of study (title, protocol number, version, investigator, site)
    • Specify all items reviewed
    • Date & place of review
    • Trial/study related decisions
    • Reasons for modifications & disapprovals

Minimum information required by ICH-GCP:

  • Date of the meeting
  • Documents reviewed (versions & dates)
  • List of members
planning a be study study protocol1
Planning a BE StudyStudy Protocol
  • „A document that describes the objective(s), design, methodology, statistical consideration and organisation of a trial. It usually gives the background and rationale of the trial …“

Ref.: ICH GCP Guidance

planning a be study study protocol2
Planning a BE StudyStudy Protocol

General Information/Title Page

  • Title
  • Protocol Number
  • Version Number/Date
  • Sponsor Details
    • Name, Address, Telephone
    • Monitor/Medical Personnel

 Responsibilities!

planning a be study study protocol3
Planning a BE StudyStudy Protocol

General Information/Title Page contd.

  • Investigator Details
    • Principal Investigator, Medical Doctor
  • Other Laboratory/Institution Details

 Responsibilities!

planning a be study study protocol4
Planning a BE StudyStudy Protocol

Protocol Development

Definition of Responsibilities

  • Organisation, premises, personnel & QMS
  • Clinical phase (timely data transfer ensured?)
  • Bioanalytical phase (timely data transfer ensured?)
  • Statistics and reporting (timely data transfer ensured?)
  • Archival
planning a be study protocol development
Planning a BE StudyProtocol Development

Drug substance / Drug products

basic knowledge about particularities e.g.

  • pharmacokinetics(t1/2, peak concentration, time of peak concentration, metabolism, variability?…)
  • practicability of roughly anticipated measurement period and/or wash-out period(crossover study possible?)
planning a be study protocol development1
Planning a BE StudyProtocol Development

Drug substance / Drug products

basic knowledge about particularities e.g.

  • important side effects(acceptable for healthy volunteers, concomitant medication necessary, acceptable regarding evaluation (e.g. vomiting); acceptable for women with childbearing potential?)
planning a be study protocol development2
Planning a BE StudyProtocol Development

Drug substance / Drug products

basic knowledge about particularities e.g.

  • concept of bioanalytical method available?
  • plasma concentrations sufficiently quantifiable (LOQ) – e.g. administration of more than one dosage form necessary/possible?
planning a be study protocol development3
Planning a BE StudyProtocol Development

DrugProducts

  • Availability
  • Certification
    • Content
    • In vitro dissolution
  • Preparation of investigative products per volunteer acc. to GMP
  • Protocol amendment for product details frequently necessary

(e. g. labeling)

planning a be study protocol development4
Planning a BE StudyProtocol Development

DrugProducts

  • batch size
    • pilot batch?
    • commercial batch?
  • not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)
planning a be study protocol development5
Planning a BE StudyProtocol Development

DrugProducts

  • assay
    • close to label claim
    • difference regarding the content of the investigative products (T and R) should preferably not be more

than 5 %

planning a be study study subjects
Planning a BE StudyStudy Subjects
  • Selection of subjects
    • participation of healthy volunteers (“in vivo model”)
    • reasonable inclusion and exclusion criteria (protocol and CRFs)
    • comprehensive verbal and written information and informed consent
    • volunteers´ insurance
    • reimbursement
planning a be study study subjects1
Planning a BE StudyStudy Subjects
  • Selection of subjects
    • males or females or both gender?
    • “…the sponsor may wish to include both…”(WHO)
planning a be study study subjects2
Planning a BE StudyStudy Subjects
  • Selection of subjects
    • Safe contraception for women (cave: interferences of contraceptives with investigative drug excluded?)
    • Phenotyping of volunteers (cave: possible side effects with e.g. “poor metabolisers” may cause drop-outs; variability reduction/explanation; fast and slow metabolizers evenly distributed in parallel group designs)
planning a be study study subjects3
Planning a BE StudyStudy Subjects
  • Selection of subjects
    • description of volunteers;smoker, vegetarian, phenotyping….
    • verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure…)
    • number of volunteers depending on variability; at least 12(EU: healthy, 18-55y; FDA: both sexes, > 18y)
    • randomisation

objective: minimising interindividual variability in order to detect product differences!

planning a be study study subjects4
Planning a BE StudyStudy Subjects
  • Number of subjects
    • Required sample size depends on intra-individual variability either known through reasonable literature or by means of a pilot study
      • “low” variability: ~ 12 – 20 volunteers
      • “high” variability: ~ 24 – 26 (plus) volunteers
planning a be study study subjects5
Planning a BE StudyStudy Subjects
  • Number of subjects ctd.
    • Required sample size depends on the expected mean difference between the test and reference formulation
  • For sample size calculation see also literature data (e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41; J Biopharm Stat 13 (2003) 529; Stat Med 18 (1999) 93 …)
    • Consideration of possible withdrawals
planning a be study study subjects6
Planning a BE StudyStudy Subjects
  • Number of subjects ctd.
    • Required sample size depends on the desired significance and power level
  • For sample size calculation see literature data (e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41; J Biopharm Stat 13 (2003) 529; Stat Med 18 (1999) 93 …)
planning a be study study subjects7
Planning a BE StudyStudy Subjects
  • Number of subjects
    • “The number of subjects to be used in the study should be estimated by considering the standards that must be passed. It should be calculated by appropriate methods (…). The number of recruited subjects should always be justified with the sample size calculationprovided in the study protocol. A minimum of 12 subjects is required.”

WHO – working document on multisource (generic) pharmaceutical products (QAS/04.093)

planning a be study study subjects8
Planning a BE StudyStudy Subjects
  • Subject withdrawals
    • subject must adhere to study requirements…

…however …

    • they are free to break off at any time!
    • definition of “drop-outs” in the protocol (reason, reimbursement policy, handling of data, follow-up…)
    • concomitant medication
    • reporting
planning a be study study subjects9
Planning a BE StudyStudy Subjects
  • Subject withdrawals contd…
    • subject must adhere to study requirements but …
    • define a time frame regarding vomiting depending also on pharmacokinetics of the drug substance, e.g. volunteers must be withdrawn in case vomiting occurs within 4 h postdose

“pre-specify!!”

planning a be study study design
Planning a BE StudyStudy Design
  • Randomization to a Crossover-design

“latin square” / balanced / randomized

  • Intra-individual comparison!
  • Parallel group design
  • Replicate design
planning a be study study design1
Planning a BE StudyStudy Design
  • others e.g.,
  • Parallel group design
  • Replicate design
planning a be study standardisation
Planning a BE StudyStandardisation
  • Procedure of drug intake
    • time of administration (fasted or fed state)
    • liquid volume
    • traceability of administrations
  • cave: e.g. granules, suspensions liquid formulations!

(require ‘method sheet’)

planning a be study standardisation1
Planning a BE StudyStandardisation
  • Fasted state e.g.
    • Confinement of subjects at least 10 h prior to drug administration
    • Last food intake ~10 h prior to drug intake
    • No food or fluids ~2 h prior to drug intake
    • Drug administration with ~150-200 ml (e.g.) water
    • Light standardized meal not before ~4 h post-dose
planning a be study standardisation2
Planning a BE StudyStandardisation
  • Standardized fluid and food intake(time, composition, amount)
  • Prohibition of alcohol
  • Restriction of xanthins(coffee*, tea, coke, chocolate, chewing gum, grapefruit….)
  • Standardized posture
  • Restriction of physical activities

*cave: withdrawal may cause headache

planning a be study standardisation3
Planning a BE StudyStandardisation
  • Fed state
    • Define time of drug administration and food intake, (e. g. drug intake within 30 min. before, immediately before or after the standardised meal)
    • High fat meal may serve to investigate the „worst case“ scenario
planning a be study study samples
Planning a BE StudyStudy Samples
  • Sampling
    • number of samples
    • sampling times (Cmax!)
    • time of sampling (extrapolated AUC max. 20 %)
    • wash-out-phase (not less than 5 half-lives)

 knowledge of basic pharmacokinetics of the particular

drug substance is inevitable!

objective: characterisation of ‚drug input‘!

(see e.g. sect. 3.1 of the EU guidance 1401/98)

planning a be study study samples1
Planning a BE StudyStudy Samples
  • Sampling times
    • appr. 3 – 4 to describe drug “input”
    • appr. 3 sampling times around peak concentration
    • appr. 3 – 4 to describe elimination

 Minimum!

planning a be study study samples2
Planning a BE StudyStudy Samples
  • Number of samples
    • sufficient to “describe” at least 80 % of total AUC
    • usually ~12– 18 samples (minimum)
planning a be study3
Planning a BE Study

Verapamil; BE study; Govi-Verlag 1989

planning a be study exceptional cases
Planning a BE StudyExceptional Cases!

„…Cmax is affected by the sampling points of truncated screening protocol. As isoniazid and pyrazinamide are highly soluble and highly permeable molecules resulting in rapid absorption….Cmax should be carefully evaluated…..AUC was found to be a robust parameter unaffected by sampling points….“

[Panchagnula et al., Pharmacol Res 48 (2003) 383]

planning a be study exceptional cases1
Planning a BE StudyExceptional Cases!

Panchagnula et al., Pharmacol Res 48 (2003) 383

planning a be study exceptional cases2
Planning a BE StudyExceptional Cases!

Panchagnula et al., Pharmacol Res 48 (2003) 383

planning a be study exceptional cases3
Planning a BE StudyExceptional Cases!

„The comparative Spearman‘s correlation analysis on the pharmacokinetic parameters Cmax, AUCt and AUCinf … showed that the 11 time points, namely 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h, were sufficient for demonstration of comparative bioavailability and bioequivalence of INH, RMP, PZA, and EMB, and that a schedule of six time points…..is not adequately reliable for determining the bioavailability and bioequivalence of anti-tuberculosis FDCs.“

[Gabriels et al., Int J Tuberc Lung Dis 11 (2007) 181]

planning a be study study samples3
Planning a BE StudyStudy Samples
  • Wash-out-phase
    • must be long enough to avoid residual concentrations
    • closely related to the limit of quantitation
    • metabolites may be considered
planning a be study sampling
Planning a BE StudySampling
  • Blood withdrawal equipment (consider bioanalytical method)
  • Preparation of plasma or serum
    • volume
    • cooling
    • anticoagulant
    • centrifugation
    • aliquotation
    • labeling
    • freezing
    • transport…
planning a be study bioanalytical method
Planning a BE StudyBioanalytical Method
  • The protocol should state
    • the bioanalytical method/detection
    • the limit of quantitation (1/10 of the expected peak concentration should be measurable)
    • the validation concept
    • whether metabolites are to be considered
planning a be study calculations
Planning a BE StudyCalculations
  • The protocol should state(-among others-)
    • the transfer of bioanalytical results for biostatistical calculations
    • the handling of missing data
    • the handling of digits
planning a be study calculations1
Planning a BE StudyCalculations
  • The protocol should state (-among others-)
    • calculation procedure/methods
    • characteristics (e.g. AUC, Cmax…)
    • possible consideration of differences of drug content
    • acceptance ranges – widening acceptable?!
planning a be study calculations2
Planning a BE StudyCalculations
  • single dose studies
    • reg. characteristics
    • AUC – extent of bioavailability(calculated by means of ‚trapezoidal rule‘)
    • AUCt – for single dose studies(t = last quantifiable concentration)
    • AUCinf – AUCt extrapolated to infinity (‚total exposure‘)

‚exposure‘

planning a be study calculations3
Planning a BE StudyCalculations
  • single dose studies
    • ‚rate‘ of bioavailability
    • Cmax – observed maximum concentration(peak exposure)
    • tmax – time at which maximum concentration occurs
planning a be study calculations4
Planning a BE Study Calculations
  • multiple dose studies
    • direct switching vs. wash-out
    • primary characteristics (e.g. AUCtau, Cmax, Cmin…)
    • consideration of fluctuation (e.g. Ptf…)
    • compare Cmin to ensure steady-state
planning a be study adverse events
Planning a BE Study - Adverse Events
  • Definitions and handling/information
    • Evaluation of seriousness
    • Evaluation of relation to investigative drugs
  • Treatment (cave: concomitant drug intake should be tested ‘a priori’ for possible analytical interferences)

serious but not study drug related 

planning a be study4
Planning a BE Study

THANK YOU FOR YOUR ATTENTION