Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Evaluation of Quality and
Interchangeability of Medicinal Products
10 – 14 September 2007
Dar Es Salaam, Tanzania
Dr. Henrike Potthast; Temporary Advisor to WHO
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
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
Pt WHO-consultantThe BfArM is a Federal Institute within the portfolio of the Federal
Federal Institute for Drugs
and Medical Devices
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
3
Pt WHO-consultantThe BfArM is a Federal Institute within the portfolio of the Federal
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Definitions
♦ „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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Definitions
♦ 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]
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Definitions
♦ „…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]
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Definitions
♦ „….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?
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Ethical 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
by,
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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Ethical Considerations
Composition requirements ICH 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Ethical 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Ethical 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)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Ethical Considerations
Approval notification to Investigator
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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Protocol
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Protocol
General Information/Title Page
♦ Title
♦ Protocol Number
♦ Version Number/Date
♦ Sponsor Details
♦ Name, Address, Telephone
♦ Monitor/Medical Personnel
♦ Investigator Details
♦ Principal Investigator, Medical Doctor
♦ Other Laboratory/Institution Details
Responsibilities!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Protocol
Protocol Development
Definition of Responsibilities
Organisation, premises, personnel & QMS
Clinical phase
Bioanalytical phase
Statistics and reporting
Archival
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Protocol Development
Drug substance / Drug products
basic knowledge about particularities e.g.
pharmacokinetics (t1/2, peak concentration, metabolism…)
practicability of roughly anticipated measurement period
and/or wash-out period (crossover study possible?)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Protocol Development
Drug substance / Drug products
basic knowledge about particularities e.g.
important side effects (acceptable for healthy volunteers?)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Protocol Development
Drug substance / Drug products
basic knowledge about particularities e.g.
concept of bioanalytical method available?
plasma concentrations sufficiently quantifiable (LOQ)
(administration of more than one dosage form necessary/possible?)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Protocol Development
Drug Products
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)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study 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!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study 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)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Subjects
Number of subjects
Required sample size depends on variability either
known through reasonable literature or by means of a
pilot study
“low” variability: ~ 12 – 20 volunteers
“high” variability: ~ 24 – 26 (plus) volunteers
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study 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 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Subjects
Subject withdrawals
subject must adhere to study requirements but …
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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Design
Crossover-design
“latin square” / balanced / randomized
Volunteer Period 1 Period 2
1 A B
2 B A
… … …
Intra-individual comparison!
Parallel group design
Replicate design
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Standardisation
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’)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Standardisation
Standardized fluid and food intake (time, composition, amount)
Prohibition of alcohol
Restriction of xanthins (coffee*, coke, chocolate, chewing gum,
grapefruit….)
Standardized posture
Restriction of physical activities
…
*cave: withdrawal may cause headache
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Standardisation
Fasted state
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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Standardisation
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 serves to investigate the „worst
case“ scenario
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Samples
♦ Sampling
♦ number of samples
♦ sampling times (Cmax!)
♦ time of sampling (extrapolated AUC max. 20 %)
♦ wash-out-phase (4 – 5 half-lifes)
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)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Samples
Number of samples
sufficient to “describe” at least 80 % of total AUC
usually ~12– 18 samples (minimum)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Samples
Sampling times
appr. 3 – 4 to describe drug “input”
appr. 3 sampling times around peak concentration
appr. 3 – 4 to describe elimination
Minimum!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Study Samples
Wash-out-phase
must be long enough to avoid residual concentrations
closely related to the limit of quantitation
metabolites may be considered
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Sampling
Blood withdrawal equipment (consider bioanalytical
method)
Preparation of plasma or serum
cooling
centrifugation
aliquotation
labeling
freezing
transport…
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Bioanalytical 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Calculations
The protocol should state (-among others-)
the transfer of bioanalytical results for biostatistical
calculations
the handling of missing data
the handling of digits
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Calculations
The protocol should state (-among others-)
calculation procedure/methods
primary characteristics (e.g. AUC, Cmax…)
possible consideration of differences of drug content
acceptance ranges
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
Modified Release Products
The protocol should state/ensure/consider
direct switching vs. wash-out
primary characteristics (e.g. AUCtau, Cmax, Cmin…)
consideration of fluctuation (e.g. Ptf…)
compare Cmin to ensure steady-state
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
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)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study-Results…
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Planning a BE Study
THANK YOU FOR YOUR
ATTENTION
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health