Planning a BE Study

pt consultant to WHO | November 20071 |

Planning a BE StudyPlanning a BE StudyPlanning a BE StudyPlanning a BE Study

Training Program on Pharmaceutical Training Program on Pharmaceutical Quality, Good Manufacturing Quality, Good Manufacturing Practice and BioequivalencePractice and Bioequivalence

Jiaxing, Zhejiang, China

5 – 9 November 2007

Dr. Henrike Potthast ([email protected])

temporary advisor to WHO


Guidance DocumentsGuidance DocumentsGuidance DocumentsGuidance 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 InformationSome Background InformationSome Background InformationSome 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 Planning a BE Study Some Background InformationSome Background Information

Planning a BE Study Planning a BE Study Some Background InformationSome Background Information

1. drugs are usually administered as dosage forms

2. the dosage form can affect drug bioavailability

3. differences in the pharmaceutical formulation can lead to different bioavailabilities

4. effects of formulation differences apply particularly to oral dosage forms and may be manifest at all stages of the absorption process

5. in vitro tests provide valuable information but are not necessarily a reliable guide to the bioavailability or therapeutic performance of the product

6. 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 Planning a BE Study DefinitionsDefinitions

Planning a BE Study Planning a BE Study DefinitionsDefinitions

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 StudyPlanning a BE Study DefinitionsDefinitions


♦ „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




♦ 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]




♦ „…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]




♦ „….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 studyPlanning a BE studyPlanning a BE studyPlanning 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 StudyPlanning a BE Study Ethical ConsiderationsEthical Considerations Planning a BE StudyPlanning a BE Study Ethical ConsiderationsEthical 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 StudyPlanning a BE Study Ethical ConsiderationsEthical ConsiderationsPlanning a BE StudyPlanning a BE Study

Ethical ConsiderationsEthical 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


Planning a BE StudyPlanning a BE Study Ethical considerationsEthical considerationsPlanning a BE StudyPlanning a BE Study

Ethical considerationsEthical 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




Required documents

Protocol (signed at least by the principal investigator)

Patient Information Sheet/Consent Form

Investigator´s Brochure

Subject recruitement procedures (e. g. advertisements)




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 StudyPlanning a BE Study Study ProtocolStudy 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




General Information/Title Page

♦ Title

♦ Protocol Number

♦ Version Number/Date

♦ Sponsor Details♦ Name, Address, Telephone♦ Monitor/Medical Personnel

Responsibilities!




General Information/Title Page contd.

♦ Investigator Details♦ Principal Investigator, Medical Doctor

♦ Other Laboratory/Institution Details

Responsibilities!




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 StudyPlanning a BE Study Protocol DevelopmentProtocol DevelopmentPlanning a BE StudyPlanning a BE Study

Protocol DevelopmentProtocol 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?)






important side effects (acceptable for healthy volunteers, concomitant medication necessary, acceptable regarding evaluation (e.g. vomiting); acceptable for women with childbearing potential?)






concept of bioanalytical method available?

plasma concentrations sufficiently quantifiable (LOQ) – e.g. administration of more than one dosage form necessary/possible?




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)




Drug Products

batch size pilot batch? commercial batch?

not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)




Drug Products

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 StudyPlanning a BE Study Study SubjectsStudy 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





males or females or both gender? “…the sponsor may wish to include

both…”(WHO)





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)




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!




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




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




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 …)




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 calculation provided in the study protocol. A minimum of 12 subjects is required.”

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




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




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 StudyPlanning a BE Study Study DesignStudy Design


Randomization to a Crossover-design

“latin square” / balanced / randomized

Intra-individual comparison!

Parallel group design

Replicate design

Volunteer Period 1 Period 2

1 A B

2 B A

… … …




others e.g.,

Parallel group design

Replicate design


Planning a BE StudyPlanning a BE Study StandardisationStandardisation


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’)




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




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




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 StudyPlanning a BE Study Study SamplesStudy 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 particulardrug substance is inevitable!

objective: characterisation of ‚drug input‘!(see e.g. sect. 3.1 of the EU guidance 1401/98)




Sampling times

appr. 3 – 4 to describe drug “input” appr. 3 sampling times around peak concentration appr. 3 – 4 to describe elimination

Minimum!




Number of samples

sufficient to “describe” at least 80 % of total AUC

usually ~12– 18 samples (minimum)







Verapamil; BE study; Govi-Verlag 1989


Planning a BE StudyPlanning a BE Study Exceptional CasesExceptional 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]




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




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




„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]




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 StudyPlanning a BE Study SamplingSampling

Planning a BE StudyPlanning a BE Study SamplingSampling

Blood withdrawal equipment (consider bioanalytical method)

Preparation of plasma or serum volume cooling anticoagulant centrifugation aliquotation labeling freezing transport…


Planning a BE StudyPlanning a BE Study Bioanalytical MethodBioanalytical MethodPlanning a BE StudyPlanning a BE Study Bioanalytical MethodBioanalytical 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 StudyPlanning a BE Study CalculationsCalculations


The protocol should state (-among others-)

the transfer of bioanalytical results for biostatistical calculations

the handling of missing data

the handling of digits




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?!




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‘




single dose studies

‚rate‘ of bioavailability

Cmax – observed maximum concentration (peak exposure)

tmax – time at which maximum concentration occurs


Planning a BE StudyPlanning a BE Study Calculations Calculations

Planning a BE StudyPlanning a BE Study Calculations 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 StudyPlanning a BE Study - Adverse Events - Adverse EventsPlanning a BE StudyPlanning a BE Study - Adverse Events - 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



THANK YOU FOR YOUR ATTENTION

Date post:	31-Dec-2015
Category:	Documents
Upload:	ryan-shepherd
View:	26 times
Download:	0 times