Artemisinin combined medicines, Kampala, February 2009 1 |1 | Training workshop on regulatory requirements for registration of Artemisinin based combined

Artemisinin combined medicines, Kampala, February 20091 |

Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to

regulatory authorities

Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to

regulatory authorities

Why are bioavailability / bioequivalence studies necessary?

An Introduction to Bioequivalence StudiesPresented by: Hans Kemmler, Consultant to WHO

Accra, 5.Nov. 2008


Background:Background:First Product to MarketFirst Product to Market

Background:Background:First Product to MarketFirst Product to Market

Innovator’s Product

Quality

Safety and efficacy– Based on extensive clinical trials– Expensive– Time consuming


Background:Background:Other products with same medicinal ingredientOther products with same medicinal ingredient

Background:Background:Other products with same medicinal ingredientOther products with same medicinal ingredient

Subsequent-entry products

Generic products

Multisource products

How do these products gain marketing authorization?


Pharmaceutical equivalencePharmaceutical equivalence

Same amount of the same active pharmaceutical ingredient– Salts, esters

Same dosage form– Comparable dosage forms– e.g., tablet vs. capsule

Same route of administration

Is pharmaceutical equivalence enough?


Sometimes pharmaceutical equivalence is enough

Sometimes pharmaceutical equivalence is enough

Aqueous solutions– Intravenous solutions– Intramuscular, subcutaneous– Oral solutions– Otic or ophthalmic solutions– Topical preparations– Solutions for nasal administration

Powders for reconstitution as solution

Gases


Sometimes it is not enoughSometimes it is not enough

Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence

Therapeutic equivalence:– Pharmaceutically equivalent– Same safety and efficacy profiles after administration of same

dose


Pharmaceutical EquivalentsPharmaceutical Equivalents

Possible Differences

Drug particle size

Excipients

Manufacturing Equipment or Process

Site of manufacture

Test Reference

Could lead to differences in product performance in vivo


Additional data is requiredAdditional data is required

Oral immediate release products with systemic action– Generally required for solid oral dosage forms

• Critical use• Narrow therapeutic range• Bioavailability problems associated with the active ingredient• Problematic polymorphism, excipient interaction, or sensitivity

to manufacturing processes


Additional data is requiredAdditional data is required

Oral modified release products with systemic action

Fixed dose combination products with systemic action– When at least one component requires study

Non-oral / non-parental products with systemic action

Non-solution products with non-systemic action


Marketing authorization of multisource products

Marketing authorization of multisource products

Extensive clinical trials to demonstrate safety and efficacy

– Interchangeability?

Demonstration of equivalence to reference (comparator) product

– Interchangeability– Therapeutic equivalence


Marketing authorization through equivalence

Marketing authorization through equivalence

Suitable methods for assessing equivalence:– Comparative pharmacokinetic studies– Comparative pharmacodynamic studies– Comparative clinical trials– Comparative in vitro tests


Comparative Pharmacokinetic StudiesComparative Pharmacokinetic Studies

In vivo measurement of active ingredient

“Some” relationship between concentration and safety/efficacy

Product performance is the key

Comparative bioavailability


Bioavailability Bioavailability

The rate and extent to which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation.”

Reference:

intravenous administration = 100% bioavailability


Important Pharmacokinetic ParametersImportant Pharmacokinetic Parameters

AUC: area under the concentration-time curve measure of the extent of bioavailability

Cmax: the observed maximum concentration of drug measure of

both the rate of absorption and the extent of bioavailability

tmax: the time after administration of drug at which Cmax is observed

measure of the rate of absorption


Plasma concentration time profilePlasma concentration time profile

Cmax

Tmax

AUC

time

concentration


BioequivalenceBioequivalence

Two products are bioequivalent if

they are pharmaceutically equivalent

bioavailabilities (both rate and extent) after administration in the same molar dose are similar to such a degree that their effects can be expected to be essentially the same


BioavailabilityBioavailability

Absolute bioavailability (F):

Relative bioavailability (Frel)

larextravascu

ravenousint

ravenousint

larextravascu

DoseDose

AUCAUC

F

1larextravascu

2larextravascu

2larextravascu

1larextravascurel Dose

DoseAUCAUC

F


Bioavailability: Same DoseBioavailability: Same Dose

Absolute bioavailability (F):

Relative bioavailability (Frel)

larextravascu

ravenousint

ravenousint

larextravascu

DoseDose

AUCAUC

F

1larextravascu

2larextravascu

2larextravascu

1larextravascurel Dose

DoseAUCAUC

F


Therapeutic EquivalenceTherapeutic Equivalence

Therapeutic equivalence:– Pharmaceutically equivalent– Same safety and efficacy profiles after administration of same

dose: bioequivalent

Interchangeability


Comparative Pharmacodynamic StudiesComparative Pharmacodynamic Studies

Not recommended when:– active ingredient is absorbed into the systemic circulation– pharmacokinetic study can be conducted

Local action / no systemic absorption


Comparative Clinical StudiesComparative Clinical Studies

Pharmacokinetic profile not possible

Lack of suitable pharmacodynamic endpoint

Typically insensitive


Comparative in vitro StudiesComparative in vitro Studies

May be suitable in lieu of in vivo studies under certain circumstances

Requirements for waiver to be discussed


When are bioequivalence studies employed?

When are bioequivalence studies employed?

Multisource product vs. Innovative product

Pre-approval changes – Bridging studies

Post-approval changes

Additional strengths of existing product


Bioequivalence Studies:Basic Design Considerations

Bioequivalence Studies:Basic Design Considerations

Minimize variability not attributable to formulations

Minimize bias

REMEMBER: goal is to compare performance of the two products


“Gold Standard” Study Design“Gold Standard” Study Design

Single-dose, two-period, crossover

Healthy volunteers

Subjects receive each formulation once

Adequate washout


Multiple-dose StudiesMultiple-dose Studies

More relevant clinically?

Less sensitive to formulation differences


Multiple-dose Studies may be employed when:


Drug is too potent/toxic for administration in healthy volunteers

– Patients / no interruption of therapy

Extended/modified release products– Accumulation using recommended dosing interval– In addition to single-dose studies




Non-linear pharmacokinetics at steady-state (e.g., saturable metabolism)

Assay not sufficiently sensitive for single-dose study


Crossover vs. Parallel DesignsCrossover vs. Parallel Designs

Crossover design preferred– Intra-subject comparison– Lower variability– Generally fewer subjects required

Parallel design may be useful– Drug with very long half-life– Crossover design not practical


Parallel Design ConsiderationsParallel Design Considerations

Ensure adequate number of subjects

Adequate sample collection – Completion of Gastrointestinal transit / absorption process– 72 hours normally sufficient


Fasted vs. Fed DesignsFasted vs. Fed Designs

Fasted study design preferred– Minimize variability not attributable to formulation– Better able to detect formulation differences


Fed Study Designs may be employed when:

Fed Study Designs may be employed when:

Significant gastrointestinal (GI) disturbance caused by fasted administration

Product labeling restricts administration to fed state


Fed Study Design ConsiderationsFed Study Design Considerations

Fed conditions depend on local diet and customs

Dependent on reason for fed design– Avoiding GI disturbance

• Minimal meal to minimize impact– Required due to drug substance / dosage form

• Modified-release products• Complicated pharmacokinetics• Known effect of food on drug substance


Fed Study Design Considerations cont.Fed Study Design Considerations cont.

Fed conditions designed to promote maximal perturbation

– High fat– High Calorie– Warm


Replicate vs. non-replicate designsReplicate vs. non-replicate designs

Standard approach– Non-replicated– Single administration of each product– Average bioequivalence


Replicate DesignsReplicate Designs

Typically four-period design– Each product administered twice

Intra-subject variability

Subject X formulation interaction

Different approaches possible– Average bioequivalence– Individual bioequivalence


Replicate DesignsReplicate Designs

Advantages– More information available– Different approaches to assessment possible

Disadvantages– Bigger commitment for volunteers– More administrations to healthy volunteers– More expensive to conduct


DiscussionDiscussion

Questions

Comments

Opinions

Documents

Artemisinin combined medicines, Kampala, February 2009 1 |1 | Training workshop on regulatory requirements for registration of Artemisinin based combined