How to define bioequivalence?
wo medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits
> rate and extent of absorption do not show a significant difference when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose’
What are some products that require biopharmaceutic data?
- oral tablets
- oral capsules
- oral suspensions
- complex intravenous solutions for injection
- applied locally where the drug substance is acting systemically
- transdermal medicines
What are some medicines that require biopharmaceutic data?
- New chemical entity
- New salt
- New fixed combination medicine
- New dosage form
- New dosage form
- New generic medicine
- New formulation that may affect bioavailability
- New modified-release formulation
What are medicines that do not require biopharmaceutic data?
- Medicinal gases
- Peritoneal dialysis solutions
- Simple aqueous solutions for intravenous injection
- Simple solutions that do not contain active drug substance
- Oral solutions that both:
> contain the same drug substance(s) in the same concentration
> do not contain excipients that may significantly affect absorption
- Drug substances that are not absorbed
- Medicines applied locally (except if acting systemically)
- Minor formulation changes (e.g., colouring agent, flavour)
what is the EMA guideline on bioequivalence?
- Number and selection of subjects
- Pharmacokinetic parameters
- Parameters to be analysed & acceptance limits
- Special considerations
- Principles of determining confidence interval
- Interpretation of confidence interval
Discuss PK parameters and acceptance limits
In single-dose studies, the parameters to be analyzed are
- AUC0-t (preferably AUC0-∞)
- Cmax
> The 90% confidence interval for the ratio of the geometric means of the test and reference products (test/reference, as a percentage) should be contained within the acceptance interval of 80-125%
> A statistical evaluation of tmax is not required ( If rapid release is claimed to be clinically relevant, there should be no apparent difference in median tmax)
What is the confidence interval using the BE method?
- Log of the parameter
- Mean of the log parameters
- Log of the parameter
- Mean of the log parameters
a. Test: 3.718
b. Reference: 3.913
3. Calculate the geometric mean (10x)
a. Geometric mean (Test): 5224 mcg.h/L
b. Geometric mean (reference): 8185 mcg.h/L
4. Ratio of GM (test/reference) = 0.64 (63.8 %)
5. Determine upper and lower confidence interval from confidence limits
> Upper: 10 (‘Mean log Ref’ + ‘Upper confidence limit’) = 104 %
> Lower: 10 (‘Mean log Ref’ + ‘Lower confidence limit’) = 39%
- Compare to acceptance interval (80-125 %)
> Ratio of geometric means - failed
>Confidence interval - failed
Not bioequivalent, based on AUC data
Bioequivalent as values for 90% confident interval for the ratio is between 80 to 125%
C max and Auc0-t are the parameters to be analyzed
What is a biosimilar
- A biosimilar is a biological medicine highly similar to another approved biological medicine (‘reference medicine’) in terms of structure, biological activity, efficacy, safety and immunogenicity
- Biosimilars are made in living organisms, hence there may be some minor differences from the reference medicine, which are not clinically meaningful (e.g., safety & efficacy)
- Approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines
- Demonstration of biosimilarity relies on comprehensive comparability studies with the reference medicine.
Compare generic meidcine and biosimilar medicines
