Generics are allowed more than 20% tolerance, so it's not the same at all?
To obtain the status of a "generic" drug, a drug must prove its bio-equivalence with the original medicine, i.e., verify that it has the same efficacy and the same safety of use. The 20% interval is used in the methodology of bioequivalence studies. Bioequivalence tests are generally carried out on healthy volunteers (to reduce the inter-individual variability inherent in the disease), from a homogeneous group (age, sex, build, smoking, alcohol, etc.) to whom the single dose of the generic drug and the original prescription is administered under standardized conditions (e.g., most often on an empty stomach). Most of the time, each subject will receive successively the generic drug and the originator drug (in a randomly defined order) while respecting a latency time between the two intakes ("wash-out" phase). Thus each patient will be their witness. This is referred to as a "cross-over" test. After administration of the drug, several blood samples are taken with a frequency and a duration previously defined to determine the plasma concentration of the active substance over time. Plasma samples are analyzed according to validated analytical methods. From these plasma assay results, individual pharmacokinetic parameters are determined to compare the bioavailability of the generic drug and the originator drug.
The comparison concerns two parameters:
the area under the curve (AUC), which makes it possible to assess the extent of absorption and therefore to assess the quantity of active principle which reaches the blood circulation ;
The maximum blood concentration (Cmax), measured at time Tmax, making it possible to assess the speed at which the active principle is found in the body.
The statistical comparison between generic drugs and originator drugs relates to the mean AUC and Cmax parameters: the ratio of means is calculated and its 90% confidence interval, i.e., the interval in which the actual value of the balance has 9 out of 10 chances of being found. Bioequivalence is demonstrated if the confidence interval [CI90] of the ratio (generic drug/originator drug) of the means of AUCs and Cmax is entirely between 80 and 125%. This interval [80% - 125%] has been defined internationally by considering that a variation of the ratio of means up to 20% has only a few clinical consequences (efficacy/safety).
What is the difference between bioequivalence and bioavailability?
Thank you for this question which allows us to clarify this point.
Bioavailability describes how an active ingredient becomes available in the body to produce its biological action. It is characterized by the number of active ingredients functional (which reach the bloodstream) and the speed of this process.
The "bioequivalence Is based on the concept of bioavailability. Thus, two drugs are bioequivalent when administered under the same conditions (same dose and same route of administration); they generate the same diffusion of active principle in the blood. This is a bioavailability equivalence, i.e., the amount of active ingredient available in the blood is the same. The speed at which this active ingredient reaches the bloodstream is also the same. The drugs are then considered to be therapeutically equivalent (same efficacy and same safety of use).
Hoping to answer your question as well as possible,
Can you confirm or deny that generic Cyproterone Acetate has less strict molecular latency?
The molecule that you cite is not one of the drugs with a narrow therapeutic margin: it is a progestogen that can by nature cause period disorders that should then be seen with your doctor.
Are generic drugs tested in patients, and what percentage of effectiveness is required for them to be approved?
To obtain marketing authorization, a generic drug must prove its bioequivalence with the original medicine, i.e., demonstrate that it acts the same way in the body. He does not have to prove the effectiveness of this molecule since the original laboratory has already demonstrated this through its program of clinical trials on numerous patients.
This is why the studies of bioequivalence are carried out in healthy volunteers to whom the generic drug and the original drug are administered successively under standardized conditions, to demonstrate that the quantity of active ingredient available in the blood and the speed at which this active ingredient reaches blood circulation are similar between the generic drug and brand-name drug. Thus, the bioequivalence studies make it possible to verify that the manufacturing processes and excipients do not call into question the efficacy and safety of the molecule.
Regarding the percentage of effectiveness of generic drugs, the statistical comparison between the generic drug and originator drug concerns two parameters:
the area under the curve (AUC);
average maximum blood concentration (Cmax).
The bioequivalence is demonstrated if the confidence interval [CI90] of the ratio (generic drug/originator drug) of the mean AUCs and Cmax is entirely between 80 and 125%. The percentage of means is calculated, and its 90% confidence interval is the interval in which the actual value of the balance has nine chances out of 10 to be found. This interval [80% - 125%] has been defined internationally by considering that a variation of the ratio of means up to 20% has only a few clinical consequences (efficacy/safety).
It is wrong to translate this information by a difference in the effectiveness of - 20% to + 25% between original drugs and generic drugs. As proof, a retrospective analysis of the Food and Drug Administration (FDA) found, in a retrospective analysis including 2,070 studies of bioequivalence submitted between 1996 and 2007 in generic drug dossiers, that the difference in AUC and Cmax between generic drug and originator drug was on average less than 5%.
Have generic drugs been tested on healthy and healthy volunteers, like brand-name drugs?
To obtain marketing authorization, a generic drug must prove its bioequivalence with the original medicine, i.e., demonstrate that it acts the same way in the body. He does not have to prove the effectiveness of this molecule since the original laboratory has already demonstrated this through its program of clinical trials on numerous patients.
This is why the studies of bioequivalence are carried out in healthy volunteers to whom the generic drug and the original drug are administered successively under standardized conditions, to demonstrate that the quantity of active ingredient available in the blood and the speed at which this active ingredient reaches blood circulation are similar between the generic drug and brand-name drug.
Thus, the bioequivalence studies make it possible to verify that the manufacturing processes and excipients do not call into question the efficacy and safety of the molecule.
Hoping to have answered your question,
In bioequivalence trials, how is the use of a small population of young, healthy, fasting volunteers relevant?
In the bioequivalence trials, you are talking about verifying that the generic drug behaves in the same way in the body as the original drug. Therefore, they guarantee therapeutic efficacy and tolerance identical to those of the original medicine, the effects of which are well known at the time of the marketing of the generic drug.
The number of patients included in the studies depends on the baseline risk, the size of the effect to be demonstrated between generic and original drug, the alpha risk (i.e., the risk of wrongly rejecting a hypothesis while it is true), and the power of the test desired (probability of detecting a difference that exists). Unlike studies measuring the efficacy and tolerance of a new molecule, a small number of patients is sufficient, in some cases, to guarantee the bioequivalence.
The bioequivalence trials are generally carried out on healthy volunteers to reduce the inter-individual variability inherent in the disease and come from a homogeneous group (age, sex, build, etc.).
The generic drug using the same molecule as the original prescription has the same efficacy and safety in use. There is, therefore, no more risk for frail people to use a generic drug when the original drug is authorized for these populations.