Bioequivalence example

Bioequivalence assessments of drugs that are insignificantly absorbed into the systemic circulation are difficult. In some cases, for such drugs a biological marker has been established for the assessment of bioequivalence. Examples of biological markers used are skin blanching in the case of hydrocorticosteroids and neutralization of stomach acid for antacids. For certain cases a pharmacodynamic end point may be more appropriate for the assessment of bioequivalence. 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

Although one cannot readily identify any comprehensive, official pronouncement on the topic of development bioequivalency, it is apparent that in many cases FDA officials have adopted a pragmatic and common-sense approach to problems of this type. Obviously, in development bioequivalency our fundamental objective should be, for example, to build an appropriate bridge between F3 and F3 and F2 and F3 such that it is legitimate to use data obtained in clinical trials with F3 and F2 to support a conclusion of safety and efficacy for F3. Depending on how substantial the differences are between Fi and F3 and F2 and F3, the required bridge can be very simple or possibly more elaborate. 

The sponsor of an NDA will normally have extensive pharmacokinetic and pharmacodynamic information available at the time the NDA is submitted. It may be appropriate to use data such as the slope of the dose-response curve in support of a contention that, for example, dissolution testing may be, in some instances at least, be sufficient for the demonstration of development bioequivalency. Certainly, we may conclude that the requirements for development bioequivalence should never be more rigorous than those applied in consideration of generic bioequivalency. 

The topic of generic bioequivalence pertains to the relative bioavailability of different versions of the same drug product, all of which may be available in the marketplace at the same time. Thus, if we continue our consideration of the example introduced in the previous section of this chapter, let us suppose that the innovator did obtain approval to market F3. Initially F3 was the only product available in the marketplace. However, when the relevant patents held by the innovator have expired, other pharmaceutical... 

There are occasions when it is not possible to use a cross-over design in a bioequivalency determination. For example, if the half-life of the drug is very long, the required washout period between the two treatment periods may be several months. Obviously, it is quite impracticable to consider such a long washout period. Test subjects are unlikely to wait patiently for long periods of time, and thus if we tried to conduct a bioequivalency study with, say, a 3-month washout period, we would probably find that a significant number of our test subjects would not be available for the second dose. 

Proponents of the clinical mirror theory of bioequivalence would like to see increased emphasis placed on quantification of pharmacodynamic values. In some instance we can readily identify how reliable and relevant pharmacodynamic values can be measured. For example, for an antihypertensive drug, measurement of blood pressure changes can be conveniently, inexpensively and objectively determined. However, for other types of drug (e.g., antidepressants) it is not easy to conceive any simple pharmacodynamic attributes that could be readily determined. 

The topic of bioequivalency tests for controlled-release products has attracted comment from a number of groups. For example, Bialer and co-workers [4] have proposed four new parameters ... 

In recent years pharmaceutical scientists have participated in lively discussions about how present methods of bioequivalency determination might legitimately and advantageously be modified. For example, the question of whether it is necessary to always take plasma samples so that AUC at the end of the test is at least 90% of AUC at time infinity has been explored [7,8], Statistical aspects of this and other possible methods of modifying protocol design are covered in a most useful book published in 1999 and in several papers [8-10,22],... 

There are special problems in bioequivalency determinations when conventional pharmacokinetic studies are not possible. For example, when drugs are administered intranasally for direct treatment of receptors in the nasal mucosa, the concentration of drug in plasma may be below the limit of quantification. In such cases we are forced to attempt measurement of clinical response. The subjectivity and/or low precision of this type of study can be a serious problem. 

As indicated in previous sections of this chapter, there has developed a quite impressive international consensus on the general principles of bioequivalency determination for drug products regulated by agencies such as FDA. However, there are other materials used with therapeutic intent for which bioequivalency may also be a legitimate concern. Herbal remedies have, in recent years, demonstrated impressive increases in sales in many parts of the world. Other substances of natural origin have gained considerable attention for their possible curative potential. For example, shark... 

In some instances, distinct polymorphic forms can be isolated that do not interconvert when suspended in a solvent system, but that also do not exhibit differences in intrinsic dissolution rates. One such example is enalapril maleate, which exists in two bioequivalent polymorphic forms of equal dissolution rate [139], and therefore of equal free energy. When solution calorimetry was used to study the system, it was found that the enthalpy difference between the two forms was very small. The difference in heats of solution of the two polymorphic forms obtained in methanol was found to be 0.51 kcal/mol, while the analogous difference obtained in acetone was 0.69 kcal/mol. These results obtained in two different solvent systems are probably equal to within experimental error. It may be concluded that the small difference in lattice enthalpies (AH) between the two forms is compensated by an almost equal and opposite small difference in the entropy term (-T AS), so that the difference in free energy (AG) is not sufficient to lead to observable differences in either dissolution rate or equilibrium solubility. The bioequivalence of the two polymorphs of enalapril maleate is therefore easily explained thermodynamically. 

Bioavailability and bioequivalence are also usually assessed in animals. Such studies are undertaken as part of pharmacokinetic and/or pharmacodynamic studies. Bioavailability relates to the proportion of a drug that actually reaches its site of action after administration. As most biopharmaceuticals are delivered parenterally (e.g. by injection), their bioavailability is virtually 100 per cent. On the other hand, administration of biopharmaceuticals by mouth would, in most instances, yield a bioavailability at or near 0 per cent. Bioavailability studies would be rendered more complex if, for example, a therapeutic peptide was being administered intranasally. 

Id. For example, the statute requires the ANDA applicant to establish bioequivalence. 

Individuals and companies often use the formal eitizen petition process to raise issues regarding the safety and efficacy of pharmaceuticals. Brand-name companies, for example, have petitioned the FDA on issues relating to bioequivalence for partieular generic dmgs. 

Frequently, the formulation used in clinical trials is not the one that is ultimately marketed. The pharmaceutical dossier is scrutinised for these variations and to ensure that studies have been carried out to prove the bioequivalence of the two. The same applies if more than one dose strength or dosage form is to be marketed, for example, tablets for adults and liquid preparations for use in children. 

In an equivalence trial we are looking to show that we are similar to some reference treatment, bioequivalence trials are the most common examples of this type of trial. 

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