Biowaivers
A biowaiver lets in vitro evidence stand in for an in vivo bioequivalence study. It can cover additional strengths of a product, dosage forms that need no equivalence data, or substances placed by the Biopharmaceutics Classification System, and each kind holds only under conditions the application has to document.
What a biowaiver is for
A biowaiver removes the requirement for expensive in vivo testing. Biowaivers eliminate unnecessary human testing while providing a fast track for drug development. They make cost savings possible by avoiding expensive clinical trials, and these savings would ideally translate into more affordable medicines for patients worldwide and universal access to quality medicines. Biowaivers serve new and generic drug development in bringing essential medicines to those who need them most.
Biowaivers are more commonly applicable to generics, but they can also apply to new drugs or to line extensions, such as a new strength or a new formulation, when certain criteria are met. Common biowaiver mechanisms include a biowaiver for additional strengths, a biowaiver for specific dosage forms and a biowaiver based on the Biopharmaceutics Classification System.
Additional strengths
A biowaiver for additional strengths applies to all types of marketing authorisation application, such as new medicinal products, generics and hybrids. Bioequivalence testing is generally performed on the higher strength and waived for the lower strength if the in vitro pharmacokinetics are proven to be equivalent. Pharmacokinetic linearity of the active substance is a prerequisite, and critically reviewed data on pharmacokinetic linearity determine which strengths are chosen for the bioequivalence study. Similarity of in vitro dissolution between the additional strengths and the strength used for bioequivalence testing is demonstrated with the similarity factor f2 or another justified method.
In general, all strengths should have the same manufacturing process, the same qualitative composition and the same ratio between the amount of each excipient and the amount of active substance. Where the composition of the strengths is not quantitatively proportional, a biowaiver may still be considered if certain conditions on the amount of active substance, the core excipients and the fillers are met.
Dosage forms that need no equivalence data
Certain pharmaceutical dosage forms are exempt from the provision of equivalence data because of their inherent characteristics. This biowaiver may apply to formulations such as aqueous oral solutions, parenteral solutions, locally acting and locally applied products, for example eye drops, nasal sprays and cutaneous solutions, and gas for inhalation. A prerequisite is that the test product should not contain a different salt of the active substance than the reference medicinal product, unless the salt has similar properties, nor a different ester, ether, isomer, mixture of isomers, complex or derivative. In addition, the excipients should not influence the bioavailability of the active substance.
For a generic, Article 10(1) of Directive 2001/83/EC requires bioequivalence to the reference medicine to be demonstrated, but in some cases bioequivalence studies are not mandatory. Simple oral solutions and aqueous solutions for intravenous or intramuscular injection, for example, need no bioequivalence study, provided they contain the same active substance in the same concentration as the currently authorised product.
The Biopharmaceutics Classification System
The Biopharmaceutics Classification System usually divides drugs into four classes by their solubility and their permeation capacity. Highly soluble compounds of high permeability are well absorbed, and their absorption rate is usually higher than their excretion rate, as with metoprolol, propranolol and captopril. For highly soluble compounds of low permeability, absorption is limited by the permeation rate, although the compound is solvated very rapidly, as with ranitidine, cimetidine and atenolol. For poorly soluble compounds of high permeability, bioavailability is limited by the solvation rate, as with naproxen, diclofenac and carbamazepine. Poorly soluble compounds of low permeability are usually not well absorbed over the intestinal mucosa, and high variability is expected, as with furosemide and hydrochlorothiazide.
Under certain circumstances, a biowaiver based on the classification can be used as a surrogate for in vivo bioequivalence, with in vitro dissolution testing used to evaluate the bioequivalence of the test and reference products. The waiver is restricted to highly soluble immediate-release solid oral dosage forms or suspensions with systemic action, that is, to Class I or Class III. Both classes have high solubility, Class I with complete and Class III with limited absorption, and the European Medicines Agency accepts the waiver for immediate-release drug products of either class. Modified-release products are not accepted. Pharmaceutical alternatives, such as a tablet against a capsule, and fixed-dose combinations may be considered if all the drug substances are Class I or Class III. The waiver can be applied only to highly soluble drug substances with known human absorption that are considered not to have a narrow therapeutic index.
The criteria for the waiver are judged on solubility, permeability, dissolution, and the quantitative and qualitative composition of the test product against the reference medicinal product. Dissolution profiles are compared by estimating the similarity factor f2, and two profiles are considered similar when f2 is between 50 and 100. In the case of very rapid solubility of both test and reference products, within 15 minutes, the profiles are considered similar and f2 testing is unnecessary. For a product with several strengths, the criteria must be applied to each strength, so the dissolution profiles of test and reference products should be compared at each strength.
Even for a Class I or Class III substance, the waiver might not be feasible in certain cases because of product-specific characteristics, for example in vitro dissolution of less than 85% within 15 minutes for Class III or within 30 minutes for Class I, in either the test or the reference product, or unacceptable differences in excipient composition. The classification of a drug substance may differ between jurisdictions, such as those of the EMA, the US FDA and the PMDA. Provisional classifications can be searched in online databases such as that of the Drug Delivery Foundation, while there is no official list of drugs with a narrow therapeutic index. Regulatory authorities review these aspects case by case.
Documenting a biowaiver
The key for a regulatory medical writer is to provide, in each situation, the documentation that fulfils the set requirements. Effective documentation needs knowledge of the rationale for the choice of biowaiver and of the conditions it must fulfil.
In a generic's dossier, the results of the bioequivalence studies, or a biowaiver's justification of why no study was performed, should be presented in Modules 2.5 and 2.7.1. If a waiver based on the classification system is submitted, Module 2.7.1 should contain a summary of the in vitro dissolution data with a justification for not performing a bioequivalence study and a list of relevant references. Module 5.3.1, the comparative bioavailability and bioequivalence study reports, should contain the relevant data justifying such a waiver. The draft ICH M9 guideline on classification-based biowaivers describes the recommended format and content of the documentation that supports a waiver of bioequivalence studies.