Generics and Equivalence of Drugs

Interchangeability of drugs is among the most contentious and complex issues in the pharmaceutical market. Relations between original drugs and generics are far from clear.

Patent protection of original drugs

You can understand the originator: the massive resources spent on molecule discovery, drug testing, market launch, careful monitoring of possible adverse effects and interactions — after a few years of continuing patent protection — seemingly become irrecoverable.

A generic drug, often reproduced by several companies simultaneously, “inherits” all those efforts, time and money. You can argue all you want that an original always remains an original and a generic is merely a generic. A common International Nonproprietary Name makes these drugs look equivalent to the consumer, and the generic — typically cheaper — more attractive.

Originator companies defend their exclusive rights in various ways, primarily through patent law. Patent protection of a molecule prohibits its reproduction for a term that varies by country but averages around 20 years. From the start of testing a new molecule and filing a patent to the drug’s market entry, 10–15 years (or more) may pass, leaving the originator on average up to 5 years to recoup costs and earn profits. As the end of the term approaches, attempts are made — exploiting nuances of patent law — to extend protection. For example, a basic patent for omeprazole was obtained in 1978; later patents covered magnesium omeprazole, a treatment for GI disease using the left-handed isomer of omeprazole, the S-enantiomer of magnesium omeprazole as a trihydrate, a new crystalline form of omeprazole, and so on. These patents allowed the originator to fight generic omeprazole market entry. The enforcement of patent rights creates a distinction between a generic drug and a copied drug (copy).

Generics and copies

Generic — a drug whose patent protection has expired. Accordingly, a generic is not the exclusive property of the pharma company that developed it or held the first sales license.

Copies — drugs on markets in countries with weak or no patent protection of the active ingredients’ molecules.

Essentially, the difference between a copy and a generic is only the breach of the legal rules of reproduction (infringing the patent holder’s rights).

Ultimately, in countries with developed patent protection consumers first encounter the original, and only then the generics try to win market share. In Russia the situation is somewhat different. First, generics account for a large share of the Russian market (78–95% depending on the source). The G7 markets: US 12% generics, Japan 30%, Germany 35%, France 50%, UK 55%, Italy 60%, Canada 64%.

Second, Soviet traditions and the long-term presence on the market of only domestic products or products from former COMECON countries have shifted brand perception. For Russian doctors Piracetam is first of all the generic Nootropil; Co-trimoxazole is better known as Biseptol; Renitec (enalapril maleate) entered everyday use under the name of its most successful Russian generic Enap; original ciprofloxacin (Tsiprobay) is substituted by the names Tsifran and Tsiprolet.

Third, as in any country with strong state protectionism in medicine, Russia chooses generics because originals are expensive. This drives generic penetration in the largest, partly-state-funded healthcare segment.

Active anti-generic communication by originators has given the term “generic” an almost derogatory ring. Implicit characteristics of a generic become “second-class,” “insufficiently studied,” “poorly characterized safety profile” — though there are no objective grounds for this.

When evaluating generics one should consider: The generic contains the same active substance as the original (patented) drug. It differs from the original by excipients (inactive ingredients, fillers, preservatives, dyes, etc.). Differences also exist in the manufacturing process itself.

Pharmaceutical, biological and therapeutic equivalence

The term “generic” is often incorrectly replaced with “equivalent medicinal substance.” Strictly speaking such a term is meaningless, because there is no concept of “equivalence of medicinal substances.” There are pharmaceutical, biological and therapeutic equivalence. The EU and US use definitions of pharmaceutical equivalence.

Drugs are pharmaceutically equivalent if they contain the same active substances in the same amount and the same dosage form and meet the requirements of the same or similar standards (EMEA, The rules governing medicinal products in the European Union Investigation of Bioavailability and Bioequivalence, v. 3C, 1998, pp. 231–244).

Pharmaceutically equivalent drugs contain the same active ingredients in the same dosage form, are intended for the same route of administration and are identical in strength or concentration (FDA Electronic Orange Book, 20th Edition, 2000).

Identity of ingredients defines pharmaceutical equivalence; to evaluate biological equivalence, comparison of absorption and distribution in humans is required. WHO: “Two drugs are considered bioequivalent if they are pharmaceutically equivalent, have the same bioavailability and, when given in the same dose, provide comparable efficacy and safety.”

EU and US have their own bioequivalence definitions.

Two drugs are bioequivalent if they are pharmaceutically equivalent or alternatives and if their bioavailabilities (rate and extent of absorption) after administration of the same molar dose are similar enough that efficacy and safety are essentially the same (EMEA, 3C, 1998, pp. 231–244).

Bioequivalent drugs — pharmaceutically equivalent or alternative drugs with comparable bioavailabilities when studied under similar experimental conditions (FDA Orange Book, 20th Ed., 2000).

Equivalence assessment is not limited to the identity of active molecules. Requirements touch on manufacturing quality control (GMP compliance), labeling, instructions, etc.

Equivalence is also assessed by physicochemical properties of the actives (particle size, polymorphism, etc.), excipient properties, manufacturing process, storage conditions and packaging.

WHO recommendations on reference products:

1. Bioequivalence of a generic should be determined against the original drug. If the original is not on the national market, it is taken from the list (primary market), where, in the manufacturer’s view, it best meets quality, safety, efficacy and labeling requirements.
2. If the original drug is unavailable, the market leader in the country may serve as the standard, provided its quality, safety and efficacy are confirmed.
3. If there is no leader either, the generic is produced in accordance with local, state or regional standards, including the International Pharmacopoeia and the WHO Guidelines for registration requirements establishing interchangeability of multi-source pharmaceutical products (WHO Technical Report Series No. 863, Geneva 1996, pp. 114–154).

A natural question arises — are the equivalence types described enough to consider a generic and an original therapeutically equivalent? Under European and US definitions, therapeutic equivalence requires not only a similar pharmacokinetic profile but also a similar pharmacodynamic (clinical) effect.

A drug is therapeutically equivalent to another if it contains the same active substance and, per clinical trials, has the same efficacy and safety as the comparator whose efficacy and safety are established (EMEA 3C, 1998, pp. 231–244).

Drugs can be considered therapeutically equivalent only if they are pharmaceutically equivalent and can be expected to have the same clinical effect and the same safety profile when used by patients according to the label (FDA Orange Book, 20th Ed., 2000).

Unlike bioequivalence, which is strictly standardized, therapeutic equivalence lacks clear definitions, leading to uncertainty among doctors and patients when choosing between generics.

In a 1998 FDA draft, it was proposed that labels indicate the presence/absence of therapeutic equivalence and the comparator product (usually the original).

Currently, when choosing a generic, one may rely on the fact that bioequivalence is an indirect confirmation of therapeutic efficacy.

Full confidence in similar efficacy within a generic line can be achieved only by comparative therapeutic-equivalence studies; these data would allow full economic benefit from broad generic use. Therapeutic-equivalence studies are becoming mandatory for bringing new generics to market.

Source: O.B. Talibov, Department of Clinical Pharmacology, Moscow State Medical and Stomatological University