Generic Drugs: Are they Equivalent?
With healthcare costs continuing to rise, generic drugs are looking more attractive than ever. The prospect of getting the same drug at a lower cost is tempting to anyone with a large drug bill -- patient or insurer alike. The savings are massive: Lipitor lost patent protection last month -- it was a $10 billion drug, and the generic versions are priced at a fraction of the original cost. In 2012, Plavix and Seroquel, two other blockbusters, will lose patent protection too -- that's another $10 billion in drug costs that will shrink. This "patent cliff" will shrivel about $255 billion in worldwide patented drug sales over the next five years. If you're taking a prescription drug and not already on a generic, you probably will be soon. And depending on where you live, you may be automatically switched to a generic version of your prescription drug as soon as it's available.
What is a generic drug?
What is referred to as a "generic" drug may vary by country, and be influenced by both medical practice and by regulatory requirements. The most common definition is that used by the World Health Organization:
A generic drug is a pharmaceutical product, usually intended to be interchangeable with an innovator product, that is manufactured without a licence from the innovator company and marketed after the expiry date of the patent or other exclusive rights.
Generic products may also be called "multi source" products. And you'll often see a drug's chemical name referred to as the "generic name" or the "non-proprietary" name, which I've described can lead to confusion among consumers who may only know their prescription by the brand name alone.
The Active Pharmaceutical Ingredient
To understand the scientific basis of generic drug evaluations, it's necessary to understand some key concepts. The first one is the active pharmaceutical ingredient or API. In Lipitor, for example, the API is atorvastatin, or to use its full chemical name, (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate. The API is the chemical that has the desired biological effect. There may be a dozen ingredients in a tablet, for example, but the API is the ingredient we're interested in. It's the API that will allow us to generalize data and studies with the drug, linking the original bench science and preclinical research, to the tablet dispensed by the pharmacy -- it's the same chemical. The fact that drugs have an API allows generic drugs to be marketed, because when we compare generics, the API is the same. In contrast, consider the scenario of an herbal remedy. A single tablet of 100mg of a raw herb might contain hundreds of different chemicals. If there is no known API or standardized active ingredient, we cannot compare between brands, or assume that clinical trials with one brand are relevant to any other product, because we have no idea which ingredient is actually having an effect, and if any other version has that same ingredient (or combination of ingredients.)
Most dosage forms (e.g., tablets and capsules) are designed to deliver the API to the site of action. Unless it's a drug that acts directly on the lining of the gastrointestinal tract, we rely on the circulatory system to carry the drug to the site of action in the body. Bioavailability refers to the amount of drug that, once ingested, reaches the bloodstream. Bioavailability is evaluated based on two measures -- the rate of absorption, and the extent of absorption:
Blood plasma level curve for a typical single dose of an oral drug
Generic manufacturers that want to duplicate a drug coming off patent then have a few challenges. First, manufacture the complicate chemical structure that is the API (or find someone else who can make it for you). Second, package it in a dosage form that resembles the patented drug. Third, show that the new generic shares the same absorption curve as the branded version. That is, they must show that two product are bioequivalent.
We now want to compare a branded drug, one that's been on the market for years, with a new generic. There is a single fundamental assumption that underlies the comparison:
Two products are considered equivalent when the rate and extent of absorption of the generic drug does not show a significant different from the rate and extent of absorption of the brand drug, when administered at the same dose under similar experimental conditions.
For practical purposes, generic versions of branded drugs have AUC and Cmax ratios that are very close to one. With significant variation in either value, it would be unlikely for the confidence intervals to lie withing the 80% to 125% range. For the sake of keeping this post short I'll leave a more detailed discussion of the statistics to the interested reader.
Myths, Misconceptions, and Controversies
Generic drugs are manufactured differently from branded drugs, and branded drug manufacturers use better processes
If the dosage form releases the same drug with the same concentration/time profile, then any minor manufacturing differences are irrelevant to the pharmacological activity. Regulators have established standardized manufacturing practices and standards, termed good manufacturing practices, that all manufacturers, brand or generic, must adhere to. Final products must meet the same product quality standards as well.
Biosimilars are bioequivalent
Biosimilars refers to follow-on versions of antibodies, proteins and other patented biological drugs, like growth hormones. Biological drugs are very large molecules that are structurally more complex that the relatively simple, smaller molecules in most tablets and injections. Their complexity means that a simple bioequivalence evaluations may be insufficient to fully describe a drug's action. Manufacturing processes may involve recombinant DNA technology, and can take place inside living cells, leading to a final dosage form which cannot be fully characterized as a single defined API. As some of the biologic drugs approved over the past few decades have lost patent protection, the challenge of verifying both pharmaceutical but also clinical equivalence of "generic" biologicals has become an evaluation challenge for regulators. So if they're not completely bioequivalent, do they have the same effects in patients? That is, are they clinically and therapeutically equivalent? While approaches between countries may vary, many are being cautious and requiring more detailed comparisons, including clinical safety and efficacy trials to adequately demonstrate that "generic" versions of biologic drugs have the same end effects. As regulators gain more experience evaluating these products, expect the testing standards to evolve.
Bioequivalence studies are always necessary to establish interchangeability
Patented drug manufacturers usually aren't willing to sacrifice their entire market share to generic competitors. Some will start producing "generic" versions of their own drug, selling them to a partner or subsidiary who will sell them as an "ultrageneric". So in many cases, at least one of the generic versions that's marketed will be truly identical (except perhaps for markings) to the branded products. Now if you think this means people won't occasionally identify the switch as the source of efficacy issues or side effects, my anecdotal experience says otherwise.
The science of bioequivalence evaluations for generics has been in place in most countries for more that 20 years with an established track record of therapeutic equivalence. These evaluation methods have been so successful in establishing generic drug standards that they are largely consistent between all of the major drug regulators worldwide. Consumers and health professionals alike can be reassured that generic drugs approved under these regulatory frameworks are indeed bioequivalent, and therefore, interchangeable with brand name products.