No doubt, healing does not only depend on the active ingredients in medicines, but it is influenced by a number of mental factors as well. Could it be possible that two medicines containing the same substance have different effects? This question is becoming quite important today as generic drugs flood the market.
Pharmaceutical research is probably the most expensive business in the world. The development of a new drug takes long years and the costs may easily top 1 billion (one thousand million) €. This investment is regained by the developers through patent protection, which is valid for about 20 years in most countries. In this period, only the patent holder is allowed to sell the drug. However, patenting is done very early during product development, so the developer can only sell the new drug without competitors for 7–10 years. Just to give the reader some idea about the size of the market: the total retail earnings (paid by patients and insurance companies) in the pharmaceutical market of the European Union was 214 billion € in 2007, that is about 430 €/person/year. Most of the profit is made by blockbuster drugs, which have yearly sales above 1 billion € under the patent protection period.
When the patent protection period is over, other companies can start selling the same active ingredient. This is rather advantageous for patients, as competition drives down the prices. Drugs containing the same active ingredients are called ge- neric drugs. The category ‘generic’ was first used in the USA in the 1980s, with the intention of helping pharmaceutical companies to compete in making drugs whose patents expired. The 1984 Drug Price Competition and Patent Term Restoration Act was signed into law by President Ronald Reagan, who made the following com- ment: “The legislation will speed up the process of Federal approval of inexpensive generic versions of many brand name drugs, make the generic versions more widely available to consumers, and grant pharmaceutical firms added incentives to develop new drugs.”
The essence of the legislation was that pharmaceutical research was helped by lengthening the patent protection period, whereas generic drug makers were helped by introducing a faster drug approval process. Europe followed suit quickly. Gener- ic drugs are not tested as extensively (laboratory, animals, healthy people, patients)
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as original drugs. The applicant must only file the results of the original approval process and show that the generic version is identical to this original in a number of respects (mass of active ingredient, method of application). Of course, the generic drug will be less expensive than the original. Generic drugs do not have the same medicine names as the originals because the names are usually trademarks, whose protection never expires. Generic drugs can easily be identified by checking the chemical name of the active ingredient and the dose.
The introduction of the generic version of an original drug into the market typi- cally occurs within 1 or 2 years of the expiry of patent protection and results in a price drop of 25–50 %. In addition, the yearly price increase of a generic drug is usually smaller than the rate of inflation, whereas the opposite is true for pat- ent protected drugs. Generic drugs therefore save a lot of money for the society as a whole. On the other hand, the competition in the generic drug market results in lower profitability. European pharmaceutical companies spend huge amounts of money (typically 17 % of their entire revenue) on developing original drugs, which keeps profit margins high for a few patent-protected drugs. With generic drugs, the primary means of gaining profits is marketing, which also requires huge amounts of money. When generic versions of a drug become available, intensive marketing often causes an increase in the amount of drug sold and, somewhat paradoxically, the overall money spent on the drug by patients and insurance companies may also increase even despite the falling prices.
As pointed out earlier, fewer tests are sufficient to approve the introduction of a generic drug. However, bioequivalence must always be demonstrated. Although it seems logical that the same active ingredient given in the same form and the same dose should have the same effects as the original, bioequivalence must be tested by measuring the concentration of the active ingredient in the blood. These ex- periments are done on healthy volunteers and the concentrations are measured after blood tests. Figure 3.1 gives an example of the time-dependence of the concentra- tion of a drug in blood plasma. Bioequivalence requires that the area under the curve (AUC) in this graph and the maximum concentration (cmax) should not be more than 20 % lower or 25 % higher than the original drug. If the reader wonders why the two numbers are different, consider this nice little statistical oddity: a 20 % drop in a value must be followed by a 25 % increase to get back to the original value. So these numbers were set to ensure that the test results do not depend on which drug is the original and which drug is the generic.
Bioequivalence also assumes that the two products are therapeutically equiva- lent, so a therapy started with one drug can be continued with the other at any time. A demonstration of therapeutic equivalence in not required for approving a generic drug, as this would involve much higher costs and the price reducing effect of the introduction of generic drugs would be less pronounced. Although the requirement for bioequivalence is that the difference between the bioavailability should be lower than 20–25 %, practice shows that generic drugs are typically within 3 % of the original. Such small differences render therapeutic equivalence studies a waste of money: the expected benefit from them would be very small, and the costs ex- tremely high.
121 3.1 Are Generic Medicines the Same as the Original?
How is it possible that patients sometimes report a change in effectiveness when their doctor prescribes a generic version of a well-known brand name drug? This phenomenon mostly has psychic origins. A patient is used to the name of a drug and trusts it, the new name may cause suspicion and finally a feeling of reduced effect, even if this cannot be proved in any objective manner. It is also typical to report more side effects. Sometimes it may even happen that the patient trusts the new drug more (something new must be better than the old) and reports it as more effec- tive. These are very similar to the placebo or nocebo effects, which are described in another chapter of this book (→ 3.6). Other factors might be significant, though. A generic drug may sometimes contain the active ingredient in a different salt form, which may have some influence on efficiency. A well-documented case is the anti- depressant paroxetine hydrochloride, which is formulated as paroxetine mesylate in one of the generic forms. A patient used to the hydrochloride reported a new side effect and decreased efficiency when the generic mesylate was used instead of the original.
Negative effects of switching from the original to a generic drug are more com- mon for drugs whose therapeutic range is narrow (there is a small difference be- tween harmfully high and uselessly low doses). This has been documented for some epilepsy drugs. The quite minor differences in blood plasma concentrations between original and generic drugs actually caused an increase in the frequency of epileptic seizures.
Under certain circumstances, generic drugs may differ from originals. But this is very rare and is limited to certain illnesses. Ideally, the doctor or pharmacist is
Fig. 3.1 Bioequivalence of two drugs. Reference drug A caused a somewhat higher maximum
concentration in blood plasma (cmax = 8.4 µg/ml, AUC = 125 µg h/ml), but drug B satisfies the bio-
equivalence criterion as its bioavailability is better than 90 % (cmax = 7.8 µg/ml, AUC = 115 µg h/ml).
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aware of the possibility and pays special attention to the possible side effects or lack of therapeutic effects. It may also happen that a generic drug is marginally more effective than the original. Generic drugs should not be confused with counterfeit medicines: in contrast to the latter, these are perfectly legal and appropriately tested. Counterfeit drugs are usually sold only on the Internet in developed countries, but more widely in the developing world. These are illegal, their efficiency and safety is not tested.