Generics – part of the solution?

Many people surely have encountered them in the pharmacy or at the doctor's office: Generic drugs. These drugs are sort of a copy of the original or reference drug. However, generics are manufactured by a different pharmaceutical company than the one that first received approval for the active ingredient.

The German Drug Law (§24b) regulates the approval of generic drugs, and defines them as: a preparation that has the same composition of active ingredients (or the same single active ingredient), the same quantity, as well as the same dosage as the original drug¹. For example, if the reference drug is a tablet with 5mg of active ingredient, then the generic drug must also be a tablet with 5mg of the same active ingredient in order to be considered a generic drug. These requirements do not apply to additives and excipients, i.e. substances that do not mingle with the drug’s efficacy. It may be, for example, that the original tablet is blue, but the generic tablet is white.

Most people associate two things with generics: a reasonable price and the question whether generics are free of animal testing.

Generics are much cheaper, but why?

This is not due to a lower quality, but to the total cost of the reference drug. It has nothing to do with the actual production itself. Drug research and development are the main cost shares when it comes to drugs: it takes a very long time (and therefore high costs for staff and lab work) to develop a drug. From the early stages of searching for and finding active ingredients, on average 13 years pass before a drug is actually launched on the market. A high number of researchers and other experts have to repeatedly analyze and carry out tests and during this process. Furthermore, the extensive animal testing studies also delay the process. Therefore, it is hardly surprising that pharmaceutical companies have to reckon with an investment of 1.0 - 1.6 billion US dollars per active ingredient. ² And this money needs to be recouped in the end. For this reason, many companies patent promising active ingredients at an early stage rather than shortly before approval. When the active ingredient is launched on the market, no other manufacturer is allowed to produce the same drug for a number of years. This gives the manufacturer of the reference drug the advantage of holding a monopoly on the market, which is linked to a high price for drugs on which there is still a patent. This enables the manufacturers to recoup their investment costs, or to invest this money in the development of new active ingredients.

In addition, companies need to cover the costs of all the active ingredients that failed on the road to approval. On average, 92 of 100 active ingredients that were effective and harmless in animal studies do not reach the market (+Dilyanas paper). ^3–5 The main reasons are that the active ingredient was not curative and/or caused side effects in humans, despite the fact that the animal tests conducted beforehand incorrectly suggested that the substance was promising and free of side effects. The animal testing system, with its high levels of inaccuracy, thus wastes significant amounts of money. There can also be strategic reasons for active ingredients not reaching the market, e.g. another manufacturer was faster in launching a particular active substance. Such reasons, however, only make up approx. 20% of the cases of drugs not reaching the market. Nearly 80% are due to an inaccurate appraisal of the drug’s effectiveness and safety in humans, due to an unnecessary reliance on animal testing. (Dilyanas paper).

After the expiration of the 20-year patent, but no earlier than 8 (usually 10) years after the market launch of a new active ingredient, other pharmaceutical companies may also manufacture the active ingredient. If the product meets the characteristics of a generic, it is much easier to obtain marketing authorization for it than for the original. The conditions are equal throughout the EU, i.e. a generic drug can be launched on the market in one country even if the reference drug has been approved in another EU country. Since packaging and the production itself are usually possible at a rather low cost, the manufacturers of generics can sell their products significantly cheaper. In some cases, generics are 20 times cheaper than the original. ⁶

Are animal tests conducted for generics?

Since the active ingredient has already undergone an extensive (initial) approval process by the original manufacturer and has been on the market for quite a long time and has therefore already been consumed by many people, a lot of data is available.

If a pharmaceutical company plans to market the drug in the same dosage form (e.g. a tablet), with the same quantity (e.g. 5 mg), then this data can be used by the generic company to apply for approval of its own preparation. For this purpose, a written confirmation of the pre-applicant must be submitted.

Normally, manufacturers of novel drugs are also required by law to submit data from, among other records, preclinical studies, i.e. animal studies. However, since the active ingredient has already been approved and established, the manufacturers would not have to conduct any new animal studies for their generics to prove safety and efficacy.

As often, unfortunately, there is a “but".  Even where generics are concerned, it is not 100% certain that their approval and manufacture will exclude animal testing. In some cases, authorities may still demand animal testing. For example, if the manufacturer cannot use existing data to demonstrate that the criteria for bioequivalence of the generic are met, and/or there are deviations or changes in the active ingredient, indication, strength, dosage form, or route of administration.

In addition to safety and efficacy in humans, however, there is another area in which a generic product must provide data: ecotoxicology, i.e., the assessment of risk to the environment. There is a guideline on this ⁷ which demands various tests, including tests on fish. A new drug must submit certain ERA data (Environmental Risk Assessment) for approval, but in the case of generic drugs it is stated that an ERA can be omitted if the absence can be justified. In reality, animal testing can still be required in the context of ecotoxicology. In addition, data protection regarding ERA data is not explicitly regulated so that pre-applicants do not need to share their data. In that case, generic manufacturers are forced to repeat the tests on animals.. ⁸ Thus, they not only impede the (earlier) production of inexpensive generics, but also cause the unnecessary repetition of painful animal experiments.

It is absurd that while the usage of multi-organ chips and 3D bio-printing is booming, animal testing is still required even for active ingredients that are the same or at least very similar to existing active ingredients. No animal testing can predict the human reaction with certainty, and the above-mentioned failure rate of drugs is ultimately largely due to ineffectiveness and/or side effects that animal testing could not predict.

First vegan drug

Even though authorities may not demand renewed animal testing very often, if in doubt, the manufacturer will be contacted in order to clear up any uncertainties. On a positive note, the first generic Paracetamol by the French company VeggiePharm has been certified by the Vegan Society, and was recently approved for the German market. However, the term “vegan” does not automatically mean animal-free. When contacting the manufacturer, we were assured that, as with most generics, no animal testing was conducted for the approval process, as the Vegan Society's seal criteria also require. It's a more circuitous and difficult path if a manufacturer wants to meet such high standards - let's hope that many more will follow this positive example.

"Take it or leave it?" - This question is up to the attending physician, along with the patient. Moreover, it depends on the disease and the treatment. I In general, it is always advisable and sensible to try to pre-emptively prevent illnesses by adopting a healthy lifestyle, so that medication is not needed in the first place. A healthy, plant-based diet, the avoidance of stimulants, and regular exercise help prevent the typical “diseases of civilization” in particular. However, if medication is required at some point regardless, nobody should avoid taking new medicines to as no animal test would be prevented by waiving a drug.

Dipl.-Biol. Julia Radzwill

References

1. Bundesministerium der Justiz Deutsches Arzneimittelgesetz (AMG), www.gesetze-im-internet.de
2. Verband Forschender Arzneimittelhersteller e.V. (vfa) So entsteht ein neues Medikament, www.vfa.de
3. Dowden H et al. Nature Reviews Drug Discovery 2019; 18(7):495–496
4. Mullard A Nature Reviews Drug Discovery 2016; 15(7):447–447
5. Thomas D et al Clinical Development Success Rates, https://pharmaintelligence.informa.com
6. Stukenberg T Der Spiegel. 20.08.2014
7. European Medicines Agency Environmental risk assessment of medicinal products for human use - Scientific guideline, www.ema.europa.eu
8. Oelkers K Sustainable Chemistry and Pharmacy 2021; 20:100399