Generic medicines

Contents 1 Introduction 1.1 History in UK 2 Politics 3 Ethics 4 Pharmacology 5 Interesting Asides 6 Bottom Line 7 References

Introduction

Generic medicines are the therapeutic equivalent of each other and are usually compared to the brand name original patented medicine where much initial clinical experience would have been gathered. However it is important to be aware that different pro-drugs of an active compound, formulations of that compound and biosimilar medicines are different and may not be directly substitutable.

In most countries, if a doctor prescribes a drug by its generic name (rINN) the pharmacist is allowed to dispense any legal (licensed) form of the same drug, whatever the brand name. Some drugs that are out of patent may not even have a brand name and be purely marketed generically. This allows the patient or commissioner of healthcare to purchase, or the pharmacist to dispense, the cheapest form of the drug consistent with the prescription. If a doctor (in most countries) prescribes by brand name only that product should be dispensed. In most countries patent law will result in monopoly marketing of a brand name product, but when the patent expires competitive supply of other generic equivalents becomes possible. While the brand name product could be regarded as just another generic medicine in this situation, in practice it almost always will continue to be marketed at a premium of typically 20 to 80% for what could be regarded as "goodwill value". In other words prescriber's and patients value the brand as a known entity.

As a matter of economics most insurers and governments that fund the supply of drugs encourage or mandate policies consistent with greater use of generic medications. There are political and ethical implications of such policies.

History in UK

Politics

The global pharmaceutical market is worth over US $550 million It is a significant employer in many Western economies, but even more importantly contributes significantly to the balance of trade of Western economies. The 50 largest pharmaceutical companies were distributed USA(US $251 billion sales, n=20), Europe (US $198 billion, n=17), Japan (US $44 Billion sales, n=12), Israel (US $5 billion, n=1), but of course have research and manufacturing bases usually in multiple parts of the world. It is a matter of documented record that in market access disagreements with governments such companies will threaten to close research facilities or withdraw from a market. And they carry out such threats, especially in small countries.

Generic manufacturers also actively lobby governments. They are likely to make points such as generic medications:

1. Reduce prices
2. Stimulate competition
3. Create (local) employment and investment opportunities
4. Stimulate innovation (a monopoly has little incentive to discover new medicines)

Ethics

Multiple conflicts of interest can occur. Examples:

• The top 20 drug companies are forecast to increase the percentage of their total ethical sales from licensed products from 17.5% to 26.1%.
• Fixed return guarantees on total drug sale income negotiated at national level
• Patients losing benefit from the placebo effect on a switch
• Patients are not involved in any financial decision
• Pharmacists, doctors and company shareholders may profit from a financial decision
• Bioequivalence unlikely with modified release preparations
• Professional independence
• "Evergreening" where patents are extended for a new indication or variation on a formulation. Marketing a pure enantiomer of a drug just when the patent on the racemic mixture is about to expire is also a variation on the "evergreening" theme.

Pharmacology

In most countries bioequivalence of the various generic versions of a drug is expected. However there are limitations

• Bioequivalence is a range in fit adults
• The criteria for bioequivalence will depend upon many factors, and may not detect interactions with say a matrix agent and the product that produces say toxic metabolites ^[3]
• Minor differences in the surface coating of the tablet, matrix agents and different salts and ester etc might be important in individual patients, disease states or other food^[4] or drugs taken at the same time^[5], especially with drugs with a low therapeutic index^[6]. However the well described experience with the introduction of generic warfarin where large numbers of patients were able to be monitored conveniently for INR change demonstrated that a 10% change could be just as easily up as down and affect a third of patients in each case.^[7].
• Effective bioequivalence is extremely difficult to attain in modified release preparations^[8] and are problematical in biologics and natural product preparations^[9] as opposed to synthesised chemicals.
• Some products such as low molecular weight heparins have characteristics that make generic competition almost impossible to imagine, as the clinical trials would need to be repeated.^[10]

Interesting Asides

• Different generics may be found in different countries for several reasons
  • Generic companies do not tend to be multinational
  • Licensing regulations vary from country to country and as a generic manufacturer never has access to the original license holders submission that resulted in a license they may have to do extra work to satisfy one country of bioequivalence unnecessary in another. This can be particularly problematical with long established drugs like metformin^[11] For example the FDAs proposed range for bioequivalence for fluoxetine of 80% to 125%^[12] is unlikely to apply in other countries.
• Demonstration of real life patient difference in bioequivalence is challenging. That there are statistically significant differences in acid secretion suppression with generic omeprazole preparations^[13] may well have no likely clinical importance in the context of the known dose response curves for the proton pump inhibitors, which may arguably be substituted for each other at equivalent dose as they act through a common intermediate inside the parietal cell.
• Cyclosporin A/Ciclosporin is an example of a drug where pharmacoequivalence in fit adults did not apply to dialysis patients. ^[14]
• Obviously it can be in the major patent holders interest to demonstrate non equivalence. In the case of aciclovir cream researchers working for GlaxoSmithKline the patent holder for Zovirax^® cream compared it with 139 generic products and found over a 7.5 fold variation in delivery of the active compound^[15]
• Bioequivalence of natural remedies is even a worse mess. If the substance is actually therapeutically inactive, patients in practice are unlikely to notice this!^[16]

Bottom Line

Most generic preparations licensed in a Western economy will be as clinically effective on product naive patients as each other. Product substitution runs the risk of patient confusion, compliance issues and a negative placebo effect, but can be economically justified in terms of health resources in many cases. It must be remembered that problems in supply of medications occur all the time so that patients and doctors may have to substitute drugs at any time, and may even have to substitute other chemical entities that there is clinical evidence for inferiority.

References