Generic medicines

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Contents

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

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A year after the foundation of the NHS in 1949 16% of medications were dispensed as proprietary preparations (ie 84% generic). But then a major era of drug discovery/patenting/marketing began so that by the peak of 1971 80% of medications prescribed were proprietary. This predominance reflected that 96% of the leading medicines prescribed in 1969 had been first introduced since 1949, and time from discovery to marketing was somewhat shorter in the days before thalidomide, leading to longer patent protection. Matters had already come to a head as was recognised in the 1967 Sainsbury report (Report of the Committee of Inquiry into the relationship of the pharmaceutical industry with the National Health Service). In 1964 the potential savings of generic substitution were estimated at only 0.5% of the NHS drug budget, rather different from the estimate 40 years later.In 1974 it was noted that "general practioners, who usually know drugs by their trade names, are confused by the medical journal habit of describing drugs only by their approved name"[1]. Intervening health policy caused a major transition so that by 2008 in primary care 83% of prescription items were prescribed generically (although 18% were only available as a branded product). The 2009 pharmaceutical price regulation scheme (PPRS) plans to use generic drug supply as a major lever to reduce the nine billion pounds NHS expenditure on branded medicines by an average of 5% a year. One proposal which is controversial, is active substitution by pharmacists, which has been estimated to save £450 million at 2008 prices[2].

Politics

The global pharmaceutical market is worth over US $550 million (2005) 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 in 2004 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% in 2002 to 26.1% by 2010.
  • 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

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The law in the EU and UK is different from that in other jurisdictions and can allow effective patent protection for an indication to continue even though generic competition exists for other indications

  • 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]
  • Doctors have been instructed to prescribe non-branded Pregabalin when prescribing for pain.[17]

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

  1. Teeling-Smith G. Trade names or approved names. Part 1. The situation. How doctors prescribe and why. Postgraduate medical journal. 1974 Feb; 50(580):65-7.
  2. The proposals to implement 'generic substitution' in primary care, further to the Pharmaceutical Price Regulation Scheme (PPRS) 2009. Consultation document
  3. Pollak PT. Altered metabolite concentrations with amiodarone generic substitution cannot be observed without monitoring. Can J Cardiol. 2001;17(11):1159-63.
  4. Waldman SA, Morganroth J. Effects of food on the bioequivalence of different verapamil sustained-release formulations. J Clin Pharmacol. 1995;35(2):163-9
  5. Van Gelderen ME, Olling M, Barends DM, Meulenbelt J, Salomons P, Rauws AG. The bioavailability of diclofenac from enteric coated products in healthy volunteers with normal and artificially decreased gastric acidity. Biopharm Drug Dispos. 1994;15(9):775-88
  6. Hibberd AD, Trevillian PR, Roger SD, Wlodarczyk JH, Stein AM, Bohringer EG, Milson-Hawke SM. Assessment of the bioequivalence of a generic cyclosporine A by a randomized controlled trial in stable renal recipients. Transplantation. 2006;81(5):711-7
  7. Witt DM, Tillman DJ, Evans CM, Plotkin TV, Sadler MA. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy. 2003 ;23(3):360-8.
  8. Schall R, Muller FR, Muller FO, Luus HG. Bioequivalence of controlled-release calcium antagonists. Clin Pharmacokinet. 1997;32(1):75-89
  9. Blakesley VA. Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate. AAPS J. 2005;7(1):42-6
  10. Fareed J, Leong WL, Hoppensteadt DA, Jeske WP, Walenga J, Wahi R, Bick RL. Generic low-molecular-weight heparins: some practical considerations. Semin Thromb Hemost. 2004;30(6):703-13
  11. Vlahov V, Thyroff-Friesinger U, Koytchev R, Bakracheva N, Gatchev E. Bioequivalence studies with metformin: comparability of reference tablets from different origins. Int J Clin Pharmacol Ther. 2005 Sep;43(9):457-62.
  12. Jovanovic D, Kilibarda V, Dordevic S, Jovanovic M, Jovic-Stosic J, Srdic D, Knezevic T. Bioequivalence testing of a new tablet formulation of generic fluoxetine. Eur J Drug Metab Pharmacokinet. 2006;31(1):35-40
  13. Shimatani T, Inoue M, Kuroiwa T, Xu J, Mieno H, Tazuma S. Acid-suppressive effects of generic omeprazole: Comparison of three brands of generic omeprazole with original omeprazole. Dig Liver Dis. 2006;
  14. Hibberd AD, Trevillian PR, Roger SD, Wlodarczyk JH, Stein AM, Bohringer EG, Milson-Hawke SM. Assessment of the bioequivalence of a generic cyclosporine A by a randomized controlled trial in stable renal recipients. Transplantation. 2006;81(5):711-7
  15. Trottet L, Owen H, Holme P, Heylings J, Collin IP, Breen AP, Siyad MN, Nandra RS, Davis AF. Are all aciclovir cream formulations bioequivalent? Int J Pharm. 2005;304(1-2):63-71
  16. Verges J, Castaneda-Hernandez G. On the bioavailability of oral chondroitin sulfate formulations: proposed criteria for bioequivalence studies. Proc West Pharmacol Soc. 2004;47:50-3
  17. Smyth D, Croker R, Goldacre B. Pregabalin: what the patent litigation means for doctors and drug companies. BMJ 2018;361, DOI: 10.1136/bmj.k2318 (https://www.bmj.com/content/361/bmj.k2318).