2.1.1 Introduction
Rising in price of medicines is a phenomenon that affects all countries across the world (Ping, et al,2008;Hassali and shafie,2008; Birkett et al, 2001;Dickson,1992;Donelan et al.,1999;Ess,2003;Kanavos,1999). (1-5az).Using generic medicine is One of the most effective ways to face this fact (King and Kanavos,2002;Mould,1992;Nilsson and Melander,2000;Smeaton,2000;Tatchell,2003; Laing et al.,2001)(6-11az).
Generic medicines are less expensive than innovator medicines, generally costing between 30-75% less than innovator brand.(Carroll,1995;Lofgrn,2004;Yarnall,1994;Lieberman,1986;Karim et al.,1996) (12-16az) .Two reasons for this low coast, first generic medicines does not need to spend money on research, development and marketing(17-20), A second reason is competition; when several manufacturers produce generic versions of a medicine, competition among these manufacturers can drive down the price (13,21-23az). Savings would be achieved through the use of generic medicines helps the Ministry of Health in reviving the health situation of Iraq.
2.1.2 Definition of generic medicines
The term 'generic medicine' is used in different ways. It can mean a product marketed under the drug's approved international non-proprietary name (INN), or it can, mean a product marketed under a different brand (proprietary) name. The world health organization (WHO) defines generic medicine as "a pharmaceutical product, usually intended to be interchangeable with the innovator product, marketed after the expiry of patent or other exclusively right". In some countries, they may be marketed in dosage form and/or strengths different from that of innovator products. (WHO,1997) (20)
According to the European Generic Medicines Association (EMEA) a generic medicine is defined as: "a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bio-equivalence with the reference medicinal product has been demonstrated by appropriate bio-availability studies."( Jan Donovan ,2003).A generic medicine is marketed in accordance with patent law and is identified either by its own brand name or by its internationally approved proprietary scientific name. A generic medicine is of the same quality, efficacy and safety as the original brand name product and undergoes strict scrutiny before it is licensed and given market approval (European Generic Medicines Association 2007 ) .
In the United States, the Food and Drug Administration (FDA), which is responsible for registering and marketing authorization, defines generic medicine as 'a medicine that is identical, or bioequivalent, to a brand name medicine in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use.' (FDA, 2010). The therapeutic good administration (TGA),which is the regulatory body for registering and licensing medical products in Australia defines generic medicine as "medicine which has the same qualitative and quantitative composition in term of active principles, same pharmaceutical form and bioavailability have been carried."(TGA, 1994)(24). In terms of basic generalization a generic medicine should be marketed without a commercial brand name, under the International Non-proprietary Name (INN), but practically generics can be classified categorically as branded generics, which means copies of pharmaceutical specialties with their own brand, semi-branded generics which means products marketed only under the INN followed by the name of the manufacturer , and unbranded generics medicines marketed under the INN (Garattini and Tediosi ,2000)(25).
2.1.3 Naming process of medication
Each a pharmaceutical substance is given an international nonproprietary name (INN) or a generic name (Guidance in INN,2009 ), the generic name is commonly used by physicians and pharmacist and usually created when a new drug is ready to be marketed (Gundersen, 1998).This INN is generated by the World Health Organisation (WHO) for all pharmaceuticals worldwide, using a procedure adopted by the WHO executive board(Guidance in INN,2009 ). Each INN is a unique name that is globally recognised and is public property (Guidelines on the use of international non-proprietary names,2009). An important feature of the INN system is that the names of pharmacologically related substances demonstrate their relationship by using a common "stem". as show in table ( 2.1 ). This enables healthcare professionals dealing with pharmaceutical products to recognize that the substance belongs to a specific group of substances, having similar pharmacological activity. (Guidance in INN,2009 )
Table 2.1 Generic name for common WHO approved stems
stem
Class of drug
Generic name
-olol
Î’-adrenoreceptor antagonists
Metoprolol, atenolol
-azepam
Benzodiazepine family
Diazepam,clonazepam
-vir
Antiviral agents
a cyclovir
-cillin
penicillines
Amoxycillin
-bendazole
Antihelmintics(thiabendazole)
Albendazole
-oxetine
Antidepressants
Fluoxetine
While a brand name medication can only be produced and sold by the company that holds the patent for the drug. Usually on the basis that it can be recognised, pronounced and remembered by health professionals and members of the public (Branded and generic medicines,2009).
In addition to, a chemical name medication which is scientific name based on the compound's chemical structure and this name not uses to identify the drug in clinical situation(Kenagy,2001) .
2.1.4 Patent protection for pharmaceutical
"The term patent usually refers to a right granted to anyone who invents or discovers any new and useful process, machine, article of manufacture, or composition of matter, or any new and useful improvement thereof." (Melzer,1998; patent,2009)
Under the World Trade Organization's (WTO) Agreement on Trade-Related Aspects of Intellectual Property Rights, patents should be available in WTO member states for any inventions, in all fields of technology including pharmaceutical companies, and the term of protection available should be the minimum twenty years. Different types of patents may have varying durations (Melzer 1998 ) .Regarding to the medicines, when the period of exclusivity expires and the patent runs out, it is possible for other pharmaceutical manufacturers to market generic forms of the innovative medicine. A generic medicine has the same qualitative and quantitative composition in active substance(s) as an innovative medicine that has already been authorized ( Lamarque et al, 2008) This means that these drugs are usually interchangeable.
Although generic prescribing is encouraged, there are some circumstances in which it is preferable to prescribe by brand name. Table ( 2.2 ) outlines the main instances where generic substitution may not be suitable. (National medicine information center, 2009)
Table ( 2.2 ). Circumstances in which generic substitution may not be suitable
Circumstance
Examples
Differing bioavailability between formulations
(drugs with narrow therapeutic index)
Carbamazepine, lithium
phenytoin, ciclosporin, theophylline
Modified-release preparations
Nifedipine; diltiazem; morphine
Medicines of biological origin
Growth hormone; erythropoietin
Similar medicines with different administration devices
Inhalers; adrenaline pre-filled syringes
2.1.5 Generic medicines in international markets
Generic medicines markets have not developed to the same degree in European countries. This variation due to differences in generic medicines policy.(1) To highlight the need for developing generic medicines markets, a study was conducted by prof.Dr.Steven Simoens to quantifying the potential savings from increased substitution of generic for innovator medicines in a number of countries for which data were available. Focusing on the off-patent market, the top 10 active substances were selected by expenditure of innovator medicines in 2004. As these active substances have the highest expenditure of innovator medicines, they would be expected to generate the largest potential savings from generic substitution. This study shows the savings that can be made if innovator medicines for the top 10 active substances are replaced by generic medicines. Tables (3-5) show the top 10 active substances for a countries (Austria, France, and UK (Simoens,2006a).
Table 2.3 Potential savings from increased generic substitution in Austria, 2004
Active substance
Public expenditure on originator medicines(£)
Savings from generic substitutions(£)
1
Lisinopril
33,545,548
7,973,247
2
Ramipril
26,715,264
11,717,770
3
Ciclosporin
22,456,438
3,545,505
4
Amlodipine
22,379,694
3,701,259
5
Metoprolol
22,017,335
9,580,570
6
Carvedilol
21,043,749
2,998,096
7
Pravastatin
19,565,709
5,364,850
8
Lamotrigine
17,006,227
5,539,110
9
Enalapril
16,588,539
2,183,517
10
Omeprazole
16,292,170
5,358,914
total
217,610,673
57,962,838 (27%)
Table 2.4 Potential savings from increased generic substitution in France, 2004
Active substance
Public expenditure on originator medicines(£)
Savings from generic substitutions(£)
1
Omeprazole
446,515,016
117,723,086
2
Paracetamol
145,522,610
23,838,883
3
Paroxetine
137,898,121
45,042,899
4
Ethinylestradiol
137,520,042
101,370,687
5
Bisoprolol
135,870,312
60,368,156
6
Hydrochlorothiazide
115,174,757
41,624,759
7
Citalopram
101,443,283
38,817,197
8
Trimetazidine
100,035,279
35,760,821
9
Fenofibrate
97,599,601
38,537,643
10
Gliclazide
92,798,116
22,206,603
Total
1,510,377,137
525,290,734 (35%)
Table 2.5. Potential savings from increased generic substitution in United Kingdom, 2004
______________________________________________________________________
Active substance
Public expenditure on originator medicines(£)
Savings from generic substitutions(£)
1
Pravastatin
173,926,201
1,827,32
2
Doxazosin
167,861,096
120,582,878
3
Beclometasone
141,198,568
8,721,002
4
Simvastatin
130,721,082
36,535,810
5
Nifedipine
93,826,729
40,906,097
6
Budesonide
88,848,854
30,632,531
7
Omeprazole
79,995,288
28,369,791
8
Fentanyl
73,644,518
67,750,188
9
Gabapentin
60,788,304
1,526,222
10
Paroxetine
59,976,234
12,993,094
total
1,070,786,874
349,844,935 (33%)
These tables indicate that increased substitution of generic for originator medicines can yield substantial savings for the top 10 active substances by expenditure of originator medicines.
The EU's generic market today is worth around 7 billion euros, compared to around 70 billion euros for the total European pharmaceutical market value. It is estimated that the value of the world generic market will reach about 38 billion euros in 2003.
The size of the generic market differs widely in the various EU member states. Generics make up a relatively large part of the medicine market in Germany (41%), Sweden (39%), Denmark (22-40%), the UK (22%) and the Netherlands (12%). In Italy, Spain and Portugal, generics barely count for 1% of the medicine market, compared to 3-4% in France. By contrast, generic medicines in the United States account for 40% of all prescribed medicines (Generic medicine, 2009).
2.1.6 Bioequivalence requirements for generic medicines according to FDA
Generic drug formulations are often substituted for 'brand name' (i.e., innovator) formulations by pharmacists in an effort to reduce the cost of prescription-drug therapy. In most states, generic substitution is allowed and encouraged, provided that the generic formulation is deemed to be therapeutically equivalent to the innovator formulation by the FDA.
Generally, before a new generic formulation of an innovative medicine can be marketed, the pharmaceutical manufacturer must prove that its action will be essentially the same as the innovator formulation. The purpose of the testing of generic medicine is not to demonstrate the clinical usefulness of the drug but to ensure that the generic medicine has the same relative bioavailability and bioequivalent to the innovator product.(92)
The term bioavailability defined as " the degree to which, or the rate at which, a medication or other substance is absorbed or becomes available at the targeted place in the body."(92). Bioavailability can be affected by inactive ingredients in the medicine such as additives that prevent the medication from dissolving in the stomach. For example, if a medication that is intended to be taken on an empty stomach is taken instead with food, this can also change the absorption rate and affect the bioavailability of the active ingredient(s). (bioavailability-diffenetion and example,2006 ).
Bioequivalence is defined as "the rate and extent of absorption of the test drug do not
show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses;" or "the extent of absorption of the test drug does not show a significant difference from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the reference drug in the rate of absorption of the drug is intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug."(Joseph,1999).While the term pharmaceutical equivalents refers to the drug products that contain identical amount of identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients.(27,91,93). Drug products are considered to be therapeutic equivalents only "if they are pharmaceutical equivalents and they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling."(Leslie,2002 ; Joseph,1999)
2.1.7 Determining bioequivalence
The typical study design employed in bioequivalence studies is the two-treatment, two-period, crossover design (Figure 2.1 ). In this study design, subjects are randomly separated into two groups of equal number. The innovator formulation is administered to group 'A' in the first study period, and the test formulation is administered to group 'B' in the first period. During the second study period, group 'A' receives the test formulation and group 'B' receives the innovator formulation. The first and second study periods are separated by a washout period, which is designed to be of sufficient duration to allow elimination of the drug administered in the first period. Subjects are separated into two groups to allow identification of 'period' or 'sequence' effects in the study results.
Fig. 2.1. Schematic representation of the standard two-treatment crossover study design commonly employed in bioequivalence trials.
This procedure is usually carried out by calculating a 90% confidence interval which is constructed around the ratio of the test and reference by means of two one-sided test procedure.(95,96,98)To show bioequivalence, it requires 90% confidence interval limits in the range of 80-125% based upon logarithm transformed AUC and Cmax data.(95,96,98).This is commonly referred to as the 80%/125% "goalposts" for the average bioequivalence criterion and currently has been adopted by most of the drug regulatory bodies in the world.(91-93,95-99)
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