CURRENT OPINION

Drug SOfe ty 1996 Oct; 15 (4): 233-242 0 114-59 16/96/00 10-0233/S05.OO/0

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Generic Drugs Therapeutic Equivalence Peter A. Meredith University Department of Medicine and Therapeutics, Western Infirmary, Gardiner Institute, Glasgow, Scotland

Summary

For economic reasons, the use of generic substitution is increasingly being supported by health authorities. Potentially, this may be problematic for drugs with a narrow therapeutic window if quality control and/or bioequivalence is not optimal. Many developing countries do not have the resources or expertise to carry out appropriate quality control resulting in widespread distribution of substandard or even counterfeit drugs. Even in countries where procedures are well regulated, substandard drugs reach the market from time to time. Interchangeability of drugs is determined by bioequivalence studies comparing the serum concentration versus time curves for the products following single dose administration to fasting volunteers in a randomised crossover design. A number of reports, largely anecdotal , of treatment failure or increased adverse events after switching brands has cast some doubts upon whether bioequivalence testing is sufficient in all cases. These reports have covered cardiovascular, respiratory, hormonal, psychotropic, anticonvulsant, anti-infective and antiint1ammatory drugs. Equivalence is particularly difficult to obtain with many sustained-release formulations. The WHO has initiated programs to prevent the distribution of substandard preparations and has drafted guidelines for testing bioequivalence based on internationally accepted reference products. Until such time as means can be provided - first , to enforce internationally accepted production standards, and second, to permit uniform testing of therapeutic agents - the safest clinical choice, particularly in countries where registration requirements and quality control are minimal, must remain the branded product.

For economic reasons, the use of generic drugs is increasing. In many countries, patent protection is absent and generic substitution of branded preparations is strongly supported by health authorities. While not the major element of a health budget, drug expenditure is an emotive issue and, politically, the simplest to address. However, if generic substitution is to be safe, careful control of the interchangeability of drugs is mandatory. In light of the critical nature of pharmaceutical products, quality assurance is a responsibility of

governments. Many developing countries, however, have yet to establish adequate drug regulatory systems. A lack of resources is the reason that many developing countries do not demand bioequivalence studies for registration of generic drugs and they have little or no possibility of implementing quality control. The results may be as reported by the Children's Vaccine Initiative Working Group on Asia,[l] that ' only 3 of 10 vaccine-producing countries in the Asia-Pacific region were assessed to have internationally acceptable standards for

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vaccine production and quality control, and effective regulatory mechanisms .... Regulatory requirements were rarely enforced'.

1. Defining Standards for Pharmaceuticals The definition of pharmacopoeial and other standards for the manufacture of pharmaceutical and biological products is among the constitutional mandates of the World Health Organization (WHO), which has taken active measures to advise developing countries on the feasibility of establishing national drug quality control laboratories, and on the technical and financial resources required.[2] Because, for many countries, the establishment of a national standards laboratory must remain a remote prospect, the WHO is attempting to develop regional drug quality control laboratories that can provide quality control facilities for testing drug samples from neighbouring countries. To date, quality control laboratories have been established in Cameroon, Ghana, Niger and Zimbabwe and WHO is supporting training programmes in the priority areas of national drug policy, drug supply systems, quality assurance and the rational use of drugs.[3) A recent WHO report was prompted by the perception that the scope of drug quality assurance has widened. No longer restricted to assuring conformity in the production and storage of registered products, quality assurance now extends to detecting and preventing the distribution of spurious and substandard pharmaceutical products.[2)

2. Generic Substitution In the more developed countries, problems with generic medications have occurred even where bioequivalence testing is a prerequisite for registration. Thus, despite apparent bioequivalence, differences in clinical response have frequently been described (examples are given later). Although many of these reports can only be regarded as anecdotal, it has called into question the validity of bioequivalence testing without clinical testing. © Adis International Limited. All rights reserved.

Meredith

Another problem may arise when generic drugs containing the same amount of active substance, but not bioequivalent to the original brand, are registered. Such drugs are active, but are not directly interchangeable with other brands, because bioavailability and plasma concentration curves may be significantly different and equipotency cannot be assumed. In the US, such drugs are B-listed in the so-called 'Orange Book', but it is probably over-optimistic to assume that such differences are universally recognised. 2.1 The US Experience Although now well regulated, experience in the US offers an interesting and cautionary historical perspective on generic substitution. Hospital formulary systems [Pharmacy and Therapeutics (P&T) committees] were widely established in the late 1940s and early 1950s in response to the burgeoning development and introduction of new drug products, including many duplicate products. At first, the purpose of P&T committees was to select drugs with the aim of ensuring that treatment was prescribed accurately and used safely. In time, drug restriction became an effective means of minimising the use of relatively costly agents when equally effective, but less expensive, drugs were available. In the words of one P&T reviewer: 'Now the trend is to eliminate from the formulary altogether the more expensive agents when drugs of equal therapeutic value, but lower cost are available' .[4) P&T committees depend on generic substitution to produce substantial reductions in hospital drug expenditures. However, if the choice of drug is based solely on direct cost, there is an inevitable risk that some of the products will not be bioequivalent and the result will be treatment failure or toxicity, increasing indirect costS.[4) With the passage of amendments to Federal Drug Laws in the 1980s (The Drug Price Competition and Patent Term Restoration Act of 1984), manufacturers were required to document only bioequivalency between the innovator and the generic products, and this modification of the drug approval process fostered explosive growth in the Drug Safety 1996 Oct; 15 (4)

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rate of generic drug submissions to the Food and Drugs Administration (FDA). By 1989, generic products accounted for one-third of all prescriptions in the US. Undoubtedly, the bulk of these products are safe and effective, as attested by the experience of patients, physicians and pharmacists; however, questions of safety and efficacy for all products are not necessarily resolved. Despite the conformity demanded by the US Pharmacopoeia (USP) for pharmaceutical entities, efforts to standardise production and testing of pharmaceutical products are encumbered by a system that requires proof of bioequivalence only for agents that have become available since passage of the 1938 Food, Drug and Cosmetic Act. The FDA responded promptly and decisively to an outbreak of attempts to circumvent the generic drug approval process. However, although only a few generic drug companies and government employees were involved in these illegal and unethical activities, the measures taken have not entirely dispelled doubts about the quality of many generic drugs. The crisis of confidence brought about by this experience simply confirmed the prejudice of many health professionals that all generic versions of a pharmaceutical entity are not necessarily equivalentJ5] The FDA, which is among the strictest health authorities in the world, has recognised that about 20% of the multi source drugs on the American market cannot be considered bioequivalent and, therefore, are not freely interchangeableJ6] Moreover, even in countries such as the US with systems that are well regulated, manufacturing problems may arise with generic products resulting in batch recall.[7] Recent experience with poor quality, low-cost drugs, imported into the US, has led the FDA to double its number of inspections at foreign pharmaceutical manufacturing plants. The agency has found serious manufacturing deficiencies, ranging from contaminated water to lax quality control in 35% of its overseas inspections in countries as varied as Switzerland and China, compared with 19% © Adis International Limited. All rights reseNed.

of domestic plants.[8] In Canada, another highly controlled and regulated market, it has been reported that 20 of 229 (9%) generic brands examined were of an unacceptable standard.[9] 2.2 Other Countries

In contrast, no reliable data can be given concerning the number of nonequivalent or substandard generics in the developing world, due to lack of control facilities in these areas. Not only is lack of bioequivalence testing a problem in small countries, but even countries such as Brazil and Turkey do not require bioequivalence testing for registration of generics. In Indonesia, no preregistration is required for pharmaceutical products and local manufacturers of generic products (the manufacture of which is restricted to Indonesian firms) do not have to demonstrate bioequivalence for their products.[3]

3. Establishing Bioequivalency Drug products are considered to be pharmaceutical equivalents when they contain the same active ingredient(s) and are identical in dosage form and strength.[IO] Agents must be formulated to meet identical standards, but may differ in properties such as size, shape, excipients and preservatives. Drugs are termed generic equivalents when they are sold under the generic name and dosage form of the innovator compound. Adverse clinical effects may result when pharmaceutical alternatives are indiscriminately substituted in the absence of proof of true generic bioequivalenceJII] 3.1 In Vivo Bioequivalence Studies

Generic products are compared with innovator agents by means of bioavailability or bioequivalence studies. Bioavailability is the sum of the rate and extent of a given drug dose that is absorbed and reaches the site of actionJl2] Because drug concentrations cannot usually be measured directly at the site of action, bioavailability studies are generally performed by measurement of drug and/or metaDrug Sofety 1996 Oc t; 15 (4)

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bolite concentration in a biological fluid such as blood, plasma, serum or urine)13] Bioequivalence studies to establish bioavailability usually compare tablet or capsule dosage forms, which may be expected to demonstrate closely similar blood concentration-time profiles. Agents intended for intravenous administration are not tested for bioequivalence because the entire dose reaches the systemic circulation. Likewise, a drug in oral solution is already dissolved and in its most readily absorbable form. Hence, differences in oral solutions are less likely to adversely affect bioequivalence. The fundamental principle on which testing for bioequivalence is based is the supposition that dosage forms that produce identical blood concentrationtime profiles in humans must produce identical therapeutic and toxic responses. However, no 2 products demonstrate completely identical profiles at every sampling point; therefore, some degree of difference must be considered acceptable. Whereas drug concentration in the systemic circulation is important, for many agents, the action of metabolites is at least equally relevant to clinical effect and, in this instance, bioequivalence studies require measurement of both the parent compound and any active metabolites)13] Bioequivalence studies of a generic drug are required to demonstrate that the parameters fall within a certain range of those of the reference compound. Determinations of bioequivalence are usually based on the results of a serum concentration versus time curve, following administration of a single drug dose to fasting volunteers in a randomised crossover design. The question as to whether bioequivalence has or has not been established is then based on the rate and extent of absorption of the 2 products in individual volunteers; this is normally defined by the area under the concentration-time curve, the peak concentration and the time to attain peak concentration. The issue that has received most attention in the analysis of these studies is the question of the most appropriate statistical methods for determining whether 2 formulations of a drug have been shown © Adis Internatio nal Limited. All rights reserved.

to be bioequivalent. A variety of different approaches have been advocated and in some instances adopted by the regulatory authorities. In the early 1980s, the FDA suggested the '75175 rule', where equivalence of a new product was defined to be that at least 75% of the volunteers would have bioavailability ratios in the range 0.75 to 1.25 of the comparator.[l4] Criticisms of the statistical validity of the '75175 rule' led to the discontinuation of its use and a number of different approaches have been proposed. These are based mainly upon construction of confidence intervals, a Bayesian approach and power calculation)15,16] Most, however, share the aim of establishing the probability that the new formulation differs from the comparator by no more or less than 20%. Bioequivalence is usually studied only in a small number of subjects. If intrasubject variability is 15.7%, 14 individuals would be required to demonstrate a ±20% variability with a significance level of 5%. If, however, intraindividual variability was 40%, 70 individuals would be required to demonstrate this difference. This led to the suggestion that both inter- and intra-individual variability should be documented both for the original product and the generic versions for drugs with a narrow therapeutic window. 117 ] 3.2 Dissolution Studies

Because the rate of dissolution in the gastrointestinal tract is known to influence the rate of drug absorption, attempts have been made to correlate in vitro dissolution test results with bioavailability in vivo. In the US, the Pharmaceutical Manufacturers' Association Joint Committee on Bioavailability has stated that dissolution testing cannot replace in vivo bioequivalency testing,118] although dissolution testing can be useful iflimited to pre-evaluation studies prior to in vivo bioequivalence studies. Furthermore, dissolution testing is a widely used technique for quality control of pharmaceutical products. Drug Safety 1996 Oc t; 15 (4)

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4. Potential Problems Associated with Substitution For a large number of products in many treatment categories, case studies and reports exist concerning treatment failure or increased adverse effects after changing to generic brands, but it must be recognised that these are largely anecdotal, and few systematic studies have been performed. These reports have covered such therapeutic categories as cardiovascular,f l91 respiratory,[20,21 1 hormonal,[22- 24 1psychotropic, I 14,251 anticonvulsant,[ 141 anti-infective[26,27 1 and anti-inflammatory[28-301 drugs (see section 5.4). Drug substitution may be associated with a substantial risk of treatment failure and/or increased toxicity in several therapeutic categories and for certain patient populations. Broad discrepancies between in vitro dissolution and clinical effect have been shown in the critical therapeutic categories of cardiovascular drugs (section 5.1), psychotropic agents (section 5.2) and anticonvulsants (section 5.3). The potential for serious adverse outcomes also exists in other categories, including low-dose oral contraceptives, bronchodilators, oral diuretics and oral anticoagulants (table I). With the obvious exception of women using oral contraceptives, patients primarily at risk include debilitated and/or elderly patients with impaired gastrointestinal, renal or hepatic function. 4.1 Bioequivalence Testing

As discussed in section 3.1, the main focus of debate over bioequivalence testing has been related to the analysis of the data generated rather than questioning the fundamental design of these studies. This is not unreasonable, as variability of up to 20% for the mean values of the bioavailability parameters may in many instances be acceptable; however, in other cases, the resulting differences in circulating drug concentrations when a patient is switched from the branded to the generic formulation, may be of pivotal importance. The end result could theoretically be a difference as great as © Adis International Umited. All rights reserved.

Table I. Critical therapeutic categories in which variations in bioavailability may alter clinical outcome Documented Cardiovascular drugs digoxin Psychotropic agents amitriptyline chlorpromazine thioridazine Anticonvulsants phenytoin Potential Low-dose oral contraceptives ethinylestradiol 3511g/etynodiol 1mg ethinylestradiol 3511g/norethisterone 1mg ethinylestradiol 3011g/norethisterone 1.5mg Bronchodilating agents theophylline Oral diuretics furosemide (frusemide) Oral anticoagulants warfarin

40% in the relative amount of drug absorbed. It is

not impossible that substitution of a generic drug within this range of variability could result in treatment failure, increased risk of adverse effects or toxicity, or even destabilisation of a patient in whom the original branded drug had been titrated.[14] When the therapeutic window is wide, variation in bioavailability may not be crucial to clinical outcome (such as with oral antibacterials, antacids, antihistamines, vitamins and certain analgesics). In this case, the dose is often so high that a difference in drug uptake will not cause any relevant changes in clinical effect or important differences in adverse effects. In others, however, minor changes in blood concentrations could have substantial repercussions in terms of treatment outcome or adverse events. Substitution of generic drugs could exacerbate the risk of clinical events (table 1),[14] depending on dose titration, therapeutic index (narrow efficacy : toxicity ratio), presystemic drug metabolism and idiosyncratic administration requirements. Drug Safety 1996 Oct; 15 (4)

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4.2 Variations in Patient Groups

Objections to in vivo bioequivalence testing have been based on the criticism that the test drug is almost invariably administered in single doses to healthy young adult male volunteers, rather than to people who more closely approximate the patients for whom the drug is intended. The question arises whether this can be regarded as representing the likely drug disposition in the target population who are likely to be receiving long term treatment, who may well be elderly or female, have impaired renal or hepatic function or diseases of the gastrointestinal tract and, in many instances, be receiving other medications. Drug concentrations may indeed be affected by patient variables such as age or disease state; however, concentrations of products with an identical drug content should be similarly affected. Confounding factors could be introduced by testing drugs in patients who are subject to fluctuations or progression in a disease process. Furthermore, ethical issues would preclude bioequivalence testing in patients who, under the best circumstances, might obtain equal benefit from the dosage forms under evaluation and, under the worst, would fail to receive a therapeutic effect.[14] However, these ethical considerations do not preclude an approach that would evaluate bioequivalence at steady state in target populations, once a product's bioequivalence had been demonstrated in single-dose studies in healthy volunteers. 131 ] Experiences with several widely used agents in different therapeutic classes have shown that the assumption of therapeutic equivalence on the basis of bioequivalence testing could be misplaced. One group of investigators commented as follows on the misleading assessment of efficacy by bioequivalence testing of 2 sustained-release formulations of a calcium antagonist: 'Therapeutic equivalence of such formulations should be established by pharmacodynamic evaluation or clinical studies using patients' .1 19 ] They noted that, while both formulations were unquestionably effective, they could not be considered equivalent or interchangeable. © Adis International Limited. All rights reserved.

Meredith

5. Specific Problems with Substitution 5.1 Cardiovascular Agents

As long ago as the early 1970s, investigators reported marked differences in the bioavailability of generic digoxin tablets, despite the supposedly equal drug content of the formulations.[14] As a result of studies that correlated lack of bioequivalence with variations in the in vitro dissolution and the clinical response, several generic digoxin formulations were withdrawn from sale. Subsequently, the FDA termed digoxin a 'critical' drug; this designation means that bioavailability has to be demonstrated to obtain approval for any generic digoxin product. Characteristics that led to the designation of digoxin as critically bioavailable are shared by numerous other agents available as generic compounds. These characteristics include: • the critical nature of digoxin therapy; • low intrinsic water solubility; • rate-limited dissolution; • narrow therapeutic index; • low active ingredient: excipient ratio in the tablet formulation. Digoxin may not be the only cardiac agent that presents problems with respect to bioequivalence. The absorption of oral procainamide, for instance, differs between healthy individuals and those with acute myocardial infarction,l14] which emphasises the possibility that bioequivalence results from healthy volunteers may not be valid in patients. Moreover, problems may arise with substitution of generic forms of propranolol and quinidine for the following reasons: (i) both drugs undergo extensive presystemic metabolism; (ii) the rate of presystemic generation of metabolites can influence treatment outcome; and (iii) the presystemic metabolism rate increases the potential for variability.[14] A highly metabolised agent with active metabolites, such as propranolol, poses yet further problems. The analytical procedures used to determine plasma concentrations in bioequivalence studies must take account of both the parent compound and one or several active metabolites. The generation Drug Safety 1996 Oct; 15(4)

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of multiple metabolites can undennine the assay methods and produce misleading results. A report of 1182 patients receiving branded propranolol, 'Inderal', versus 586 receiving generic propranolol suggested a 40% higher incidence of adverse effects with the generic drug.f32] In the US market, cardiovascular drugs not approved by the FDA (available before 1938) or rated inequivalent (B) include digoxin, altered-release quinidine, extended-release procainamide, disopyramide, reserpine, hydralazine/hydrochlorothiazide, hydrochlorothiazideltriamterene, extended-release isosorbide dinitrate and verapamiJ.l4] Joshi et al. [33] have demonstrated a considerable lack ofbioequivalence between different diltiazem preparations. In a study by Carter et al.,[34] bioequivalence between 2 generic verapamil preparations was found in young healthy volunteers, whereas in elderly hypertensive patients, one generic product had a maximum serum concentration (C max ) and an area under the concentration-time curve (AUC) that were 77 and 43% greater, respectively, than those of the brand name product (p < 0.02). This was associated with greater prolongation of the PR interval. Substantial brand differences in the uptake of sublingual nifedipine have also been reported.[35] 5.2 Psychotropic Agents

With psychotropic drugs, the minimum effective blood concentration required to evoke a therapeutic response is highly variable. The dosage of such agents must, therefore, be carefully titrated to the needs of individual patients. Like some of the cardiovascular compounds, many psychotropic agents (including chlorpromazine, thioridazine and amitriptyline) undergo extensive presystemic transformation , with generation of numerous active metabolites, which, as has already been noted, results in difficulty in interpreting bioequivalence. Studies comparing generic and branded forms of chlorpromazine have indicated that the products are not therapeutically equivalent and that there are clear discrepancies, both in therapeutic doses and in the rates and severity of adverse effects.f 14 ] Sev© Adis International Limited. All rights reserved.

eral investigators have reported relapses in patients who were switched from branded forms of the tricyclic antidepressant amitriptyline or the antipsychotic thioridazine to supposedly equivalent generic forms of the drugs. Symptomatic improvement gradually returned when brand-name therapy was reinstituted.f 14 ] Colaizzi and Lowenthal,[14] reviewing these events, noted that the FDA has criticised the reports as anecdotal and admit that there have as yet been no reports of widespread treatment failures resulting from generic drug substitution. These authors warn, however, that 'the quality of treatment and care is occasionally compromised by generic substitution - and especially by indiscriminate interchange in generic products' . Psychotropic drugs listed in the US as having nonequivalent brands include amitriptyline, nortriptyline, desipramine, trimipramine and lithium,l3] 5.3 Anticonvulsants

Anticonvulsant drugs listed in the US as nonequivalent include phenytoin, phenobarbital and carbamazepine. [3] The anticonvulsant agent phenytoin is characterised by a narrow efficacy: toxicity ratio and nonlinear disposition characteristics. Recommended serum concentrations are in the range of 8 to 20 mg/L. Concentrations above 20 mg/L have been associated with an increased risk of acute cerebellar syndrome, delirium and coma, among other serious adverse effects. Marked differences in absorption between generic and branded capsules of phenytoin emphasise the risk of substitution. The FDA has acknowledged this risk in a warning that interchange could have serious clinical consequences. As Colaizzi and Lowenthal have observed:[14] 'Once classified as therapeutically equivalent, these products are now viewed as distinct noninterchangeable entities. With phenytoin, as with digoxin and many other drugs, slight changes in formulation can cause significant alternations in bioavailability' . Drug Safety 1996 Oct: 15 (4)

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5.4 Nonsteroidal Anti-Inflammatory Drugs

The results of a pilot study[28] of 25 different brands of piroxicam capsules marketed internationally disclosed that 72% of the brands failed to meet the USP requirements for dissolution. A further study[29] was, therefore, undertaken to compare the dissolution performance of a wider range of international piroxicam products. The study evaluated 85 generic formulations of piroxicam from 21 countries to determine whether the agents met the USP dissolution and potency requirements. Only 8 of the tested products reached both the potency and dissolution standards; one of the 8 was the innovator's branded product. Of the tested formulations , 80% failed to meet the dissolution requirements and 59% failed to meet the potency requirements. In all, more than 90% of the generic products failed the USP in vitro quality assurance criteria for both dissolution and potency. Even in the absence of bioavailability data, it is evident that the great majority of the generic products could not be considered equivalent to the branded product according to accepted measures of product quality. 5.5 Sustained-Release Formulations

A randomised, open, crossover trial[19J compared the pharmacokinetic and pharmacodynamic profiles of 2 sustained-release formulations of the calcium antagonist diltiazem in healthy male volunteers; both formulations (,Bi-Tildiem' and 'Cardizem SR') were administered as a single oral 120mg dose, with a 7-day washout period between treatments. There were no important pharmacodynamic effects discernible in these healthy volunteers and thus no significant differences between the formulations . However, despite a significant difference with respect to AUC, C max and the apparent half-life (ty), these 2 sustained-release formulations were approved in their respective countries on the basis of safety and efficacy in the treatment of angina pectoris, hypertension and arrhythmias. © Adis Internaftonal Umited. All rights reserved.

The results of the study[19] confirmed that while the 2 formulations are effective, the two different formulations of the same agent have different pharmacokinetics and are not bioequivalent and, therefore, not interchangeable. The study also confirmed that diltiazem does not elicit significant pharmacodynamic responses in healthy volunteers, which demonstrates that, in many instances, studies in patients are necessary to determine equivalence of pharmacodynamics. Similar potential problems have been identified with sustained-release formulations of verapamii. Two formulations of sustained-release verapamil, which had previously been shown to be bioequivalent based upon conventional comparisons in fasting healthy volunteers, were shown not to be bioequivalent when the individuals were fed prior to drug administrationP6] This was apparent from an increase in the AUC of both verapamil and its major metabolite norverapamil, with concentrations of verapamil that were 50% higher in the first 6 hours after the generic form of the drug was administered compared with the reference formulation. The increased drug concentrations were associated with conduction disturbances, as evidenced by a significant increase in PR interval and a higher incidence of first-degree heart block. Similarly disquieting evidence of nonequivalence has been found for other sustained-release formulations. In 1993, the Royal Pharmaceutical Society of Great Britain (RPSGB )[20] addressed the issue in a strongly worded statement, claiming that ' the modified-release, oral preparations, which have a variety of different release mechanisms and dissolution rates, are unlikely to have the same pharmacokinetic profiles, even if the same quantity of active constituent is contained in each preparation'. It is, therefore, essential that patients taking these modified-release, oral preparations, who have been stabilised on a particular brand, continue to receive the same product. The British National Formulary recommends that specified modifiedrelease oral preparations of diItiazem, nifedipine or Drug Safety 1996 Oct; 15 (4)

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theophylline should be prescribed by brand name.[3?] Additionally, it is essential that a patient discharged from hospital should be maintained on the brand with which that patient was stabilised as an inpatient. [20]

6. Conclusions Programmes have been initiated by the WHO with the aim of preventing the distribution of substandard pharmaceutical preparations. In particular, the WHO has emphasised the need for countries to 'recognise and strengthen the role of the pharmacist within Drug Regulatory Authorities, in pharmaceutical manufacturing facilities and in the community at large as a necessary prerequisite to assuring the quality of pharmaceutical and biological products, both at the time of manufacture and within the distribution chain' .[1] Perhaps the highest aim of the pharmacist has been expressed in the Code of Ethics of the RPSGB :[38] 'A pharmacist should not purchase, sell or supply any medicinal product where there is a reason to doubt the quality or safety'. The WHO provides education and training materials to countries that request information. Pakistan, for example, which has a longstanding problem with regulation of the national medicines supply, has enlisted the help of the WHO in setting up a rational medicines use network.[3] Health professionals have expressed concern about the number of medicines on sale in Pakistan, which are often supplied in 'formulations of dubious quality from irregular outlets, such as village markets' .[3] The goal of the network is to raise public awareness about the safe use and potential risk of medicines. However, it must be appreciated that this problem is not exclusively one of the developing world and incidences of substandard products have been widely reported in developed countries. The WHO has drafted guidelines for marketing authorisation requirements applicable to generic pharmaceutical productsJ2] The guidelines propose that testing for bioequivalence and other criteria of clinical interchangeability be based on a © Adis International Limited. All rights reserved.

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single internationally accepted reference product. This recommendation is intended to allay concerns that the bioavailability of generic forms of certain agents is unreliable and, in some cases, insufficient to achieve an adequate clinical response. While these concerns currently focus specifically on fixed combination drugs for treating tuberculosis, the principle is, of course, equally applicable to the gamut of therapeutic agents. The long term task of formulating international reference compounds has fallen to collaborating centres in Denmark, The Netherlands, Sweden, the UK and the US; unfortunately, the costs of such a project far exceed the resources available to the international body. The failure of a product to meet standards of potency and dissolution decreases the effectiveness of the drug and raises troubling questions concerning safety and tolerability. In addition, it should be appreciated that any questions of inadequate safety and tolerability have inevitable financial consequences that potentially considerably outweigh the simple cost differential of proprietary and generic formulations. Consumers can only have confidence in a system when they are assured that all drugs have been tested to standards requiring evidence of safety, efficacy and quality.D] The wide range of indications for agents found to be substandard suggests that the problem may extend throughout the range of therapeutic classes. It should not automatically be assumed that the potential problems associated with lack of bioequivalence is confined to the few instances cited in this survey. Experience with a range of agents in an equal range of therapeutic classes has shown that uniformity cannot be assured without in vivo bioequivalence testing based on international reference compounds. Furthermore, considerable caution should be exercised with regard to the interchangeability of sustained-release formulations . Until such time as means can be provided first, to enforce internationally accepted production standards, and second, to permit uniform testing of therapeutic agents - the safest clinical choice, particularly in countries where registration Drug Safety 1996 Oct; 15 (4)

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require ments and quality control are minimal, must remain the branded product.

References I. Children's Vaccine Initiative. Working Group Meeting on Asia Initiative. Rockefeller Archives Center, New York; 1993 Jul 28-30. Document CVIIMAC-5/93.12 2. World Health Organization. Implementation of WHO's revised drug strategy: report by the Director-General. A47/8, April 5, 1994: 1-26 3. Pharmaceutical counterfeiting and anti-counterfeiting measures. SCRIP Reports. New York: PJB Publications, 1994: 1-185 4. Hendlles L, Hochhaus G, Kazerounian S. Generic and alternative brand-name pharmaceutical equivalents: select with caution. Am J Hosp Pharm 1993; 50: 323-9 5. Zellmer WA. Generic drug products [editorial]. Am J Hosp Pharm 1989; 46: 2005 6. Nightingale SL, Morrison Je. Generic drugs and the prescribing physician. JAMA 1987; 258: 1200-4 7. Nifedipine capsules seized at Chase. SCRIP 1994; 16: 1980 8. Drew e. Medicines from afar raise safety concerns. NY Times 1995 Oct 29: I (col. I) 9. Maddock DH. Use of generic medicines and importance of brand names. Pharm J 1986; 30: 228-32 10. US Department of Health and Human Services Food and Drug Administration. Approved drug products with therapeutic equivalence evaluations. 11th ed. Bethesda (Md): US Government Printing Office, 1991 II. Levy RA. Therapeutic inequivalence of pharmaceutical alternatives. Am Pharm 1985; NS25 : 29-39 12. US Department of Health and Human Services Food and Drug Administration. Approved drug products with therapeutic equivalence evaluations. 10th ed. Rockville (Md): US Government Printing Office, 1990 13. Meyer Me. Drug product selection. Pt 2. Scientific basis of bioavailability and bioequivalence testing. Am Pharm 1991 ; N531: 47-52 14. Colaizzi JL, Lowenthal DT. Critical therapeutic categories: a contraindication to generic substitution? Clin Ther 1986; 8: 370-9 15. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987; 15: 657-80 16. Anderson S, Hauck Ww. Consideration of individual bioequivalence. J Pharmacokinet Biopharm 1990; 18: 259-73 17. Benet LZ, Goyan JE. Bioequivalence and narrow therapeutic index drugs. Pharmacotherapy 1995; 15: 433-40 18. Pharmaceutical Manufacturers' Association Joint Committee on Bioavailability. The role of dissolution testing in drug quality, bioavailability and bioequivalence testing . Pharm Technol 1985; 9: 62-6 19. Guimont S, Landriault H, Klischer K, et al. Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulation s of diltiazem in healthy volunteers. Biopharm Drug Dispos 1993; 14: 767-78

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20. Royal Pharmaceutical Society Council Advice. Pharm J 1993; 251 : 528 21. Haglund K. Slow release theophyllines: don 't substitute. Medical Tribune 1987; 28: 13 22. Hayward JL, Fentiman IS. Generic prescribing [letter). BMJ 1986;292: 762 23. Ansbacher R. Generic drugs: bioequivalence and bioavailability [letter]. JAMA 1988; 259: 220 24. Ramos-Gabatin A, Jacobson JM, Young RL.ln vivo comparison of levothyroxine preparations. JAMA 1982; 247: 203-5 25. Dubovsky. Severe nortriptyline intoxication due to change from a generic to a trade preparation. J Nerv Ment Dis 1987; 175: 115-7 26. Wildfeuer A, Zimmermann T, Eibel G, et al. Relative bioavailability of sultamicillin in healthy volunteers following administration of two tablet formulations. J Intern Med Res 1992; 20SuppI.1:4A-IIA 27. Taylor RB, Shakoor 0, Behrens RH. Drug quality, a contributor to drug resistance [letter). Lancet 1995; 346: 122 28. Barone JA, Lordi NG, Byerly WG, et al. Comparative dissolution performance of internationally available piroxicam products . Drug Intell Clin Pharm 1988; 22: 35-40 29. Byerly WG, Barone JA , Kopcha M, et al. Comparison of dissolution and potency of internationally available piroxicam: generic variability. J Int Postgrad Med 1990: 3: 3- IO 30. Bochner F, Somogyi AA, Wilson KM. Bioinequivalence of four 100 mg oral aspirin formulations in healthy volunteers. Clin Pharmacokinet 1991: 21: 394-9 31. Kaniwa N, Aoyagi N, Agata H, et al. Application of the NONMEM method to evaluation of the bioavailability of drug products. J Pharm Sci 1990; 79: 1116-20 32. Sanderson JH, Lewis JA. Differences in side-effect incidence in patients on proprietary and generic propranolol. Lancet 1986; I: 967-8 33. Joshi MV, Gokhale PC, Pohujani SM, et al. Bioinequivalence of marketed diltiazem preparations. Eur J Clin Pharmacol 1990; 39: 189-90 34. Carter BL, Noyes MA, Demmler RW. Differences in serum concentrations of and responses to generic verapamil in the elderly. Pharmacotherapy 1993; 13: 359-68 35. Rietbrock N, Kausch M, Engelhardt M, et al. Non-bioequivalence of sublingual nifedipine. Br J Clin Pharmacol 1987 ; 23: 589-90 36. Waldman SA, Morganroth J. Effects of food on the bioequivalence of different verapamil sustained-release formulations. J Clin Pharmacol 1995; 35: 163-9 37. British National Formulary No.3 !. London: The Pharmaceutical Press, 1996 38. Royal Pharmaceutical Society of Great Britain. Code of ethics. Medicines, ethics and practice. London: RPSGB, 1992: 77

Correspondence and reprints: Dr Peter A. Meredith, University Department of Medicine and Therapeutics, Western Infirmary, Gardiner Institute, Glasgow Gll 6NT, Scotland.

Drug Safety 1996 Oct: 15 (4)