Priority Medicines for Europe and the World

7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

Priority Medicines for Europe and the World "A Public Health Approach to Innovation"

Background Paper

Fixed Dose Combinations as an Innovative Delivery Mechanism

By Warren Kaplan, Ph.D., JD, MPH

7 October 2004

7.1-1 7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

Table of Contents

Executive Summary...... 3 1. Introduction...... 4 1.1 FDCs as Anti-hyptertensive and Anti-cholesterol Agents...... 5 1.2 FDCs as Antimicrobials...... 6 2. Advantages and Disadvantages of Fixed Dose Combinations...... 10 2.1 Presumed Advantages...... 10 2.2 Presumed Disadvantages...... 10 2.3 A Look at Some Evidence with regard to Adherence and Antimicrobial Resistance...... 11 3. Obstacles to Use of Fixed Dose Combinations...... 12 3.1 Regulatory/pharmacological Obstacles...... 12 3.2 Legal/Intellectual Property...... 14 4. Recommendations for the Future: A Research Agenda...... 16 4.1 Provide Empirical Evidence of the Potential Advantages of FDCs...... 16 4.2 Integrate FDC issues into International/domestic IP laws...... 17 4.3 Provide Incentives to the Private Sector...... 17 4.4 A Proposal for “Fixed Dose Combination Centers of Excellence”...... 18 5. Conclusions...... 18 References...... 19

Appendix

Executive Summary  Fixed dose combination drugs can be defined as two or more drugs in a single formulation, each drug having independent modes of action, the combination of which are synergistic or additive or complementary in their effect. “Free” combinations can be defined as two or more drugs in separate formulations, each taken usually at the same time. Many consider combination therapy in whatever form to be essential to the treatment of hypertension and other cardiovascular conditions, as well as major infectious diseases such as HIV, tuberculosis (TB) and malaria and to the prevention of drug resistance.  Fixed dose combination therapy has been used routinely to treat certain chronic conditions such as hypertension but the use of such therapy to treat infectious diseases has been limited to TB, malaria and HIV.  The general lack of enthusiasm among certain regulatory agencies for fixed dose combinations of antibiotics appears to stem from the late 1960s in the United States when the FDA initiated a review of all medicines approved prior to 1962 and strongly encouraged monotherapy.  There is renewed interest particularly in anti-retroviral fixed dose combinations but there is limited empirical evidence to support or refute the main purported advantages of fixed dose combinations, namely increased patient compliance and amelioration of antimicrobial resistance.  Specially designed clinical trials, epidemiological, social, and behavioral studies can test the potential for fixed dose combinations to inhibit the development of antimicrobial resistance, to secondarily prevent cardiovascular disease, and to improve patient compliance for a variety of chronically-taken medications.  There are pharmacologic, regulatory and intellectual property/legal barriers to the widespread use of fixed dose combinations but all such barriers are capable of being overcome with a comprehensive strategy and cooperation between and among the private and public sectors.  We propose one or more fixed dose combination Centers of Excellence which would act as “clearinghouses” for information about fixed dose combination therapy, coordinate field studies of fixed dose combinations and assemble and maintain the best evidence regarding their process development, regulatory and legal issues

1. Introduction The pharmaceutical and biomedical device industry has a keen interest in developing methods of delivering medications that rely on sustained release from a matrix or binder or other structures that contains the medication. Over the last decades, a wide range of such methods have been developed: osmotically/membrane controlled types; diffusion membrane controlled types, surface/dissolution controlled types; diffusion matrix controlled and non- diffusion (swelling) matrix types. There are advantages and disadvantages to each 1 2 and such devices can range in complexity. There is certainly a need for new sustained release dosage forms, particular for pediatric dosages and geriatric dosages. At present, funding in the public sector is limited for such technologies.

With few exceptions, regulators and the pharmaceutical industry has generally been wary of fixed dose combinations (FDCs) as an innovative delivery mechanism in this context, even though FDCs may be useful to improve adherence and can simplify procurement, storage and distribution of medicines. There are a variety of reasons for this reluctance (See Section 3). However, FDCs are an important approach to addressing the management of both chronic and acute diseases and more attention and research should be paid to their use.

Fixed dose combination drugs can be defined as two or more drugs in a single formulation, each drug having independent modes of action, or the combination of which are synergistic or additive or complementary in their effect. “Free” combinations can be defined as two or more drugs in separate formulations, each taken usually at the same time. Many consider combination therapy in whatever form to be essential to the treatment of hypertension and other cardiovascular conditions, as well as major infectious diseases such as HIV, tuberculosis (TB) and malaria and to the prevention of drug resistance.

A recent meeting at the World Health Organization (See Section 1.2.3) addressed the main issues related to FDCs for the treatment of AIDS, TB and malaria. Such as meeting represents the pendulum starting to swing back towards FDCs. A recent paper by Wald et al. (See Background Chapter 6.3) proposed the widespread use of a cardiovascular "polypill" and in Chapter 6.3 we advocate for the evaluation of two different FDCs for the secondary prevention of heart attack and stroke.

How FDCs are produced may vary depending on their individual active components and on the indication(s) that they target. Currently, there are no uniform principles, guidelines, or international standards addressing the formulation and production of FDCs and their potential benefits or disadvantages in treating chronic and acute diseases. In particular, aside from their use in tuberculosis3, 4 , malaria5, 6, 7, HIV8, and hypertension (See Section 1.1) and the recent interest in a "polypill", little attention has been given to the promotion, availability, and rational use of fixed dose combinations of therapeutics to manage infections caused by multiply drug resistant pathogens and to manage chronic conditions such as cardiovascular disease, diabetes, or cancer.

Fixed dose combinations simplify treatment regimens and likely facilitate the implementation of interventional programs. FDCs are likely to improve patient adherence. 7.1-4 7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

Two epidemiological studies (EUROASPIRE I and II:European Action on Secondary and Primary Prevention through Intervention to Reduce Events) looked at many thousands of coronary patients in two surveys- taken 5 years apart. The prevalence of smoking remained almost unchanged. The prevalence of obesity (body-mass index > or = 30 kg/m2) increased substantially. The proportion with high blood pressure (> or = 140/90 mm Hg) was virtually the same . The adverse lifestyle trends among European CHD patients are problematic, as is the lack of any improvement in blood-pressure management, and the fact that most CHD patients are still not achieving the cholesterol goal of less than 5 mmol/L. As a review noted, “There is a collective failure of medical practice in Europe to achieve the substantial potential among patients with CHD to reduce the risk of recurrent disease and death.” 9 Improvement in patient adherence is particularly important as many patients are either simply not getting the medicines they need and/or are not taking the medicines they get.

1.1 FDCs as Anti-hyptertensive and Anti-cholesterol Agents

Combination therapy, usually free combinations, have been used routinely to control hypertension. Physicians in the 1950s and 1960s frequently treated hypertensive patients with combination therapy--reserpine and a diuretic or reserpine, hydralazine and hydrochlorothiazide among others.10 Blood pressure goals were achieved in a high percentage of patients with these regimens, and, if not, other medicines such as a ganglionic blocking agent or guanethidine (Ismelin) were added .10 Although the dosages in the combination tablets were high by today's standards, most patients tolerated this approach to initial therapy without too much difficulty.10 Since the 1970s and 1980s, however, an emphasis has been placed on monotherapy and "individualization of treatment" .11 Some objections to initial combination therapy included increased cost, more side effects, loss of dosing flexibility and unsuitable pharmacokinetics. Indeed, most standard pharmacology textbooks discouraged fixed-dose combination therapy. See Section 1.2.1.

About a decade ago, fixed-dose combinations of a low-dose bisoprolol-hydrochlorothiazide (Ziac) and betaxolol-chlorthalidone (Kerledex) were approved as initial once-a-day therapy for hypertension. 12 This approval by the U.S. Food and Drug Administration was based on studies demonstrating that the effects of the components of these drugs were additive, that side effects of the combinations were lower and that the percentage of responders was greater than with larger dosages of the individual components of the combination. 13 This combination, however, is apparently not commercially available. Other combination therapies for hypertension (free and fixed dose combinations) are, however, effective. 14 15 16 17 Examples include the following:

1. ACE inhibitor-diuretic combinations such as captopril-hydrochlorothiazide, enalapril-hydrochlorothiazide (Vaseretic), lisinopril-hydrochlorothiazide (Prinzide), and benazepril-hydrochlorothiazide (Lotensin HCT); 2. beta blocker-diuretic combinations such as propranolol-hydrochlorothiazide (Inderide), atenolol-chlorthalidone (Tenoretic), or bisoprolol-hydrochlorothiazide; 3. an alpha blocker-diuretic combination (prazosin-polythiazide [Minizide]);

4. calcium antagonist-ACE inhibitor combinations such as benazepril- amlodipine (Lotrel), felodipine-enalapril (Lexxel), diltiazem-enalapril (Teczem), and

5. an angiotensin-II receptor antagonist (AT1 blocker) and diuretic combination (losartan-hydrochlorothiazide [Hyzaar]), or valsartan-hydrochlorothiazide [Co- Diovan®].

Diuretics and ß-adrenergic blocking drugs are the most favored first-line treatments of patients with systemic hypertension because together they can lower blood pressure more effectively than when either drug is used alone. A number of fixed-dose diuretic/ß-blocker formulations are commercially available utilizing conventional doses of thiazides (hydrochlorothiazide [HCTZ], 25 to 50 mg daily) and various ß-blockers (labetalol, metoprolol. propranolol, propranolol extended release [ER], and timolol), bendroflumenthiazide (5 mg with nadolol), and chlorthalidone (25 mg with atenolol).18 19 Recent approvals of fixed dose combinations for cardiovascular risk factors suggest that we may routinely see more use of FDCs in this context (See also Background Chapter 6.3 ). For example, in September 2000, AstraZeneca received FDA approval for Atacand HCT™ for second line treatment of hypertension. This FDC combines the angiotensin II receptor blocker Atacand® with the diuretic hydrochlorothiazide. In 2004, the FDA approved Pfizer’s CADUET® which combines as an FDC the antihypertensive calcium channel blocker amlodipine besylate and the lipid lowering statin atorvastatin calcium.

1.2 FDCs as Antimicrobials

The situation with regard to antimicrobial FDCs is more complex . There are just a few antibacterial FDCs marketed in most developed countries, the best known being cotrimoxazole (trimethoprim and sulfamethoxazole) introduced into the U.S. in 1973 and available in the UK since 1969 .20 Synercid® is a FDC of quinupristin and dalfopristin. Both of these are semisynthetic pristinamycin derivatives, and one of Synercid’s approved indications is for the treatment of patients with serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia. Synercid® has been approved for marketing in the United States for this indication under FDA’s accelerated approval regulations that allow marketing of products for use in life-threatening conditions when other therapies are not available. Augmentin ® is a combination of amoxicillin (a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram- positive and gram-negative microorganisms) and clavulanic acid (a ß -lactam, which protects the amoxicillin from being inactivatyed by ß -lactamase enzymes commonly found in microorganisms). Notwithstanding these therapeutic combinations, regulators have been wary of antibiotics as FDCs.

1.2.1 The DESI Study in the U.S.

We believe the general lack of interest to using FDCs for antibacterial purposes , with some notable exceptions, can be traced to the long shadow cast by U.S. policy in the 1970s with regard to FDCs.

The 1962 Kefauver-Harris amendments 21 to the 1938 Food, Drug and Cosmetics Act were passed in the wake of the thalidomide birth defect tragedies and in these amendments, drugs were mandated to be safe as well as effective with respect to manufacturing claims before they could be put on the market. In the United States in 1970, combination drugs accounted for over 50% of pharmaceutical products and for 40% of the best selling drugs in the U.S. 22 23 About this time, the FDA commissioned a National Academy of Sciences (NAS) study to develop a “fixed combination” policy by evaluating drugs that had been approved before 1962 on the basis of safety alone. This evaluation, the Drug Efficacy Study Implementation (DESI), looked at the many fixed dose combinations that were being marketed. 22 Under the provisions of the amendments, all drugs approved as safe from 1938 to 1962 (referred to as pre-62 drugs) were permitted to remain on the market while evidence of their effectiveness was reviewed. The program established under which the FDA would review the effectiveness of drugs approved between 1938 and 1962 was named the Drug Efficacy Study Implementation (DESI) program.

If the DESI review indicated a lack of substantial evidence of a drug's effectiveness for all of its labeled indications, the FDA published a Notice of Opportunity for a hearing (NOOH) in the Federal Register concerning its proposal to withdraw approval of the drug for marketing. At that time, a manufacturer of that drug or identical, related or similar (IRS) drugs could request a hearing and provide FDA with documentation of the effectiveness of the drug product before a final determination was made. Drugs for which a NOOH has been published are referred to as less-than-effective (LTE) drugs. Each calendar quarter, continuing to the present, the Center for Medicaire and Medicaid Services (CMS) publishes a list of LTE drugs.24 The DESI study found that only 45 of some 1200 FDC drugs were rated as effective. 22 The DESI study had little regard for fixed dose combinations of penicillin with sulfonamides or with streptomycin and concluded that these combinations were ineffective.25

This concern about the addition of extra ingredients of no value led to the “combination rule” for prescription drug products formalized by the FDA,26 requiring that each component of the combination contribute to the claimed effect of the product:

“ … (a) Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective … for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug”).

In 1970, the American Council on Drugs asserted that FDCs are “ … in most instances, not recommended”. This strong policy statement, particularly against antibiotic FDCs, was reiterated in the then-current edition of Goodman & Gilman, the ‘bible’ of pharmacology 27 :

“ it appears patently clear that these mixtures have no place on the treatment of infection… We would be remiss in our duties as physicians, teachers and investigators were we to encourage, adopt and recommend the use of … drugs of any sort in fixed combinations that do not offer the physical discretion as to the choice of components or of the ratios in which they are used. Encouraging … use of such ‘fixed dose’ antibiotic mixtures … represents a major backward step in the management of infections”. i

This early skepticism about antibiotic FDCs affected subsequent developments. The DESI study was well aware that two or more drugs are required to retard the emergence of drug resistance to tuberculosis. Notwithstanding, use of FDC in tuberculosis was endorsed in the U.S. only in 1994.28 The endorsement of FDCs was, at best, weak as use of FDC “… may enhance patient adherence and may reduce risk of inappropriate monotherapy and may prevent development of secondary drug resistance.” FDCs were “strongly encouraged” in adults.

1.2.2 The Position of the World Health Organization

In 1978, the first expert committee dealing with the Essential Medicines List, developed criteria for FDCs for the World Health Organization based on the fact that there were too many irrational drug combinations being sold, particularly in developing countries. Indeed, the early WHO lists of 250 essential drugs included combinations of only 7 drugs . 29 The policy towards FDCs by the World Health Organization (WHO) has recently undergone a major shift. The WHO new Essential Medicines List now includes FDC anti-TB products and anti-retrovirals.30 Moreover, WHO now recommends use of arteminisin fixed dose combinations to treat malaria. 30

1.2.3 Recent events: WHO and African FDC meetings, FDA FDC guidelines, Pharmaceutical industry’s renewed interest in FDCs as antiretrovirals

In December 2003, the World Health Organization hosted a meeting designed to bring together current views on the present status and future challenges with regard to clinical, regulatory, intellectual property, and production issues of FDCs for HIV/AIDS, malaria, and TB (papers submitted are available online at http://www.who.int/medicines/organization/ par/FDC/FDCmain.shtml). Shortly thereafter, in March 2004, a conference on FDCs (co- sponsored by the Joint United Nations Programme on HIV/AIDS (UNAIDS), the World Health Organization (WHO), the Southern African Development Community (SADC)and the United States Department of Health and Human Services (HHS)) was held in Botswana, designed to produce a draft “Scientific and Technical Principles for Fixed-Dose Combination Drug Products (Principles Document).”

i The present (10th) version (2001) states that the use of FDCs is “advantageous only if the ratio of the fixed doses corresponds to the needs of the individual patient.” However, use of weight adjusted FDCs for TB suggests that such stringent standards may not be needed. For early reviews of free and fixed dose combination drugs, see Fixed dose combination of drugs. J. Am. Med. Assoc. 1970; 213: 1172-1175 and Shenfield GM, Fixed combination drug therapy. Drugs. 1982; 23: 462-480.

In May 2004, the U.S. government announced an expedited pathway for the FDA to review low- fixed dose combinations, co-packaged therapies (using free combinations into a single packaging for distribution) and/or single ingredient HIV therapies for use by grant recipients of the U.S. President's Emergency Plan for AIDS Relief. [PEPFAR] .31 Although the U.S. government has clearly declared its willingness to allow PEPFAR grant recipients to purchase FDCs , generic companies that make anti-HIV medications as combinations must submit to a new FDA review process.

This is unfortunate since it seems now beyond question that certain generic FDCs are clinically effective. A recent open clinical study in 60 patients treated in Cameroon has demonstrated the efficacy and safety of a generic fixed-dose combination (lamivudine, stavudine and nevirapine).32

Another recent study from India on the safety and long-term clinical and immunological effectiveness of generic anti-retroviral FDC formulations (AZT/3TC/NVP and d4T/3TC/NVP) recruited 1253 and found a significant improvement in the mean CD4 counts over time. Most improvement occurred within 3-6 months of initiation of HAART and was sustained for up to 2 years.33

As the World Health Organization already has already declared many of these same generic drugs safe on the basis of a rigorous “pre-qualification” evaluation, 34 the U.S. government announcement that it will, in effect, only use FDA approved FDCs for its PEPFAR grant recipients, engendered some confusion and anger among public health workers and others in the field.

On the same day that the Bush administration made its May 16 announcement regarding FDA requirements for FDCs, three brand-name companies quickly said they would discuss collaborating. 35 Bristol-Myers Squibb Company, Gilead Sciences and Merck & Co. are in discussions to develop a once-daily, fixed dose combination of three anti-HIV drugs and are considering co-packaging options for the individual products. The multi-company collaboration to create a product with three already-patented HIV/AIDS medicines is the first of its kind. The proposed single tablet would include two Gilead drugs, Viread® and Emtriva®. The third drug is marketed in the US and Canada by BMS as Sustiva® and elsewhere by Merck as Stocrin®. The companies plan to seek regulatory review and approval of the three-drug fixed-dose combination. It is ironic that, in the past, brand-name companies said they could not cooperate to combine their individually patented drugs into one pill out of fear of prosecution under antitrust laws . It now seems clear that if the financial incentives are in place and the owners agree, even patented components can be combined into an FDC without apparent legal complications. (See Section 3.2).

2. Advantages and Disadvantages of Fixed Dose Combinations The conventional wisdom is that FDCs are desirable because they improve patient compliance and adherence, reduce costs, and slowe the advance of antimicrobial resistance (AMR).

2.1 Presumed Advantages  Simpler dosage schedule improves compliance and therefore improves treatment outcomes  Reduces inadvertent medication errors  Prevents and/or slows attainment of antimicrobial resistance by eliminating monotherapy (i.e, one drug is never by itself in circulation)  Allows for synergistic combinations (i.e., trimethoprim/sulfamethoxazole combination allows each drug to selectively interfere with successive steps in bacterial folate metabolisms  Reduces drug shortages by simplifying drug storage and handling, and thus lowers risk of being "out of stock"  Only 1 expiry date simplifies dosing (single products may have different expiry dates)  Procurement, management and handling of drugs is simplified  Lower production, packing and shipping costs  Side effects may be reduced by using one drug of the combination for this purpose  Potential for drug abuse can be minimized by using one drug of the combination for this purpose (i.e., excessive use of the antidiarrheal narcotic diphenoxylate is discouraged by side effects of atropine in the FDC atropine + diphenoxylate)

2.2 Presumed Disadvantages

 FDCs are sometimes more expensive than separate tablets, although not invariably so.  Potential quality problems when drugs are combined, especially with rifampicin in FDCs for TB. This requires bio-availability testing  If a patient is allergic or has a side-effect to 1 component, the FDC must be stopped and replaced by separate tablets, although this issue exists even with single dose formulations.  Dosing is inflexible and cannot easily be regulated to patient’s needs (each patient has unique characteristics such as weight, age, pharmacogenetics, co-morbidity, that may alter drug metabolism and effect). This criticism does not, however, apply to TB or HIV/AIDS where FDCs are made with weight-adjusted dosages .

 Incompatible pharmacokinetics is irrational because of different elimination ½ lives of individual components.  Drug interactions may lead to alteration of the therapeutic effect

2.3 A Look at Some Evidence with regard to Adherence and Antimicrobial Resistance

2.3.1 Does FDC use Improve Patient Adherence?ii

Fixed dose combination medications have the potential to address a main therapy-related factor affecting adherence to medication, the complexity of the dosing regimen. FDCs are being designed to reduce both the pill burden and the dosing frequency. In certain conditions, e.g. cardiovascular disease, synergistic effects of the medications combined in the FDC allows a reduced dose of individual components and this, in turn, is likely to reduce side effects. Development of FDC regimens that do not require timing of doses in relation to food is also likely to bring adherence benefits. Despite the importance of improving adherence, there are surprisingly few large, reliable trials of the effect of combining medications on adherence with treatment. The reliability of many of the trials is suspect because outcome measures were heterogeneous, almost all the studies were too small or had inadequate follow-up time, and were therefore likely to miss small to moderate-sized effects.

There is little reliable evidence about the effect of FDC medications or blister packaging on adherence and/or treatment outcomes in TB, malaria or HIV/AIDS, and even less originating from the poorly resourced environments of greatest need. Extrapolating from the weak evidence of benefit from all settings and disease conditions, it seems likely that simplifying treatment regimens and reducing pill numbers will improve adherence to medication. However, large simple randomized trials to compare FDC treatment with the same doses of separately dispensed medications are required to quantify the adherence and treatment benefits of FDCs for each disease.

2.3.2 Does FDC use Eliminate or Slow Development of AMR?iii

The idea that AMR can be delayed or even prevented by combining drugs with different targets as so-called “free” combinations or FDCs has been shown in animal models of malaria and circumstantially in field trials of tuberculosis drugs but is difficult to rigorously test in the field. The literature directed to determining if FDCs or free combinations are more effective in slowing or eliminating the development of AMR is weak. In this regard, we summarize our conclusions below: ii This section is largely adapted from the paper by J. Connor, “Review of the evidence on better compliance and treatment outcomes with Fixed-dose combinations when compared with separate dispensing and/or ‘co- blistering’" , available at http://www.who.int/medicines/organization/par/FDC/FDCmain.shtml, last accessed 14 July 2004. iii This section is largely adapted from the paper by W. Kaplan, “Review of the evidence on effect of fixed-dose combinations on the development of clinical resistance when compared with separate dispensing and/or ‘co- blistering’" , available at http://www.who.int/medicines/organization/par/FDC/FDCmain.shtml, last accessed 14 July 2004. 7.1-11 7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

 Most head to head comparisons/trials of monotherapy versus fixed combination versus free combinations are safety and efficacy studies;  Only relatively recently has individual resistance to anti-TB and anti-malarials been measured at the molecular level;  Responses of TB, malaria and HIV pathogens to combination drugs are very complex, particularly for malaria and HIV and the more and different combinations that will be used, the more complex will be the interactions;  Free combination drugs are generally more prone than FDCs to dispensing and patient error. No studies of which we are aware have systematically looked at the effect of blister packs compared to FDCs and/or free combinations with regard to development of resistant pathogens. In this regard there seem few studies on health outcomes generally;  Some studies suggest that decreasing overall antibiotic use may reverse bacterial resistance in human populations. One cannot assume from this that combination therapy will have the same effect. It is thus critical to know if using FDCs will prevent the appearance of drug resistance and/or reverse existing rates of drug resistance at both individual and population levels. The primary difficulty in assessing the evidence will be to actually measure developing/ongoing antimicrobial resistance in community-based populations in field situations.

3. Obstacles to Use of Fixed Dose Combinations Formidable obstacles still prevent the widespread introduction of FDCs, including problems with bioavailability of one or more components36 (See also Section 3.1), lack of regulatory quality control, and pressure from interest groups in some developing countries to maintain irrational combinations. 37 We briefly summarize some of the most important barriers.

3.1 Regulatory/pharmacological Obstacles

Uncertainties regarding the quality of FDC formulations and their registration, and barriers to effective implementation in national programs, have limited the widespread use of FDCs. 38 Bioavailability of individual components may change when put into combination with other components. For example, variable bioavailability of the TB drug rifampicin from solid oral dosage forms has been reported whereas bioavailability problems with the isoniazid, pyrazinamide and ethambutol components of FDCs have not been encountered, presumably because of the much greater water solubility and more rapid rates of absorption of these latter drugs.39 Hence, using FDC tablets with poor rifampicin bioavailability could lead directly to treatment failure and may encourage drug resistance. Other FDC components may have similar issues.

Packages of medicines with more than one active substance often lack an indication of strength. For instance in Norway, with many different brands of imported drugs for Parkinson’s disease, ingredients are often not classified as active or non-active on product labels and product names often do not indicate if the medicine is a combination product 7.1-12 7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

(FDC). 40 Indicating "strength" of an FDC as a single number is misleading and gives an impression of only one active ingredient. FDC formulations available on the market are characterized by a large variety of different dosage ratios of the drugs. This plethora of different formulations and different dosages has created considerable confusion impacting the application of standardized therapeutic regimens. Hence, there is a need for uniformity of dosage on the part of manufacturers to avoid confusing prescribers. If several different strengths of FDCs are available, and many do not confirm to recommended strengths, prescription of the correct treatment regimens may be difficult.40

Economic pressure exerted on the government by various stakeholders is important .This is illustrated by India’s attempts to ban certain FDCs. The individual state drug authorities in India have often indiscriminately granted manufacturing licenses and this is one reason why there are so many irrational drug combinations in India. 41 In response, the Drug Controller General of India has been withdrawing from the market potentially harmful combinations licensed by the states.41 The focus of India’s regulatory action is the vast range of irrational, but highly profitable drugs which may not even contribute to the AMR problem. In India, FDCs include multi-component “tonic” formulations which the government has decided are useless for overall well-being.41 Nonetheless, they are marketed and widely regarded as “health supplements” and their market has continued to grow.41 To eliminate such FDCs that are supporting the drug industry and the national economy may be difficult. In the context of AMR, the policy question is whether one bans certain anti-infective FDCs simply because their irrational use may lead to resistance. The answer to this lies not in removal from the market but in more stringent regulation of manufacture, prescription, and use. In India, as of 2002, there are no less than 22 different pediatric FDC formulations for TB. 42 No Indian manufacturer even came close to the WHO recommended pediatric dosages. In fact, many of the pediatric 4-dose FDCs in India exceeded the WHO- recommended adult dosages.42 (See Annex 7.1.1)

Concerns of manufacturers over the regulatory process arise from varying registration requirements across different countries. As we have seen in Section 1, even within the U.S. there has been a debate between manufacturers and regulatory authorities regarding the use of FDCs. Regulatory authorities have banned many of the FDCs from time to time (see e.g., reference 22 and also Section 1.2.1) and have yet to provide any clear-cut guidelines regarding the use and evaluation of these dosage forms. In this regard, the recent U.S. guidelines are welcome.

In order to improve implementation of FDCs in general, their use must be standardized and national and international responsibilities should be clearly defined.43 This is, unfortunately, an expensive and time-consuming undertaking since international organizations and institutions and principal manufacturers would have to change their production protocols regarding bioavailability and quality control.44

Various fundamental requirements for the registration of FDC products mentioned by regulatory authorities include the following 45 46 47 48 49 :

 Each component must make a contribution to the claimed effect;

 The dosage of each component must be such that the combination is safe and effective for use;  As a special application of the first requirement, a component may be added, either to enhance the safety or effectiveness of the principle active ingredient or to minimize the potential for abuse of this ingredient;  The duration of action of drugs should not differ significantly;  Drugs should not have narrow therapeutic index or critical dosage range.

High “new drug“ registration fees in some of countries are also a barrier to the entry of FDCs into the market.iv We note, however, that the registration fees for generic products are often much lower than those for branded products. Indeed, there is no fee in the U.S. FDA for generic registration.50 On the other hand, some countries have protectionist registration fees favoring locally produced medicines rather than imported ones50 and this may be a disincentive for large manufacturing facilities.

Therefore, time constraints, costs of clinical trials, chemical and pharmacologic compatibility of different components and regulatory problems are strong disincentives for manufacturers to produce FDC tablets.51 52

See Appendix 7.1

3.2 Legal/Intellectual Property

Patented medicines are priced far above marginal cost and patent holders are rewarded for research and development (R&D) with grants of exclusive commercial rights (primarily patents, copyrights and trademarks) so that intellectual property laws allow the “investor” to regain some of the benefits of their research and innovation. Fixed dose combination drugs have the potential to involve multiple patents held by different parties. The transaction costs associated with bargaining over property rights for components of the FDC can arguably lead to both blocking of commercial development and, if already manufactured, to lack of access “on the ground”.

The most difficult obstacle to availability of FDCs may well be in the area of managing conflicting IPRs of the individual FDC components. This is exemplified by the antiretroviral FDCs. Trizivir ®, approved by the FDA in November 2000 for the treatment of HIV in adults and adolescents, is a fixed-dose combination of Ziagen® (abacavir sulfate 300mg/ABC), Retrovir® (zidovudine 300mg/AZT), and Epivir® (lamivudine 150mg/3TC).53 All are nucleoside reverse transcriptase inhibitors (NRTIs) already approved by FDA. Abacir sulfate was discovered and developed by GlaxoSmithKline and all rights to technology, including intermediates, were licensed to Glaxo Wellcome by the University of Minnesota in 1992. Lamivudine was discovered by BioChem Pharma of Laval, Quebec, Canada and licensed to Glaxo Wellcome in 1990. Zidovudine was synthesized in 1964 but a ‘method of use’ patent was awarded to Burroughs Wellcome in 1988. Therefore, Glaxo has outright intellectual iv These fees are waived by the FDA pursuant to the May 16th guidelines for FDCs. 7.1-14 7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

property ownership or exclusive rights to all three components of Trizivir®. In contrast, CIPLA, Ltd, an Indian drug company, makes the FDC “Triomune” which contains nevirapine, stavudine (d4T) and lamivudine (3TC) in one pill. Each component is owned by a different party; Yale licensing to Bristol-Myers Squibb (stavudine), BioPharma/Glaxo (lamivudine) and Boehringer Ingelheim (nevirapine). India is able to manufacture these antiretrovirals domestically because its patent system only allows pharmaceutical method patents so India can “design around” these patents by using a different method than that claimed in the patent. 54

Significantly, the pharmaceutical industry is beginning to consolidate its potentially conflicting IPRs with regard to future FDCs. We noted in Section 1.2.3 the quick acknowledgement on 16 May 2004 that several manufacturers would be willing to cooperate to produce FDCs whose components are patented by different entities. There are various ways to overcome or ameliorate the effects of IPRs on access to FDCs. Some unilateral and bilateral mechanisms include:

 Put the ‘invention’ (e.g., fixed dosage combinations) into the public domain and avoid IP/patent rights entirely or try to “design around” existing IP for FDCs.  Make patents harder to get so that only real advances in medicines will be patented.  Create exceptions to patent infringement so that various entities are spared the transaction costs of licensing or, more particularly, patent litigation.  Use voluntary and, if needed, compulsory licensing between patent owners.

Other mechanisms include the creation of multilateral, collective business models for R&D and transacting IPRs. These might include the creation of voluntary or government- mandated patent pools. (See Section 4.2) Another possibility would be to develop various IP information and transactional “clearinghouses” specifically for IP related to fixed dose combination drugs. Such a clearinghouse should be able to identify all relevant IPRs over a given (i.e., FDC) technology and, indicate which are and which are not available to be negotiated, and if they are, how they can be accessed. It should create a pricing scheme and terms of contract and a royalty disbursement accounting system.

Multiple components of FDCs can lead to complex issues of IPR access and implicates other factors such as R&D funding mechanisms and global IP rules. Creative approaches to the problem are required. Those middle and lower income countries capable of producing FDCs (Brazil, India, Eastern Europe, probably Thailand, South Africa, Egypt, Jordan and a few others) are required by global IP rules to ensure full product patent protection by 2005. Thus, countries like India must provide patent protection for FDC components. Thus is likely to fundamentally change the nature of the pharmaceutical industries in those countries that have previously relied on weak domestic patent protection to make cheap copies of important drugs that are patented elsewhere. Now, these medicines will have to be patented in-country. There are, at least, three consequences of the post-2005 IP world for FDC manufacture, use and sale:

 Voluntary licensing and the threat of, if not actual use of, compulsory licensing will become more important;  Prices of patented FDCs in these “post-2005” countries are likely to remain high or increase, as pharmaceutical companies continue to try and recover their sunk costs of R&D;  Combinations of off-patent drugs or combinations containing at least one off-patent drug will become of interest;  More creative ways to incentivize development of new FDCs and provide R&D funding (open sourcing, R&D consortia and so on) without exacerbating IP and market failures will be needed.

4. Recommendations for the Future: a Research Agenda There exist several questions regarding the future of fixed dose combinations:

1. Although there is a clear public health need for FDCs what are the clinically desireable combinations? 2. What is the actual evidence to support the rationales for use of FDCs ? 3. Are the legal and IP bottlenecks to increased FDC access more apparent than real? 4. What are the “real world” formulation and quality assurance issues? 5. Can there be standardized regulatory requirements for “combination” products? Should synergy be required for combinations or is this too high a hurdle?

4.1 Provide Empirical Evidence of the Potential Advantages of FDCs

Decreasing overall antibiotic use may reverse bacterial resistance in human populations55 56 57, but one cannot assume that combination therapy will have the same effect. For instance, anti-malarial free combination therapy in parts of Thailand has slowed development of resistance in individuals but evidence at the population level that wider use of combination therapy (free and FDC) will slow resistance is not available.5 It is thus critical to know if using FDCs will prevent the appearance of drug resistance and/or reverse existing rates of drug resistance at both the individual and population levels.

The rationale for using FDCs to stem the tide of MDR-TB or MDR-malaria is intuitively appealing but there is little unequivocal evidence in this regard and the manner of formulating the evidence is often inappropriate. For instance, the United Kingdom has low rates of drug resistance to tuberculosis and about 75% of rifampicin is sold as FDCs.58 In the U.S., which has high rates of such drug resistance, only 15-18% of rifampicin is sold as FDCs. These facts have supported a claim that the low use of FDC in the U.S. is a reason for high rates of drug resistance.59 This kind of ‘ecological’ evidence is misleading since it cannot infer causality. It will likely be difficult, but not impossible, to actually measure changes in ongoing antimicrobial resistance in field situations, but well-thought out epidemiological

studies should nonetheless be undertaken to provide evidence as to whether FDCs really slow or eliminate AMR.

It is appealing to suggest that FDCs improve compliance because patient compliance is best with once-daily dosing. The WHO has acknowledged, however, that “ … little direct information exists to support the notion that use of FDC tablets in the treatment of TB enhances patient compliance with therapy.”3 Once-daily regimens, even of FDCs, may not prevent omission of doses and this will be continue to be an issue during self-medication phases of TB treatment in the absence of directly observed therapy. In a study of patterns of drug compliance using electronic monitoring, days without any dosing events were twice as often with the once a day regimen than the twice a day regimen.60 Episodes of 3 or more subsequent days without dosing events were also observed more often with the once a day than the twice daily regimen.60 Clearly more “direct”, evidence- based data is required in this area.

4.2 Integrate FDC issues into International/domestic IP laws

Efforts are underway to craft national intellectual property legislation so that it comports with public health concerns. 61 One way to have fuller use of the potential for FDCs are the compulsory licensing provisions of national and international IPRs in the world trading system (i.e., TRIPS) frameworks. They should be used to force availability of an FDC whose components are owned by different entities. Under compulsory licensing, a national authority gives a local producer the right to produce a patented product without explicit permission from the patent holder. Therefore, one solution to the multiple ownership problem exemplified by “Triomune” would be to force availability of FDCs when IPR issues become too complex.

Another way to manage multiple ownership issues of FDC and increase access for both research and clinical purposes would be to encourage patent pooling. 62 In one type of “patent pool”, one or more patent owners agree to license one or more of their patents to one or more third parties. Patent pools have played an important role in shaping the industry and the law in the U.S.62 Regional intellectual property organizations such as OAPI (Organization Africaine de la Propriete Intellectuelle) and ARIPO (African Regional Intellectual Property Organization) should take the lead in studying these arrangements to see if they can improve access to FDCs.

4.3 Provide Incentives to the Private Sector

The private sector should invest in research and development of FDCs for those pathogenic conditions where FDCs may prove useful, particularly in relationship to slowing down or eliminating AMR. Governments should fund research and development on FDC anti- infectives using tax breaks and other subsidies. In exchange for development of a new FDC, governments could extend the life of a selected non-antiinfective drug patent for a short time. Indeed, drug regulatory agencies should require that FDCs be created as a vehicle for certain anti-infective agents or to treat certain diseases. The FDC Augmentin® (amoxicillin/clavulonic acid) could have been just such an example. Since it is in the best 7.1-17 7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

long-term business interests of the private sector to extend their market share, this can be accomplished by combining a new drug with an off-patent generic into an FDC, as has been done with Malarone®.5 Mechanisms of price differentiation should be developed. 63 This will allow the private sector to extend market share and recoup R&D expenses (which are likely to be small for old drug combinations) in the developed countries, and the less developed nations will receive a low-cost FDC drug.

4.4 A Proposal for “Fixed Dose Combination Centers of Excellence”

Within the EU Framework program Centers of Excellence project are regularly supported. We propose that such an activity would create the means for comparing all aspects of FDCs, using internationally approved standards. This would extend from basic pharmaceutical formulation research to bioavailability standard setting and to proposing "ideal" FDC formulations. The entity would also do clinical evaluations of new FDCs and similar delivery technologies. Multidisciplinary research on all aspects of adherence as it relates to the use of FDCs would also be studied. To carry out this role, it would coordinate existing and planned multicountry clinical field studies of FDCs, with emphasis on gathering empirical evidence of the effect of FDCs on compliance and resistance.

This entity could also help in “capacity building” for developing countries by being a training center for their technical staff, with emphasis on FDC production, quality control and regulatory skills. At all points, it should coordinate its activities with European and international regulatory and clinical trials agencies. The organization would thus serve several purposes: 1. act as “clearinghouse” for information about fixed dose combination therapy; 2. coordinate field studies of FDCs, and 3. assemble and maintain the best evidence regarding FDC process development, regulatory and legal issues

5. Conclusions Use of fixed dose combinations is not a panacea that can eliminate AMR, strokes, heart attacks, or solve patient compliance issues. Nonetheless, regulatory authorities, drug manufacturers, professional societies and policy makers should at a minimum recognize that fixed dose combination therapy can be an innovative delivery system useful in many important public health issues. Fixed dose combinations should be a critical component of any effort to solve the AMR crisis. More experimental evidence, however, is required outside of the TB and malaria contexts, such as co-infections in HIV-immunocompromised patients. There are many opportunities for specifically designed clinical trials, epidemiological, social, and behavioral studies to carefully test the potential for fixed dose combinations to inhibit or even eliminate AMR, to secondarily prevent cardiovascular disease, and to improve patient compliance for a variety of chronically-taken medications.

A global perspective, comprehensive strategy and coordinated action are urgently needed.

References

7.1-19 1 Urquhart, J., Controlled drug delivery: therapeutic and pharmacological aspects, J. Internal Medicine, 248, 2000, 357-376. 2 Crommelin, D.J.A., Bissig, M., Gouveia, W. and Tredree, R., Storage and handling of biopharmaceuticals: problems and solutions - A workshop discussion. European Journal of Hospital Pharmacists, 8, 2003, 100-105. 3 World Health Organization, Fixed Dose Combination Tablets for the treatment of tuberculosis, 1999, WHO/CDS/CPC/TB/99.267. 4 The Economics of Tuberculosis Drug Development, 2001, The Global Alliance for Tuberculosis Drug Development, available at http://www.tballiance.org/pdf/rpt_per.PDF. Accessed, December 10, 2001. 5 Bloland, PB, Ettling, M, Meek, M. Combination therapy for malaria in Africa: hype or hope?. Bull. World Health Organization. 2000; 78; 1378-1 6 Bloland, PB. Drug Resistance in Malaria. World Health Organization, 2001, WHO/CDS/CSR/DRS/2001.4, available at http://www.who.int/emc- documents/antimicrobial_resistance/docs/malaria.pdf. Accessed Jan. 10, 2002. 7 Looasreesuwon, S., Chuylay, JD, Canfield, CH, Hutchinson, DB. Malarone® (atovaquone and proguanil (HCL): a review of its clinical development for treatment of malaria. Am. J. Trop. Med. Hyg. 1999;60: 533-541. 8 Cipla Launches 3-in-1 AIDS Pill, Clin. Infec. Diseases 2001; 33: ii (15 September 2001). See also CIPLA website at http://www.cipla.com/ourproducts/18/triomune.htm Accessed Dec. 13, 2001.

9 EUROASPIRE Study Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II surveys in nine countries. Lancet 2001; 357: 997-1003. 10 Oster JR, Epstein M. Fixed-dose combination medications for the treatment of hypertension: a critical review. J Clin Hypertens 1987;3:278-93. 11 Moser M. and Prisant LM, 1997. Low-Dose Combination Therapy in Hypertension, American family physician, 56:1-5 at http://www.aafp.org/afp/971001ap/edit_1.html. 12 Fenichel RR, Lipicky RJ. 1994. Combination products as first-time pharmacotherapy. Arch Intern Med. 154:1429-30 . 13 Frishman WH, Bryzinski BS, Coulson LR, DeQuattro VL, Vlachakis ND, Mroczek WJ, et al. 1994. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med 154:1461-8 [published erratum appears in Arch Intern Med 1995;155:709]. 14 Prisant LM, Weir MR, Papademetriou V, Weber MA, Adegbile IA, Alemayehu D, et al. Low-dose drug combination therapy: an alternative first-line approach to hypertension treatment. Am Heart J 1995;130:359-66 15 Frishman WH, Burris JF, Mroczek WJ, Weir MR, Alemayehu D, Simon JS, et al. First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension. J Clin Pharmacol 1995;35:182-8. 16 MacKay JH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med 1996;156:278-85. 17 Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. Arch Intern Med 1994; 154:737-43. 18 The joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. (JNC-V) Arch Intern Med 1993; 153:154–183. 19 Frishman WH. Current cardiovascular drugs, 2nd ed. Philadelphia: Current Medicine, 1995: 279– 280. 20 Wormser GP , Keusch GT. Trimethoprim-Sulfamethoxazole in the United States. Ann. Intern. Med., 1979; 91: 420-429. 21 Kefauver-Harris Amendments, Public Law 87-781, codified as amended Section 502(e) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 352(e). 22 Bazell RJ. Drug efficacy study: FDA yields on fixed combinations. Science 1971: 172: 1013-1015 23 Cohen, E, Goldschmid A, Garty M. Fixed-dose combination therapy in the United States, Britain, and Israel. Israeli Med. Assoc. Journal 2001 3: 572-574. 24 LTE List, at http://www.cms.hhs.gov/medicaid/drugs/desi.pdf, last accessed 11 July 2004. 25 Fixed Dose Combinations of Antimicrobiologic Agents. National Academy of Sciences – Drug Efficacy Study. New Eng. J. Med. 1969; 280: 1149-1154. 26 21 Code of Federal Regulations Section 300.50 (1998). 27 L. Goodman & A. Gilman, The Pharmacological Basis of Therapeutics, McGraw Hill. 28 Bass et al., Am J. Resp. Crit. Care Med. 1994; 149: 1359-1374. 29 The Selection of Essential Drugs. Report of the WHO Expert Committee. Geneva: World Health Organization, 1977, WHO Technical report series no. 615. 30 WHO Essential Medicines Library, at http://mednet3.who.int/eml/eml_intro.asp, last accessed 11 July 2004. 31 [http://www.fda.gov/oc/initiatives/hiv/hivguidance.htmlGuidance for Industry Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV DRAFT GUIDANCE http://www.dhhs.gov/news/press/2004pres/20040516a.html 32 Laurent C., Kouanfack C., Koulla-Shiro S., et al. for ANRS 1274 study group, 2004, Effectiveness and safety of ageneric fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1- infected adults in Cameroon : open-label multicentre trial, Lancet 364:29-34. 33 Pujari S, Patel A, Patel K, Dravid A, Patel J, Mane Aand Bhagat S. 2003. Fixed Dose Combinations for HIV/AIDS, Tuberculosis, and Malaria, Current status and future challenges from clinical, regulatory, intellectual property, and production perspectives (December 2003), SAFETY AND LONG-TERM EFFECTIVENESS OF GENERIC FIXED-DOSE FORMULATIONS OF NEVIRAPINE-BASED HAART AMONGST ANTIRETROVIRAL-NAÏVE HIV-INFECTED PATIENTS IN INDIA, at http://www.who.int/medicines/organization/par/FDC/Pujari.doc, last accessed 12 July 2004. 34 World Health Organization, Essential Medicines and Policy Department, Prequalification Project, at http://mednet3.who.int/prequal/, last accessed 11 July 2004. 35 Press release on internet.. http://www.aar.com.au/pubs/bt/25may04/bio08.htm, http://www.essentialdrugs.org/indiadrug/archive/200312/msg00006.php 36 Ellard GA, Fourie PB. Rifampicin bioavailability: a review of its pharmacology and the chemotherapeutic necessity for ensuring optimal absorption. Int. J. Tuberc. Lung Dis. 1999; 3: S301-S308. 37 Narendranath KG. Ban or curb on major fixed dose combinations imminent, many anti-epileptic and mucolytic –antibiotics preparations under critical review, October 23, 2000 , at http://www.pharmabiz.com/edit/edit.asp. Accessed December 15, 2001. 38 Blomberg B, Evans P, Phanouvong S, Nunn P. Informal consultation on 4-drug fixed dose combinations (4FDCs) compliant with the WHO model list of essential drugs. 15-17 August 2001. Geneva: World Health Organization; 2002. WHO/CDS/TB/2002.299. 39 Sweetman SC. Martindale: the complete drug reference. 33rd edition. London: Pharmaceutical Press; 2002: 205-206, 215-217, 240-241. 40 Lyftingsmo S. Why strength of a medicine is not the sum of its parts and needs regulation. The Pharmaceutical Journal 2001; 266: 851, reprinted at [email protected], 25 Jun 2001. 41 Francis, PA. Strengthening of Central Drug Administration, July 20, 2000, at http://www.pharmabiz.com/edit/edit.asp. Accessed December 15, 2001. 42 Ruchi R, Faridi MMA, Agarwal KN, Gupta P. Antitubercular Drug Formulations for Children. Indian J. Pediatrics 2001; 38: 400-406, available at http://www.indianpediatrics.net/april2001/april-400- 406.htm. Accessed January 3, 2002. 43 Chaulet P. Implementation of fixed-dose combinations in tuberculosis control: outline of responsibilities. Int. J. Tuberc Lung Dis. 1999; 3: S353-S357. 44 Blomberg B, Spinaci S, Fourie B Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull WHO 2001; 79(1):61-68. 45 The European Agency for the Evaluation of Medicinal Products, Human Medicines Evaluation Unit. Committee for Proprietary Medicinal Products (CPMP): Note for guidance on fixed combination medicinal products. 1996. CPMP/EWP/240/95. 46 USP 24/NF 19 (Supplement 2). Rockville, MD: United States Pharmacopoeial convention 2000: 2854- 2855. 47 USP 26/NF 21. Rockville, MD: United States Pharmacopoeial convention 2003a: 1640, 1643-1646. 48 WHO. The use of essential drugs: thirteenth report of the WHO Expert Committee (including the revised Model List of Essential Drugs). Geneva: World Health Organization; 2003. 49 WHO. Treatment of tuberculosis. Guidelines for national programmes. 3rd ed. Geneva: World Health Organization; 2003. WHO/CDS/TB/2003.313. WHO. Treatment of tuberculosis. Guidelines for national programmes. 3rd ed. Geneva: World Health Organization; 2003. WHO/CDS/TB/2003.313. 50 Kaplan, WA, Laing R. 2003. Paying for pharmaceutical registration in developing countries, Health Policy and Planning, 18: 237-248. 51 Blomberg B, Evans P, Phanouvong S, Nunn P. Informal consultation on 4-drug fixed dose combinations (4FDCs) compliant with the WHO model list of essential drugs. 15-17 August 2001. Geneva: World Health Organization; 2002. WHO/CDS/TB/2002.299.] 52 Norval P, Blomberg B, Kitler M, Dye C, Spinaci S. Estimate of the global market for rifampicin- containing fixed-dose combination tablets. Int J Tuberc Lung Dis, 1999;3:S292-S300. 53 GlaxoSmithKline, Trizivir® package insert, available at http://www.glaxowellcome.com/pi/trizivir.pdf. Accessed Dec. 3, 2001. 54 Koshy S. The Effect of TRIPs on Indian Patent Law. Boston Univ. J. Sci Tech. Law. 1995; 1: paragraphs 1-40, available at http://www.bu.edu/law/scitech/volume 1/KOSH4.PDF. Accessed October 15, 2001. See also Edwin Mansfield, Intellectual Property Protection, Foreign Direct Investment and Technology Transfer, International Finance Corporation Discussion Paper No. 19, The World Bank (l994), at http://www.worldbank.org/html/extpb/abshtml/12759.htm. Accessed June 2, 2001 55 Pena C, Pujol M, Ardanuy C, Ricart A, Pallares R, Liňares J et al. Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended spectrum beta lactamases, Antimicrob. Agents Chemother. 1998; 42: 53-58. 56 Rahal JJ, Urban C, Horn D, Freeman K, Segal-Maurer S, Maurer J. et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. J. Am. Med. Assoc. 1998; 280: 1233-1237. 57 Seppala H, Kaukka T, Vuopio-Varkila J, Helenius H, Lager K et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. New Engl. J. Med. 1997; 337: 441-446 58 Moulding T, Dutt AK, Reichman LB. Fixed dose combinations of antitiuberculosus medications to prevent drug resistance. Ann. Int. Med. 1995; 122: 951-954. 59 Davies PD. Tuberculosis in the United States. Letter, Am Rev. Respir. Dis. 1993; 147: 497 60 Kruse W, Rampmaier J, Ullrich G, Weber E. Patterns of drug compliance with medication to be taken once and twice daily assessed by continuous electronic monitoring in primary care. Int J Clin Pharmacol Ther. 1994; 32: 453-457. 61 Correa, C. Integrating Public Health Concerns into Patent Legislation in Developing Countries. South Centre, 2000. Geneva, Switzerland. 62 Clark J, Piccolo J, Stanton B, Tyson K. Patent Pools: A Solution to the Problem of access in Biotechnology Patents?, at http://www.uspto.gov/web/offices/pac/dapp/opla/patentpool.pdf. U.S. Patent and Trademark Office, Dec. 5, 2000. Accessed Jan. 10, 2002. 63 Report of the Workshop on Differential Pricing & Financing of Essential Drugs, April 2001, Hosbjor, Norway, WHO/WTO Secretariat Workshop, Høbsjør, Norway, available at http://www.who.int/medicines/docs/par/equitable_pricing.doc. Background papers to this conference are available at http://www.wto.org/english/tratop_e/trips_e/wto_background_e.doc. Accessed November 15, 2001