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
1.2
2.
Advantages and Disadvantages of Fixed Dose Combinations ........................................ 10
2.1
2.2
2.3
3.
Presumed Advantages.............................................................................................................. 10
Presumed Disadvantages ......................................................................................................... 10
A Look at Some Evidence with regard to Adherence and Antimicrobial Resistance...... 11
Obstacles to Use of Fixed Dose Combinations ................................................................... 12
3.1
3.2
4.
FDCs as Anti-hyptertensive and Anti-cholesterol Agents .................................................... 5
FDCs as Antimicrobials .............................................................................................................. 6
Regulatory/pharmacological Obstacles.................................................................................. 12
Legal/Intellectual Property ...................................................................................................... 14
Recommendations for the Future: A Research Agenda ..................................................... 16
4.1
4.2
4.3
4.4
Provide Empirical Evidence of the Potential Advantages of FDCs ................................... 16
Integrate FDC issues into International/domestic IP laws .................................................. 17
Provide Incentives to the Private Sector ................................................................................ 17
A Proposal for “Fixed Dose Combination Centers of Excellence” .................................... 18
5. Conclusions................................................................................................................................ 18
References ........................................................................................................................................... 19
Annex
Appendix
7.1-2
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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
7.1-3
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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 nondiffusion (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]);
7.1-5
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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 [CoDiovan®].
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 grampositive 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.
7.1-6
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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 :
7.1-7
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
“ 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 (cosponsored 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).”
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.
i
7.1-8
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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).
7.1-9
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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.
7.1-10
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

2.3
2.3.1
Drug interactions may lead to alteration of the therapeutic effect
A Look at Some Evidence with regard to Adherence and Antimicrobial
Resistance
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:
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 ‘coblistering’" , 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 ‘coblistering’" , available at http://www.who.int/medicines/organization/par/FDC/FDCmain.shtml, last accessed 14
July 2004.
ii
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;
7.1-13
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

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 16 th 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 governmentmandated 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:
7.1-15
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism

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
7.1-16
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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 antiinfectives 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.
7.1-18
7.1 Fixed Dose Combinations as an Innovative Delivery Mechanism
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