Review Article

Improving Access to High-Cost Cancer Drugs in

Latin America: Much to Be Done
Rossana Ruiz, MD1,2,3; Kathrin Strasser-Weippl, MD4; Diego Touya, MD5; Carmen Herrero Vincent, MD6;
Abraham Hernandez-Blanquisett, MD2,3; Jessica St. Louis2,3; Alexandra Bukowski2,3; and Paul E. Goss, MD, PhD2,3

Lack of access to high-cost medications is a complex issue at the intersection of economics, medicine, politics, and ethics, and it
poses a significant threat to global health care. The problem is even more significant in low- and middle-income countries, such as
those in Latin America, where governments and individuals struggle to pay for products that are priced at several times the level of
their per capita gross domestic product. In this review, we examine the determinants for increasing drug costs and how Latin Ameri-
can countries face this burgeoning crisis. We emphasize that a number of opportunities and strategies to reduce costs and improve
access exist and should be identified and implemented, ideally within a regional approach with multiple stakeholders involved and
based on systematic and transparent cost-effectiveness analyses. Cancer 2017;123:1313-23. VC 2017 American Cancer Society.

KEYWORDS: molecular targeted therapy, drug industry, pharmaceutical economics, health care costs, access to health care, cost/
benefit analysis.

THE RISING COST OF CANCER WORLDWIDE

The cost of cancer drugs, although not the highest individual cost overall in cancer control, has risen concomitantly with
the shift from the use of conventional cytotoxic chemotherapy to newer targeted agents. The median annual price of can-
cer drugs has increased from US $12,000 before 2000 to more than US $120,000 by 2015,1 which is several times the per
capita gross domestic product (GDP) of any country in the Latin American region.2 In 2014, targeted therapies accounted
for almost 50% of the US $100 billion spent on oncology drugs (including therapeutics and supportive medicines). In-
deed, the term “financial toxicity” has entered the oncologic vocabulary in an attempt to describe the economic distress
that goes hand-in-hand with most cancer treatments.3
The World Health Organization (WHO) defines essential medicines as those that “satisfy the priority health care
needs of a population and therefore should be available at all times in adequate amounts and in appropriate dosage forms,
at a price the community can afford.”4 Over the past year, 3 high-cost antineoplastic targeted therapies—imatinib, rituxi-
mab, and trastuzumab—have been added to the WHO’s Model List of Essential Medicines.5 Because of financial con-
straints, implementing this recommendation across all of Latin America is a major challenge for national governments.
Lack of access to high-cost medicines is a complex issue that involves not only economic, but also political and ethical
issues, and has become a global threat to the sustainability of health care systems. Herein, we provide an overview of the
problem of access to high-cost cancer drugs, specifically in Latin America. Our objective is to describe and discuss possible
solutions to this burgeoning crisis from a physician’s perspective.

REASONS FOR INCREASING DRUG COSTS

Drug development is a lengthy, complex, and expensive process. It includes preclinical testing, 3 phases of clinical trials,
and, if successful, the regulatory approval phase. Together, this process takes between 7 and 19 years to produce a market-
able drug.6 Because the clinical approval success rate ranges between 16% and 19% of candidate drugs,7,8 the price of an
approved drug reflects the costs of both successful and unsuccessful initiatives. A recent report published in 2014 by
the Tufts Center for the Study of Drug Development,9 a nonprofit academic research group partially funded by
pharmaceutical and biotechnology firms, estimated the cost of developing a drug that gains market approval at around

Correspondence to: Paul E. Goss, MD, PhD, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Lawrence House, LRH-302, Boston, MA 02114; Fax:
(617) 643-0589; pgoss@mgh.harvard.edu
1
Instituto Nacional de Enfermedades Neopl asicas, Lima, Peru; 2Global Cancer Institute, Boston, Massachusetts; 3Massachusetts General Hospital, Boston, Massachu-
setts; 4Wilhelminen Hospital, Vienna, Austria; 5“Dr. Manuel Quintela” Hospital Clinics, Montevideo, Uruguay; 6Valencian Institute of Oncology, Valencia, Spain.

See referenced editorial article on pages 1292-7, this issue.

DOI: 10.1002/cncr.30549, Received: August 12, 2016; Revised: September 15, 2016; Accepted: September 22, 2016, Published online February 9, 2017 in Wiley
Online Library (wileyonlinelibrary.com)

Cancer April 15, 2017 1313

Review Article
US $2.6 billion,10 which represents a 145% increase over
the estimate the center made in 2003.11 However, an inde-
pendent evaluation of research and development at that time
stated that a more realistic estimate would correspond to less
than 10% of what was claimed.12 For many drugs, the pre-
clinical phase of research is funded by academia, which is
mostly financed with taxpayers’ money.13,14 In the case of
anticancer drugs, 85% of basic research is supported this
way, whereas pharmaceutical companies spend only 1.3% of
their revenues on this initial phase of drug development.15
Approximately 5% to 13% of drug companies’ expenses oc-
cur at the clinical trial level, whereas 20% to 45% are allocat-
ed to advertisement, including marketing and
administration.16 In 2013, a group of 100 expert oncologists
concluded the following: “Of the many complex factors in-
volved, price often seems to follow a simple formula: start
with the price for the most recent similar drug on the market
and price a new drug within 10-20% of that price (usually
higher).”17 Surprisingly, various industry insiders have cor-
roborated this information.18 Ultimately, drug prices seem
to be set at whatever the market will bear.
In the market, cancer drugs behave differently from
medications for other chronic diseases. For example, due
to the life-threatening nature and complexity of cancer,
regardless of rising costs, there is a willingness among
patients and physicians to accept and pay high prices for
cancer drugs. In other words, the demand for cancer drugs
is largely inelastic, or insensitive to changes in price.19 Ad-
ditionally, high-cost cancer medications are protected by
patents, which make them expensive single-source mo-
nopoly products.19,20 Also, as the great majority of cancers
are incurable and the beneficial effect of most drugs is
short and finite, the approval of a new drug does not nec-
essarily mean that others available are no longer required.
In fact, each new approved agent is frequently used either
in combination, or sequentially, with existing drugs.21,22
Thus, despite the fact that various anticancer drugs may
be approved for similar cancer indications, pharmaceuti-
cal companies usually avoid price competition.16
Additionally troubling is the fact that many new
cancer medications can offer statistically significant gains,
which may not necessarily translate into clinically mean-
ingful benefits. With a sufficiently large clinical trial sam-
ple size, a small prolongation of survival of days or weeks
can achieve statistical significance.21
EVALUATING COST-EFFECTIVENESS AND
VALUE OF CANCER TREATMENT
Once a medication has shown efficacy in a clinical
trial, organizations such as the US Food and Drug
1314
Administration and the European Medicines Agency
(EMA) evaluate its benefits and risks independently of its
price to grant regulatory approval. Currently, the rising
cost of health technologies (including drugs, medical devi-
ces, vaccines, and procedures), paired with limited health
care budgets and competing societal priorities, is pushing
public and private institutions worldwide to seek mecha-
nisms that allow health systems to perform with greater ef-
ficiency and equity. Proof thereof is the fact that the
“value” of a cancer treatment (i.e., assessments of its cost,
efficacy, and safety)23 is increasingly being used when de-
ciding if a new technology should be incorporated into
the preventive, diagnostic, or therapeutic repertoire of a
health system. Both the American Society of Clinical On-
cology24 and the European Society for Medical Oncolo-
gy25 have recently launched frameworks to define the
value of cancer care in different clinical scenarios.
Various methodologies are employed by health
economists to perform cost-effectiveness analyses. Two
key metrics are quality-adjusted life-years (QALYs) and
incremental cost effectiveness ratio (ICER). QALYs refer
to the number of years of life that would be gained by an
intervention, adjusted for quality of life (QoL), whereby
QALY 5 life expectancy 3 QoL. QoL ranges from 0.0 to
1.0, exhibiting maximum value in perfect health. It is af-
fected by the efficacy and toxicity of the therapy and deter-
mined through standardized tools that assess vision,
hearing, mobility, cognition, speech, pain, dexterity, and
emotion. As a result, gaining 1 year of life with a QoL of
0.5 equates to a gain of half a year in perfect health (i.e.,
half a quality-adjusted life year: QALY 5 1 3 0.5 5 0.5
years).21,24,26 The ICER is defined as the ratio of addi-
tional cost to incremental benefit of an intervention and is
expressed as the cost per QALY. For example, suppose
that the standard treatment for a certain condition costs
$2000 and provides 0.5 QALYs, and a new treatment is
priced at $10,000 and provides 1.5 QALYs. To calculate
the ICER, the difference in costs between the 2 treatments
is divided by the difference in QALYs between the 2 treat-
ments: ICER 5 ($10,000 – $2000)/(1.5 – 0.5) 5 $8000
per QALY gained. The obtained ICER is then compared
against a threshold deemed acceptable by a designated en-
tity.21,24 For example, the WHO proposes using the
wealth of a country or per capita GDP when deciding on
the economic limits for funding an intervention. A drug
with an ICER that is lower or equal to the per capita GDP
would be regarded as very cost-effective, one with an
ICER 1 to 3 times GDP would be deemed cost-effective,
and one with an ICER more than 3 times the GDP would
be considered cost-ineffective.27
Cancer April 15, 2017

Frequently, these cost-effectiveness evaluations form
part of a process of health technology assessment (HTA),
which is defined as the “systematic evaluation of medical
technologies regarding their effectiveness, appropriate-
ness, and efficiency, as well as social and ethical aspects
and implications.”28 These evaluations aim to provide
structured, evidence-based input to policymaking on
health care priority setting, reimbursements, and coverage
decisions to achieve the best value in the allocation of pub-
lic resources.29 In light of these objectives, HTA has been
called “the bridge between evidence and policy-
making.”30 HTA is performed by public or private organ-
izations, through regulatory bodies and advisory commit-
tees. These entities are composed of a variety of
stakeholders including physicians, academics, pharma-
cists, health economists, insurance and industry represen-
tatives, and patients.31 HTA also importantly contributes
to the improvement of care through scientific knowledge,
particularly by supporting the development or updating
of clinical practice guidelines and standards of health ser-
vice provision.32,33
Probably the most well-known example of a regula-
tory body performing HTA is the National Institute for
Health and Care Excellence (NICE), which was set up by
the UK government in 1999 as a formal independent or-
ganization with the mission of integrating clinical and
economic analyses to determine whether it is worth
spending public money on a medicine to be accessible
through the National Health Service.24 This institution
uses an ICER cutoff of £20,000 to £30,000 per QALY (a
little less than US $50,000), above which it is unlikely it
will pay for a drug. Life-extending treatments (>3
months) for a small population of patients with short life
expectancy (<24 months) can exceed NICE’s cost-
effectiveness cutoff of £30,000.34 Because NICE presents
its documents for public scrutiny, it is considered one of
the most transparent and visible agencies worldwide.
NICE has 3 centers of excellence: HTA, Public Health,
and Clinical Practice Guidelines.35 This institution has
significantly contributed to the globalization of HTA. In
2008, NICE established an international division, which
helps foreign policy makers with tailoring guidelines to
their own settings, performing cost-effectiveness analyses,
training human resources and policy makers, and imple-
menting independent and transparent resource allocation
processes prepared to overcome lobbying and other drug
approval pressures.36
HTA agencies are not flawless, and if evaluations are
not performed diligently, there is the risk of harming
patients or the public. For example, decisions by NICE, as
Cancer April 15, 2017
High-Cost Cancer Drugs in Latin America/Ruiz et al
well as those of its international counterparts, have gener-
ated significant controversy around delayed approval for
useful drugs and the use of arbitrary economic thresh-
olds.37-40 However, as a commentary from the Mayo
Clinic stated: “imperfections in cost-effectiveness analyses
should not be an excuse for inaction.”21
SPECIFIC CHALLENGES TO LATIN
AMERICAN HEALTH CARE SYSTEMS
Despite a lower incidence of cancer compared with the
United States and Europe, cancer mortality rates in Latin
America are higher. The all-cancer mortality-to-incidence
ratio for Latin America is 0.59, compared with 0.35 in the
United States.41 This gap is driven largely by more ad-
vanced stage of disease at initial presentation, as well as
barriers to access to care. By 2030, the number of cancer
cases is estimated to increase by 35% in South America
and by 42% in Central America and Mexico, posing an
enormous challenge to Latin American health care sys-
tems, which are typically highly fragmented and
underfunded.41
Regardless of the fact that cancer in low- and
middle-income countries (LMICs) accounts for 77% of
the disability-adjusted life-years (DALYs) lost world-
wide,42 only 5% of global resources for cancer are con-
sumed in the developing world.43 Furthermore, only a
minor percentage of national GDPs in Latin America
(ranging from less than 5% in Venezuela and Peru to
more than 10% in Costa Rica and Cuba) is destined for
use in health care.44 On average, the percentage of Latin
American GDP devoted to health is 7.7%, compared with
18% in the United States. The overall mean expenditure
per new cancer patient in the region is US $7.92 com-
pared with US $183, US $244, and US $460 spent by the
United Kingdom, Japan, and the United States, respec-
tively. The overall cost of cancer care has been calculated
to represent 0.12% of gross national income per capita in
South America versus 0.51%, 0.6%, and 1.02% in the
United Kingdom, Japan, and the United States, respec-
tively.41 These statistics highlight the striking inequity
and shortage of resources for cancer care and control in
Latin America.
Among 37 new cancer drugs launched worldwide
between 2009 and 2013, only 17 are available in Mexico
and 10 in Brazil, the leading so-called “pharmerging”
countries in the region.45 However, even if more drugs do
become available, these are usually only accessible for a
privileged minority of the population enrolled in private
insurance programs. Frequently, public insurance in
many countries in the region exclude anticancer essential
1315
Review Article
drugs or restrict their use for some indications. For exam-
ple, in Brazil, Chile, and Peru, trastuzumab is not covered
by the public health systems for treatment of HER2-
positive breast cancer in the metastatic setting.46
Drug prices, especially from single sources, vary dra-
matically among nations,22,47,48 and Latin America is no
exception. For example, in 2012, the price of a year’s
worth of adjuvant trastuzumab for breast cancer in Latin
America ranged from US $25,636 in Uruguay to US
$61,302 in Brazil.49 In fact, several anticancer drugs are
more highly priced in many LMICs than in high-income
nations.50,51 Of importance, no relationship exists be-
tween pharmaceutical prices in LMICs and national
GDPs.51 In 2011, a study that compared prices of high-
cost drugs, including 8 cancer-targeted therapies, found
that the United Kingdom paid less for these drugs than
Argentina, Brazil, Paraguay, and Uruguay, in all cases.
Specifically, these drugs in the United Kingdom cost 29%
to 75% of what they cost in Argentina. The same study
concluded that, at that time, Argentina could have saved
64% of what was spent on high-cost medications if the
country had bought each drug from the country that was
purchasing them at the lowest price.50
A recent study explored the cost-effectiveness of 12
months of adjuvant trastuzumab for HER2-positive
breast cancer in 7 Latin American countries: Argentina,
Bolivia, Brazil, Colombia, Chile, Peru, and Uruguay.52
Following the recommendation of the WHO, 3 times the
GDP per capita was established as the threshold below
which an intervention could be considered cost-effective.
The investigators found that the ICER, expressed in terms
of times the GDP per capita per QALY gained, ranged be-
tween 3.6 in Uruguay to 35.5 in Bolivia. This calculation
means that although cost-effective in other settings, tras-
tuzumab, as currently priced, is not cost-effective in Latin
America using the WHO threshold. It was concluded that
the price of trastuzumab would need to drop between
69.6% and 94.9% to become cost-effective in these
countries.
Access to health is recognized as a constitutional
right in most Latin American countries.19,53,54 Based on
this legislated perspective, and encouraged by the media,
citizens unable to access therapies through regular chan-
nels of the health system increasingly resort to filing legal
suits against the government, citing their constitutional
right to health care.53 The judiciary frequently finds itself
ruling on financing a specific drug for a particular patient.
This trend toward judicialization of medicine has varying
grades and has an impact in most Latin American coun-
tries. For example, in 2009, the Colombian Ministry of
1316
Health estimated that the direct cost of litigation only in
the contributive insurance program (directed at those for-
mally employed) reached US $300 million. In Brazil,
240,000 legal patient claims were made in 2010, account-
ing for US $550 million. In the Brazilian state of S~ao
Paulo alone, US $380 million were paid on claims for
high-cost medications.55 In general, Latin American judi-
cial authorities tend to rule in favor of patients’ claims19: a
systematic review including 30 right-to-health litigation
studies found that plaintiffs were favored in the great ma-
jority of cases: in Colombia (75%-87%), Costa Rica
(89.7%), and Brazil (70%-100%).56 These litigations,
steadily overruling national funding policies, can under-
mine the sustainability of public health care systems by di-
verting resources away from rational use for the collective
benefit of the general public.53,57
POTENTIAL SOLUTIONS
In view of this background, we propose a set of potential
solutions to help control and reduce the high cost of can-
cer drugs in Latin America.
Increase and Redistribution of Budget for
Cancer Care
Cancer is a burgeoning health priority in Latin America,
and adequate public funding is needed. Having acknowl-
edged the existence of inequities, a rise in public spending
on cancer is desirable. However, even when increasing the
budget, its efficient distribution is necessary to make
funding available for expensive treatments when required.
Implementing preventive measures, health education pro-
grams, and early diagnosis strategies, as well as improving
care at the end of life (to avoid futile treatment) and re-
ducing medical imaging costs, are just some examples of
effective interventions to accomplish these objectives.20,58
Strengthening cost-effectiveness analyses and
health technology assessment
In the context of underfunded health care systems, it
becomes imperative in Latin America to allocate the limit-
ed budget available to technologies that provide the equi-
table and best value for patients without neglecting other
important interventions. Within the region, cost-
effectiveness evaluations and HTA are relatively new pro-
cesses, with different grades of implementation and devel-
opment among countries.23 Mapping HTA development
within a country is methodologically complex and implies
evaluations of both the degree of institutionalization and
of the HTA process itself (including identification, priori-
ty setting, assessment, appraisal, reporting, timely
Cancer April 15, 2017

dissemination, and implementation in policy and prac-
tice).59 In addition, when establishing these agencies in
Latin America, numerous barriers have to be overcome.
These include fragmentation of health care systems; short-
age of resources, most importantly human capital, knowl-
edge, and expertise; lack of local data from cancer
registries; and weak institutional structures susceptible to
pressure from suppliers, lobbyists, and other unwanted
influences.59-61
A systematic evaluation of the status of HTA in Lat-
in America is lacking. Nevertheless, significant progress
has been made recently.62 The endorsement of Resolution
CSP28.R9 at the 2012 Pan American Health Conference
by all Pan American Health Organization (PAHO) mem-
bers constitutes an unprecedented case of a region-wide
HTA initiative, widely accepted and promoted.63
At the national level, examples of HTA include the
Institute for Clinical Effectiveness and Health Policy
(IECS)64 and the Coordinator Unit for Evaluation and
Implementation of Health Technology (UCEETS) in Ar-
gentina65; the National Commission for the Incorpora-
tion of Technologies (CONITEC) in Brazil66; the
Institute of Technology Assessment in Health in Colom-
bia67; the National Centre for Health Technology Excel-
lence in Health (CENETEC) in Mexico68; and the
National Resources Fund (FNR) in Uruguay. At least Ar-
gentina, Brazil, and Mexico formally use systematic HTA
within their decision-making processes for drug approval
and funding.69-71
The Argentinean Ministry of Health authorities cre-
ated the UCEETS to ascertain the cost and impact of
health technologies. Its duties include the development of
an annual plan of inclusion and prioritization of new tech-
nologies; the evaluation of previously established technol-
ogies; and the generation of HTA products, particularly
clinical practice guidelines and technical reports. Another
institutional body dedicated to HTA in Argentina is the
IECS, which was designed as a “Collaborating Centre of
Health Technology Assessment” by PAHO/WHO in
2013 and acts as a guide to other countries in the region,
such as Bolivia, Panama, and Peru.72
In Brazil, the ultimate decision to fund new technol-
ogies in the public sector lies within the domain of the
Ministry of Health and is based, by law, on the recom-
mendations of CONITEC. This latter entity is also in
charge of keeping the list of essential drugs up to date.
The executive secretary of CONITEC, operated by the
Department of Management and Incorporation of Health
Technologies, coordinates CONITEC activities and is re-
sponsible for the emission of technical reports taking into
Cancer April 15, 2017
High-Cost Cancer Drugs in Latin America/Ruiz et al
consideration scientific evidence, economic evaluation,
and impact of each technology assessed.73 As a result of
their analysis, trastuzumab was incorporated into the
treatment of early-stage and locally advanced HER2-
positive breast cancer, but only after a price reduction of
44.8% had been negotiated and 2 new formulations (60
and 150 mg) had been provided.74
In Mexico, HTA has also been adopted as a national
strategy, which is required for the incorporation of new
technologies in the public and social security system.
CENETEC is the HTA agency of the Mexican Ministry
of Health.49
In the case of Uruguay, the National Therapeutic
Formulary (FTM) commission of the Ministry of Health
defines and reviews the list of essential medicines for every
health institution, private or public. Scientific evidence
and cost-effectiveness evaluations, as well as budget im-
pact analyses ensuring financial sustainability, are re-
quired to incorporate technologies by the FTM. The
FNR is a non-state public institution that finances the
FTM and aims to ensure equitable access to highly spe-
cialized medical procedures and expensive drugs.75 Im-
portantly, Uruguay has tracked the outcomes and impact
of various approved medications using real-world regis-
tries since 2010.76
Despite the progress achieved within the region, expe-
rience with HTA is still limited to few countries. When fac-
ing the challenge of formally developing a systematic and
transparent arms-length process for HTA in Latin Ameri-
can countries, many lessons can be learned from prior in-
ternational experiences, particularly from Latin America.77
In addition, to be able to adapt HTA reports from other
countries, national and regional capacities for conducting
economic impact studies are urgently needed.53,78
Collective Negotiation and Procurement
As discussed, the price of high-cost medications often
varies between and even within countries in Latin Ameri-
ca.19,50 This is partly due to the fragmentation of the de-
mand and the asymmetry of information among buyers.19
In this regard, joint purchasing as a region would offer in-
dividual countries the opportunity to participate in collec-
tive, multinational transactions that enhance their
negotiation power with drug companies while potentially
decreasing administrative costs.19,43 Single-buyer negotia-
tion therefore affords the chance of drugs becoming avail-
able at fixed lower prices. Ideally, these joint transactions
require that the participants have comparable policies and
decision-making frameworks that facilitate routine
collaboration.79
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In September 2015, countries from the intergovern-
mental regional organizations UNASUR and MERCO-
SUR (which together include the countries of Argentina,
Bolivia, Brazil, Colombia, Chile, Ecuador, Guyana,
Paraguay, Peru, Suriname, Uruguay, and Venezuela) en-
dorsed the creation of a committee for joint bargaining
and purchase of high-cost medications.80 During a suc-
cessful initial round of negotiations with a number of
pharmaceutical companies, the health ministers agreed to
purchase darunavir—an antiretroviral agent for the treat-
ment of human immunodeficiency virus (HIV) and
acquired immune deficiency syndrome (AIDS)—at a
price significantly less than the lowest price available pre-
viously in the region, resulting in collective cost savings of
around US $20 million for participating countries. The
plan is to purchase anticancer drugs through this joint bar-
gaining strategy.81
In addition, the WHO’s Model List of Essential
Medicines5 assists policymakers in reducing costs by help-
ing them in the challenging task of identifying those med-
icines that will have the greatest impact on public health
and therefore allocating limited resources effectively.
Inclusion of a drug on the WHO list represents a crucial
step for improving its affordability,82 because it serves as a
powerful tool to be used by the region for price negotia-
tion and procurement with pharmaceutical companies, as
well as by nongovernmental organizations, professional
associations, and patient organizations to pressure govern-
ments and payers.
Creation of Resource Funds
A strategy closely linked to joint bargaining and procure-
ment is the creation of international funds that facilitate
the acquisition of medicines at lower prices due to large-
volume purchases. This strategy is especially beneficial to
smaller, less developed countries that otherwise would
have to pay higher prices for small quantities. An interest-
ing example is the Revolving Fund of the PAHO. Mem-
ber states pool their national resources and PAHO acts as
a procurement agent, negotiating annual arrangements
with the suppliers on behalf of the Member States. As a re-
sult, high-quality vaccines have been procured at 4.25%
of their net cost.83 For example, in 2015 the bivalent
Human Papilloma Virus (HPV) vaccine price for LMICs
in Latin America was US $8.50 per dose84 compared with
a cost of US $107 per dose in the United States.85
Differential Pricing Policies
Differential or tiered pricing in health care consists of
stratifying a service or drug price in relation to average
1318
national income and willingness to pay. This means prod-
ucts will be more expensive in high-income countries and
more affordable in LMICs.37,86 This strategy allows coun-
tries to limit the cost of new treatments and has successful-
ly been applied to vaccines and HIV drugs. In the case of
innovative cancer drugs, as a general rule, the industry car-
ries on applying global pricing policies.51 However, lately
the threat of compulsory licensing has promoted the in-
troduction of tiered pricing for selected cancer products
from GlaxoSmithKline, Eli Lilly, Sanofi, and Roche.60
From the pharmaceutical industry’s perspective, the
major risk of differential pricing is parallel importing of
medications from poorer countries to wealthy ones, a situ-
ation which can be avoided by open discounts through
controlled access programs.60,87
All strategies that increase affordability lead to
higher levels of access and thus potentially create predict-
able markets with solid drug penetration that may
ultimately generate better returns for drug companies.16
Use of Generics and Biosimilars Through
Flexibility of Patent Laws
Whereas generics are both structural and therapeutic
equivalents of chemical low-molecular weight drugs, bio-
similars are therapeutically equivalent, but not identical,
reproductions of an original biotherapeutic agent. To be
approved, generic drugs must only demonstrate bioequiv-
alence or a bioavailability (rate and extent of absorption)
not significantly different from that of the reference drug.
On the other hand, biosimilars will be required to demon-
strate safety, purity, and potency for the intended use
within clinical studies.88 The use of generics and biosimi-
lars offers cost-saving alternatives with comparable effica-
cy and safety to innovative new products for many
indications in oncology, which is why their role in oncolo-
gy is expected to attain great importance in the coming
years. For example, it is estimated that the European
Union and the United States will achieve annual savings
of US $20.8 billion when patents of 3 antineoplastic
monoclonal antibodies—rituximab, trastuzumab, and
bevacizumab—expire in 2020.89 Nevertheless, producing
or buying generics and biosimilars is framed within strict
regulations.
In 1994, the World Trade Organization (WTO)
Trade-Related Aspects of Intellectual Property Rights
(TRIPS) agreement provided significant harmonization
on pharmaceutical copyrights across national laws. TRIPS
promotes innovation by compensating inventors of new
drugs with government-granted monopolies known as
patents, usually for 20 years.90 If, in the interest of public
Cancer April 15, 2017

health or national emergency, governments request a vol-
untary licensing on a patented medicine and this is de-
nied, TRIPS enables countries to issue “compulsory
licensing” for the manufacture of generic medications
while patent protection is still in effect.91 The Doha
Declaration of 2001 further allows countries lacking drug
production capacity to export medications produced un-
der compulsory licensing and explicitly adds that “each
Member [of the WTO] has the right to grant compulsory
licenses and the freedom to determine the grounds upon
which such licenses are granted.”92
In 2008, the Thai government issued compulsory
licenses for docetaxel, letrozole, and erlotinib. The impact
of this intervention was estimated to achieve savings of
more than US $140 million over 5 years.60,93 In the case
of imatinib, a compulsory license was about to be issued
too; however, the manufacturer made a last-minute offer
to the Thai government to deliver the medicine free to all
patients under universal coverage, provided no compulso-
ry license would be issued subsequently.94 Likewise, in
2012, the Indian government awarded a compulsory
license to manufacture a generic and cheaper alternative
to the drug sorafenib.21
In November 2014, a number of medical, academic,
and nonprofit Colombian organizations requested a dec-
laration of public interest to allow access to imatinib,95 an
unquestionably effective drug included in the WHO’s
Model List of Essential Medicines in 2015.5 Whereas the
Colombian gross national income per capita is US
$12,910,96 the median annual cost of Gleevec (Novartis
brand name of imatinib) per patient in Colombia is ap-
proximately US $20,000.97 The introduction of generic
imatinib could potentially reduce expenses by 68% to
77%.95 The Colombian government confronted open
pressure from the Swiss government to reject the request,
alleging flagrant disobedience of WTO TRIPS, being this
deeply condemned by a large group of international non-
governmental organizations.98 On June 17, 2016, after
months of unsuccessful negotiations with Novartis, the
Colombian Minister of Health finally issued Resolution
2475, declaring that it would be in the public interest for
the government of Colombia to control the price of imati-
nib by setting a price limit on the drug. This constitutes
the first step on the path toward compulsory licensing.99
The pharmaceutical industry claims, with little evi-
dence, that not supporting copyrights in LMICs could
have a negative impact on innovation because it may limit
economic incentives, and that high prices granted by pat-
ents are indispensable for recouping investment in re-
search and continuing investigation.60 However, this
Cancer April 15, 2017
High-Cost Cancer Drugs in Latin America/Ruiz et al
argument is rendered invalid when considering the fact
that around 80% of profit from cancer drugs comes from
high-income countries in which compulsory licensing is
rarely granted.60 Indeed, various observational studies
found that pharmaceutical companies whose products
underwent compulsory licensing did not experience a de-
cline in the rate of new drugs patented or in their innova-
tion activity.100,101 On the other hand, there have been
cases in which the use of compulsory licenses led to pres-
sure by the pharmaceutical industry, loss of investment,
and trade frictions with the countries producing patented
drugs.98,102 In addition, compulsory licenses may raise ef-
ficacy and safety concerns of generics and biosimilars.103
Among the new challenges posed by the current sci-
entific revolution is the restructuring of patent law to
achieve a new balance between public and private com-
mercial interests. At least, as PAHO has stated, Latin
American countries must ensure that the flexibilities of
the TRIPS agreement are incorporated into their legal
frameworks53 and, when resorting to these mechanisms, it
is preferable to do so within regional or subregional deci-
sions to better deal with external pressures and avoid com-
mercial sanctions.19
Evidence-Based Adaptation of Schemes of
Treatment
Under conditions of extreme lack of access in which ad-
herence to clinical guidelines applicable in high-income
settings may not be financially feasible—and only after
having exhausted other options—adapting treatment regi-
mens in terms of dosage, frequency, or duration may
be considered as an alternative strategy to improve
access.104,105
As an example, a 9-week study of trastuzumab given
concurrently with chemotherapy for breast cancer in the
adjuvant setting (FinHER) suggested a similar benefit
from much shorter administration of the monoclonal an-
tibody.106 A Cochrane meta-analysis reaffirmed this fact
and concluded that this regimen did not differ in efficacy
from studies of longer administrations of trastuzumab.107
In light of these results, the Pharmaceutical Management
Agency of New Zealand initially limited trastuzumab
funding to cover only a 9-week treatment course108 but
eventually extended the funding to cover a 12-month
treatment.109 Remarkably, a Belgian cost-effectiveness
analysis estimated that with this shorter scheme, it would
be possible to treat 20% more patients with approximately
one-fourth of the budget.110 A scientific evidence-based ap-
proach—alongside resource-sensitive guidelines—to find
1319
Review Article
less costly and therapeutically optimal alternatives is
desirable.
Participation in Clinical Research
Latin America is emerging as an attractive setting for the
conduct of clinical trials. The region has the regulatory
framework and clinical infrastructure, as well as the num-
ber of patients, required to support high-quality research.
Three Latin American countries—Brazil, Mexico, and
Argentina—have been continuously ranked in the top 25
countries with high participation in pharmaceutical phase
2/3 clinical trials since 2007.111 In 2012, 4.6% of world-
wide cancer clinical trials were registered in Latin Ameri-
ca, and 66% of them were sponsored by industry.41 To
some extent, participation in clinical trials allows access to
both standard and investigational drugs that are otherwise
not available in Latin America. However, this practice
raises ethical issues related to economic conflicts of inter-
est, the adequacy of informed consent, and the subsequent
availability and affordability of approved therapies.87 In
fact, some argue that clinical trials conducted in Latin
America rarely respond to the true public health priorities
of the region and therefore may be distracting scientific
resources from addressing cancer control issues of greater
importance.112
WHAT CAN ONCOLOGISTS DO?
In 2012, 3 important physicians at the Memorial Sloan
Kettering Cancer Center gained public attention when
they declared in The New York Times that their center
would abstain from including ziv-aflibercept, a new colon
cancer drug, in the hospital formulary because of its unfa-
vorable cost/benefit ratio.113 A month later, the manufac-
turer, Sanofi, announced that it would offer a discount of
50% off the list price for this drug.18,114
This example shows that physicians advocating for
underserved populations can do more than just act as
spectators in this crisis. Instead of passively accepting
what the industry provides, evidence should be analyzed
critically in terms of real clinical benefit of novel agents to
patients to safeguard rational medicine use. In this regard,
physicians are responsible for developing national guide-
lines for cancer treatment and ensuring that cancer drugs
with favorable cost/benefit ratios are included in national
formularies.115
A great proportion of oncologists are unfamiliar
with the costs of treatment, and many feel inadequately
trained to have cost discussions with patients.58,116 Partic-
ularly in LMICs, medical education—both primary and
continuing—should be expanded to include critical
1320
review of evidence for interventions and to incorporate
knowledge of costs and understanding of cost-
effectiveness analyses.37 With the correct tools, doctors
are in a strategic position to participate in discussions of
economic priorities in health care and to influence all
stakeholders.16,53,117
CONCLUSION
Innovative drugs have improved cancer outcomes signifi-
cantly. Unfortunately, their skyrocketing prices have
made them prohibitively expensive for most Latin Ameri-
can health care systems, as well as for other LMICs and
even wealthier nations. The current oncology pricing
structure is no longer sustainable and is threatening the
economy of health systems. Even more alarming is the
fact that many of the most expensive medicines do not
yield meaningful clinical benefits to patients.
Much needs to be done to address this burgeoning
crisis. Among the initial steps needed to rationally allocate
limited resources is the incorporation of systematic and
transparent cost-effectiveness analyses performed through
independent, multidisciplinary committees or health
technology agencies. On the basis of these evaluations, a
number of complementary strategies can be devised, in-
cluding, but not limited to, negotiation, collective bar-
gaining, financing and procurement, differential pricing,
increased use of evidence-based adapted treatment
schemes and of quality generics and biosimilars through
TRIPS flexibilities, and involvement in clinical trials.
We believe that the recommendations presented
throughout this review are likely to be more effective with-
in a synergistic regional approach. The problems and chal-
lenges of Latin American health care systems transcend
national jurisdictional boundaries and should be faced
collectively to optimize national capacities, share and
compare best practices, and transfer scientific and techni-
cal capabilities.
Finally, all stakeholders, including the general pub-
lic, must be aware that ensuring access to high-cost drugs,
by itself, is unlikely to improve cancer mortality rates
substantially in the region. Cancer care is a long continu-
um with multiple sites for intervention, ranging from
access to care and prevention to primary treatment
and supportive care. Access to high-cost cancer drugs
represents only a small aspect of this challenge.
FUNDING SUPPORT
R.R., J.S., A.B, and P.E.G. have received funding from the Avon
Breast Cancer Crusade, which had no role in the planning or writ-
ing of the manuscript.
Cancer April 15, 2017

CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
AUTHOR CONTRIBUTIONS
Rossana Ruiz: Wrote the first draft of the manuscript. RR, KSW,
DT, CHV, AH-B, JS, AB, and PEG participated in the literature
search, and were involved in manuscript planning and writing. All
authors: Read and approved the final manuscript.
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