Nordea Asset Management Clinical trials outside Europe
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Nordea Asset Management
Clinical trials outside Europe
Photo: iStockphoto
Graphic design: Lina Johansson . Sense Design
September 2013
Clinical trials outside Europe
Research Paper . Nordea Asset Management 2013
SUMMARY & KEY FINDINGS
SUMMARY All companies shall conduct clinical trials in
Clinical trials that test medicines for use in the compliance with this guideline. Patient safety and
European Union (EU) increasingly take place in ethical conduct are at core.
low and middle income countries (new markets),
for example Argentina, Brazil, China, India, Peru • Principle 2.3 in the ICH GCP2 states that “the
and South Africa. The relocation takes place by rights, safety, and well-being of the trial subjects
offshoring and/or outsourcing. are the most important considerations and should
prevail over interests of science and society”.
Speed, cost cutting, access to vast genetic popula-
tions and prospective markets are among the The pharmaceutical company holds the legal
drivers of relocation. responsibility of a clinical trial, regardless of
location and if it is an in-house or outsourced
All these markets have a common denominator; clinical trial. That is quite unique. Over the years it
vulnerable trial participants. All patients partici- has become increasingly common that companies
pating in clinical trials, regardless of location are outsource the clinical trial to contract research
vulnerable as they are ill and in need of medical organisations (CROs). However, the respon-
treatment. What makes the trial participants on sibility and accountability of the pharmaceutical
these markets particularly vulnerable is a combi- company remain and regulation has tightened
nation of poverty, illiteracy and inefficient which makes supply chain management essential
monitoring of designated bodies. These circum- to pharmaceuticals in the development of new
stances do not automatically make it unsuitable to products.
conduct clinical trials on these markets. However,
it makes it absolutely crucial to comply with If a product is to be registered in Europe, the
regulations and enforce ethical guidelines. clinical trials that have proceeded to the applica-
tion must comply with the Declaration of Helsinki3
There is one guideline that prevails and that is (the global ethical standard that forms the core of
referred to in national legislation in several ICH GCP) and be in harmony with European
countries – the ICH GCP1 Guideline. standards.
1 CLINICAL TRIALS OUTSIDE EUROPE
Whether the management systems that are in place All in all, the combination of smart system design,
today are adequate in protecting trial participants evaluation of applications and inspections
is hard to verify independently because of a lack of contribute to a proper behaviour by companies.
transparency of the audit results, in combination There is no business case to perform clinical trials
with instances of insufficient monitoring by in an unethical or dubious manner.
authorities.
• Watchdogs claim that transparency is weak and
The view raised by watchdogs on clinical trials on hinder interested bodies to monitor company
new markets differs significantly from the views behaviour. The further claim that accountability is
presented by the industry and national authorities. very rare and that monitoring by designated
The biased views make it more difficult to under- authorities is inefficient in too many cases. They
stand the actual state. claim that the risk for a pharmaceutical company
to be “caught” and held accountable of ethical
• The industry presents policies and guidelines, misconduct may exist in theory, not so much in
description of due diligence and audit processes reality. The inefficiency in monitoring and the lack
and claim that all clinical trials are conducted with of accountability is considered to put trial partici-
the principle that they must pass a third party pants at risk. They present cases of violation of
inspection and regulatory supervision. They also ethical guidelines where patient safety has failed.
present the case of access to medicine as an
important positive outcome of relocating clinical
trials to new markets.4 1. The International Conference on Harmonisation (ICH), Good
Clinical Practice (GCP)
2. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Prod-
• Representative from the national medical
ucts/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guide-
product agency claims that scrutiny is possible and line.pdf
effective despite offshoring and outsourcing, and 3. Ethics for Drug Testing in Low and Middle Income Countries:
that international mandatory registrations system SOMO, 2008
are designed to protect patient safety and that 4. Interview with Bengt Matsson, 2013
these systems are hard to cheat.
KEY FINDINGS
Clinical trials on new markets have the oppor- Trial participants are particularly vulnerable and
tunity to bring access to medicine and know their rights are not always safeguarded,
how, if conducted properly resulting in violation of their rights and harming
their health
Transparency can improve, enabling interested
parties to monitor companies’ behaviour Several companies seem to have elaborate
systems to manage their supply chain with
Accountability for ethical misconduct is rare regard to applicable guidelines and ethical
standards, but disclosure must improve to
Proof of enforcement of principal ethical enable evaluation of efficiency
standards and guidelines is seldom public
Monitoring by authorities and other national/
regional bodies lack resources and is
sometimes insufficient
CLINICAL TRIALS OUTSIDE EUROPE 2
Table of Contents Summary & Key findings 1 Basic information on clinical trials 4 Introduction to the issue 5 Regulation and monitoring bodies 7 Supply chain management 9 Outsourcing to contract research organisations 11 Transparency and Accountability 12 What to look for in dialogue on clinical trial conduct 13 Appendix 1: Sources Appendix 2: Principles in the ICH Good Clinical Practice Guideline Appendix 3: Leaders in disclosure on R&D Appendix 4: Access to Medicine Index 2012 – Overall ranking and R&D ranking
BASICS
BASIC INFORMATION ON CLINICAL TRIALS (100-300 patients) to see if it is effective
Any investigation involving human subjects that is and to further evaluate its safety
intended to discover or verify the clinical, • In Phase III trials; the experimental study
pharmacological and/or other pharmacodynamics drug or treatment is given to large groups of
effects of an investigational product, and/or to people
identify any adverse reactions to an investigational • Phase IV; takes place after a product has
product, and/or to study absorption, distribution, been registered and launch on market
metabolism, and excretion of an investigational
product with the object of determining its safety A clinical trial can be global, regional or national.
and/or efficacy. The genetic population that has participated in the
study must be relevant to the population that is
Clinical trials are the most crucial and expensive aimed to use the new product. If the trial popula-
part of developing a new product. Clinical trials are tion is different from the intended user popula-
conducted in phases. tion, the applying company must proof that the
product will behave in the same way on the inten-
• In Phase I; researchers test an experimental ded user population. This is done via an additional
drug or treatment in a small group of people clinical trial.
(20-80 healthy participants and/ or
patients) for the first time to evaluate its Clinical trials are strictly regulated and should be
safety, determine a safe dosage range, and carried out with the principle that they must pass
identify side effects through scrutiny.
• In Phase II; the experimental study drug or
treatment is given to a larger group of people
CLINICAL TRIALS OUTSIDE EUROPE 4INTRODUCTION
INTRODUCTION TO THE ISSUE • Economic growth in these regions often
Clinical trials that test medicines for use in the coincide with admission of new products
European Union (EU) increasingly take place in • The prospective market
low and middle income countries (new markets), • A more industry friendly enforcement of
for example Argentina, Brazil, China, Peru and regulation5
South Africa. The relocation takes place by
offshoring and/or outsourcing. CONCERNS IN THIS CONTEXT
There is a global ethical standard, e.g. the
Some of the major drivers for relocation are; Declaration of Helsinki and a set of guidelines that
• Cost reduction each clinical trial shall comply with, regardless
• Speed in the approval and recruitment location.
process
• Patient infrastructure is good (vast genetic Many trial participants in the new markets are
population, access to registered patients) poor and have limited access to health care, in
• Access to a vast population with diverse need many cases due to inequalities within the health
for treatment (diverse illness) care system. The inequalities are sometimes
• It is easy to recruit trial participants further complicated by widespread corruption.
5 CLINICAL TRIALS OUTSIDE EUROPEThese are circumstances that make the opportu- performing the trial so that all proper measures
nity to participate in a clinical trial and receive are taken to ensure that the patient is informed,
treatment for free a very tempting position for do understand and take part by its own free will.
many. For many patients it can be the only chance
to receive treatment at all. Recruitment of patients In some of the new markets, informed consent has
therefore becomes quite easy. limited value as the patients are in such a vulner-
able situation due to need of medical treatment,
Informed consent6 illiteracy and an inability to actually evaluate the
Informed consent is one of the most essential circumstances.7
aspects of patient safety and is at the core of
applicable regulation and guidelines.
Informed consent is a process by which the patient 5. Putting Contract Research Organisations on the Radar :
voluntarily confirms its willingness to participate SOMO, CSER and Salud y Fármacos, 2011
in a particular trial, after having been informed of 6. Principle 4.8 in the Good Clinical Practice Guideline http://
all aspects of the trial that are relevant to its own www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
decision to participate. Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf
7. Putting Contract Research Organisations on the Radar:
Informed consent is documented by means of a SOMO, CSER and Salud y Fármacos, 2011
written, signed and dated informed consent form.
The patient’s ability to make an informed decision
must always be taken into account by the company
CLINICAL TRIALS OUTSIDE EUROPE 6REGULATION AND MONITORING BODIES The EMA consists of 30 national regulatory
The European Medicines Agency (EMA) is agencies. These respective national agencies also
together with the US Food and Drug Administra- have the responsibility to perform the GCP
tion (FDA) the most important drug trial regulator inspections, when required.
in the world.
STANDARDS AND GUIDELINES ICH GCP is the overarching guideline for
There are international guidelines and practices European, American and Japanese companies.
regarding ethical conduct and protection of Good Clinical Practice (GCP) is an international
human participants that all companies should ethical and scientific quality standard for design-
comply with. ing, conducting, recording and reporting trials
that involve the participation of human subjects.
The Declaration of Helsinki is the
predominant standard. It is referred to in inter- • The ICH GCP principles enforces the
national guidelines and national legislation. spirit of the of the Deceleration of
It embraces the most comprehensive ethical Helsinki
standard for medical research involving human • The ICH GCP applies in Europe, North
subjects. America and Japan
• The World Health Organization (WHO)
• The Declaration of Helsinki is applicable has created corresponding guidelines that
to both the company and any contract applies to other regions in the world.
research organisation (CRO)
• The EMA is to inspect that the Declaration
of Helsinki has been complied with
7 CLINICAL TRIALS OUTSIDE EUROPEREGULATION AND STANDARDS
A Good Clinical Practice (GCP) inspection It is estimated that about two per cent of the
A GCP inspection aims at ensuring that the trial world’s annual clinical trials are inspected by
has been conducted in accordance with the ICH regional bodies (EMA, FDA, WHO) or local
GCP Guideline. national agencies. Scarce resources at these
agencies in relation to the number of trials that
The priorities in the inspection are; takes place make it necessary to prioritize among
Patient safety and ethical conduct the applications.
• Proof of informed consent
• Compensation i.e. insurance About 70-80 inspections are conducted by EMA
• If the trial concerns a chronic disease, annually; 1/3 in Europe and 2/3 outside Europe
the inspection also includes access to post (e.g. North America, Eastern Europe and/or new
trial treatment markets).
Data quality
Compliance with other laws and regulation
(e.g. documents that enable a reconstruction of
the trial)
CLINICAL TRIALS OUTSIDE EUROPE 8SUPPLY CHAIN MANAGEMENT
SUPPLY CHAIN MANAGEMENT Funded by the Bill & Melinda Gates Foundation
As pointed out previously, the pharmaceutical and the UK and Dutch governments, the Index has
company has the official responsibility and is been published every two years since 2008).
accountable for all research conducted within or
on behalf of the company. That means that the Another study shows that several of the pharma-
company bears the legal responsibility for any ceuticals have elaborate systems in place through
harm that might happen to patients that partici- which they manage their supply chain respon-
pate in a clinical trial on the company’s behalf. sibility, including;
The responsibility remains although the clinical • Due diligence in CRO selection
trial has been conducted by a third party • Contracts
(e.g. CRO). • Auditing and training of CROs
• Clinical investigators and trial sites
According to Access to Medicine Index 2012
“few companies have robust measures to ensure Whether these systems are adequate in protecting
clinical trials conducted by contractors are safe trial participants is hard to verify independently,
and ethical with the majority providing no because of a lack of transparency of the audit
evidence of exerting real influence over the way results, in combination with instances of
their contractors conduct trials or adequate insufficient monitoring by authorities.9
assurance of benefits returned to host communi-
ties”8 . (The Access to Medicine Index indepen-
dently ranks pharmaceutical companies’ efforts to
improve access to medicine in developing
countries.
9 CLINICAL TRIALS OUTSIDE EUROPEDanielsson10 who is a GCP inspector has access to Certain control mechanisms are mandatory and
information that is not necessarily disclosed to the any malfunction or lack of control that risk the
public and in his experience, most big companies patient’s safety or non-compliance with ethical
have proper management systems that are requirements will be identified in a GCP
effective. inspection.
In order for companies to fulfil the Declaration of
Helsinki it is suggested that;11
• Companies should have codes of conduct to • Companies should perform due diligence
ensure safe and ethical delivery of clinical activities when selecting of the CROs that will
trials, that governs own employees and any work on their behalf
CROs working on their behalf
• Companies should ensure post-trial access to
• Companies should perform systematic medicine in all cases where there is a need
monitoring of own operations and CRO
performance
8. Access to Medicine Index 2012
9. Putting Contract Research Organisations on the Radar:
SOMO, CSER and Salud y Fármacos, 2011
10. Interview with Gunnar Danielsson, 2013
11. Access to Medicine Index 2012
CLINICAL TRIALS OUTSIDE EUROPE 10OUTSORCING
OUTSORCING TO CONTRACT RESEARCH Danielsson claims that the use of a CRO does not
ORGANISATIONS reduce the level of insight or scrutiny throughout
A contract research organisation (CRO) is an the clinical trial process but it does include a
organisation or a person that is contracted to greater number of parties to include in the inspec-
manage various steps in the product development tion. The GCP inspection evaluates exactly the
process. same documentation, protocols and procedures
regardless if the trial has been carried out
It is currently estimated that around half of the in-house or by a CRO.
world’s clinical trials are outsourced to CROs.
A significant growth of CROs has taken place in It may be regarded as a problem that interested
China and India.12 parties such as NGOs cannot access information
on how pharmaceuticals safeguard the clinical
Patient recruitment is an important aspect of CRO trials participants and that such information is not
work, the ability to recruit and retain enough public and can only be accessed by national
patients is essential to its success. agencies and inspections.
DO CRO’S OBSCURE SCRUTINY? The trend of outsourcing to CROs does not seem
The watchdogs fear that the vast outsourcing to to increase the risk of violations. The distribution
CROs reduces transparency, complicates the of document violations is quite even among
clinical trial inspections and hinder accountability. in-house and outsourced clinical trials.13
Danielsson (GCP inspector) don not share that
concern. The CRO is considered to be part of the 12. The clinical trials industry in South Africa: Ethics, Rules and
applying company. Realities: Wemos, 2013
13. Interview with Annelies den Boer, 2013
11 CLINICAL TRIALS OUTSIDE EUROPETRANSPARENCY AND ACCOUNTABILITY EU is currently debating a new legislation, which if
Transparency - or lack of it it’s passed - with certain amendments, will
Few, if any companies disclose information on how demand companies to become more transparent
they actually fulfil the Declaration of Helsinki and by making more information available. That would
enforce the ICH GCP Guidelines throughout its be an important step forward.
value chain. In general, companies do not provide
information about the CROs they hire, making it Accountability - or lack of it
impossible for interested parties to monitor their Watchdogs say that (lack of) accountability for
behaviour.14 CRO behaviour is where one of the widest gaps
exists between current industry performance and
A review performed by Access to Medicine Index expectations for clinical trial participant wellbeing
in 2012 shows that only 25% of the reviewed in developing countries.16
companies provides information on how they
enforce standards of ethical conduct on their It seems that the “risk of scrutiny and account-
clinical trial contractors in line with the ability” primarily exist in theory.
Declaration of Helsinki.15
Companies can improve transparency and 14. http://www.accesstomedicineindex.org/sites/www.
accountability through; accesstomedicineindex.org/files/key-findings-2012-
access-to-medicine_index.pdf
• Timely disclosure of clinical trial results 15. Appendix 4: Access to Medicine Index 2012 - list of
• Controversies related to clinical trials companies included
• Details of any CROs used and details of 16. Access to Medicine Index 2012
codes of conduct and supporting monitoring
and enforcement
Not even the European Medicines Agency (EMA),
the superior drug trial regulator in the Europe, has
access to individual company’s CRO audit reports
per default. Those reports may only be accessed if
the regular evaluation of an application raises
concerns.
CLINICAL TRIALS OUTSIDE EUROPE 12WHAT TO LOOK FOR
WHAT TO LOOK FOR IN CLINICAL
TRIAL CONDUCT
A clinical trial inherent several ethical risks and dependent on that trial personnel is treating her
the patient is vulnerable due to obvious fact that or him in the proper way.
it is ill, lack medical expertise and is completely
When we approach a pharmaceutical company on Information on contracts and controls (audit
the subject of clinical trials outside Europe we look reports) in relation to service providers, especially
and ask for; contract research organisations (CROs).
A detailed description of how the company Information on how the company ensures that
work in order to comply with the Declaration patient treatment and approach is in harmony with
of Helsinki and the ICH GCP Guideline, e.g.: what is accepted in Europe (not only the legislative
enforcement) when working with contractors.
• Did the company provide post-trial
treatment access or benefits to Information on how and in what way that a
participants? human rights perspective encompasses the trial
• Did the company provide compensation? process.
• How does the company justify the use of
placebo?
• How does the research benefit the
population where the trial took place?
13 CLINICAL TRIALS OUTSIDE EUROPEAPPENDIX 1: SOURCES
Policy and guidelines The Globalization of Clinical Trials: Testimonies from
The Declaration of Helsinki human subjects; Wemos, 2010
http://www.fda.gov/ohrms/dockets/ http://www.wemos.nl/files/Documenten%20
dockets/06d0331/06D-0331-EC20-Attach-1. Informatief/Bestanden%20voor%20’Medicijnen’/
pdf Testimonies_Wemos.pdf
The ICH GCP Guideline Ethics for Drug Testing in Low and Middle Income
http://www.ich.org/fileadmin/Public_Web_Site/ Countries - Considerations for European Market
ICH_Products/Guidelines/Efficacy/E6_R1/ Authorisation; SOMO, 2008
Step4/E6_R1__Guideline.pdf http://www.fairdrugs.org/uploads/files/Eth-
Joint Position on the Disclosure of Clinical Trial ics_for_Drug_Testing_feb_2008.pdf
http://www.lif.se/default.aspx?id=45590
Briefing paper: Protection of Clinical Trial Partici- Media/ articles
pants in Countries outside the EU (2012) http://www.theatlantic.com/international/ar-
http://www.wemos.nl/files/Documenten%20 chive/2012/01/the-super-resistant-bacteria-that-
Informatief/Bestanden%20voor%20’Medicijnen’/ has-india-hell-scared/251731/
Briefing_paper_Pharma_web.pdf http://www.foreignaffairs.com/articles/137358/
sonia-shah/when-superbugs-attack
Government http://www.independent.co.uk/news/world/asia/
http://www.europarl.europa.eu/sides/getAllAn- from-tragedy-to-travesty-drugs-tested-on-survivors-
swers.do?reference=E-2008-1167&language=SV of-bhopal-6262412.html
http://ec.europa.eu/health/human-use/clinical- http://www.independent.co.uk/life-style/health-
trials/index_en.htm and-families/health-news/delhi-to-examine-weak-
http://europa.eu/rapid/press-release_MEMO-12- regulation-of-clinical-trials-6262754.html#
566_en.htm http://www.independent.co.uk/voices/editorials/
http://www.euractiv.com/health/health-ngo-critisis- leading-article-drugs-firms-must-not-prey-on-pover-
es-commission-news-519449 ty-6261959.html
http://www.independent.co.uk/news/world/asia/
Reports without-consent-how-drugs-companies-exploit-
Access to Medicine Index 2012 (2012/2013) indian-guinea-pigs-6261919.html
http://www.accesstomedicineindex.org/sites/ http://www.bbc.co.uk/news/magazine-20136654
www.accesstomedicineindex.org/files/general/ http://www.independent.co.uk/news/uk/home-
research-and-development-2012-access-to- news/drugs-policy-advisor-under-fire-over-links-to-
medicine-index.pdf pharmaceutical-company-6261736.html#
Putting Contract research organisation on the
Radar; Somo, 2011 Video
http://somo.nl/publications-en/Publica- http://pulitzercenter.org/reporting/india-global-
tion_3615/at_download/fullfile health-crisis-super-antibiotic-resistant-bacteria-
The Clinical Trials Industry in South Africa: Ethics, ndm-1-medical-tourism
Rules and Realities; Wemos, 2013 http://www.aljazeera.com/programmes/faultlin
http://www.wemos.nl/files/Documenten%20 es/2011/07/2011711112453541600.html
Informatief/Bestanden%20voor%20’Medicijnen’/
Clinical_Trials_Industry_South_Africa_2013_v3.
pdf
CLINICAL TRIALS OUTSIDE EUROPE 14APPENDIX 1: THE PRINCIPLES OF ICH GCP17
2.1 Clinical trials should be conducted in accord- 2.11 The confidentiality of records that could
ance with the ethical principles that have their origin identify subjects should be protected, respecting
in the Declaration of Helsinki, and that are consist- the privacy and confidentiality rules in accordance
ent with GCP and the applicable regulatory with the applicable regulatory requirement(s).
requirement(s).
2.12 Investigational products should be manu-
2.2 Before a trial is initiated, foreseeable risks and factured, handled, and stored in accordance with
inconveniences should be weighed against the applicable good manufacturing practice (GMP).
anticipated benefit for the individual trial subject and They should be used in accordance with the
society. A trial should be initiated and continued only approved protocol.
if the anticipated benefits justify the risks.
2.13 Systems with procedures that assure the
2.3 The rights, safety, and well-being of the trial quality of every aspect of the trial should be
subjects are the most important considerations and implemented.
should prevail over interests of science and society.
2.4 The available nonclinical and clinical information 17. Copy from Good Clinical Practice Guideline
on an investigational product should be adequate to http://www.ich.org/fileadmin/Public_Web_
support the proposed clinical trial. Site/ICH_Products/Guidelines/Efficacy/E6_
R1/Step4/E6_R1__Guideline.pdf
2.5 Clinical trials should be scientifically sound, and
described in a clear, detailed protocol.
2.6 A trial should be conducted in compliance with
the protocol that has received prior institutional
review board (IRB)/independent ethics committee
(IEC) approval/favourable opinion.
2.7 The medical care given to, and medical
decisions made on behalf of, subjects should always
be the responsibility of a qualified physician or, when
appropriate, of a qualified dentist.
2.8 Each individual involved in conducting a trial
should be qualified by education, training, and
experience to perform his or her respective task(s).
2.9 Freely given informed consent should be
obtained from every subject prior to clinical trial
participation.
2.10 All clinical trial information should be recorded,
handled, and stored in a way that allows its accurate
reporting, interpretation and verification.
15 CLINICAL TRIALS OUTSIDE EUROPEAPPENDIX 1: LEADERS IN DISCLOSURE
ON R&D
Highlight on disclosure of clinical trial conduct • Novartis, although dropping three places to
The Access to Medicine Index 2012 highlights the 4th, is still among the leading companies in
qualities making company leaders regarding many of the R&D-related indicators,
specific focus areas. Below refers to R&D. Among including making significant investments in
the criteria you find information on clinical trial R&D for neglected tropical diseases
conduct and accountability for CRO conduct:18 (NTDs), engaging in several relevant R&D
partnerships, taking responsibility for the
• GlaxoSmithKline ranks 1st by quite a wide conduct of CROs involved in clinical trials
margin demonstrating leadership across and having in place clear processes for
nearly all indicators. Its pipeline is fuller than assuring post-trial access to medicine for
previously for new medicines and for adap- trial participants.
tive research directed at the needs of the
poor, and this is complemented by R&D Please observe that above ranking is not the overall
partnerships and sharing of intellectual ranking, it is the ranking regarding R&D. For
property. Its transparency in all major areas overall ranking, see Appendix 4.
of R&D that affect access is better than that
of any other company. Its mechanisms for
ensuring clinical trials are conducted 18. http://www.accesstomedicineindex.org/
ethically, including allowing for continued research-development
access post-trial to medicines for clinical
trial participants, are also superior.
• Sanofi, ranking 2nd, has a good pipeline in
both innovative and adaptive R&D that
covers a broad range of relevant diseases. At
the time f the 2010 Index it had no adaptive
products. The company also has numerous
R&D partnerships. Compared to 2010, it
has improved its position in relation to
ensuring patient access to medicines after
clinical trial participation and its disclosure
of the results of clinical trials. It shows a
strong commitment to ensuring that
contract research organisations (CROs)
conducting clinical trials on its behalf
uphold ethical standards, and follows
through by monitoring and enforcing its
standards for clinical trial conduct.
CLINICAL TRIALS OUTSIDE EUROPE 16APPENDIX 4: ACCESS TO MEDICINE INDEX 2012 List of companies included in the index 2012 and their overall ranking.19 19. http://www.accesstomedicineindex.org/ranking 17 CLINICAL TRIALS OUTSIDE EUROPE
APPENDIX 4: ACCESS TO MEDICINE INDEX 2012
List of companies the index 2012 and ranking regarding research and development.20
20. http://www.accesstomedicineindex.org/ranking
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