Chapter 2: The policy context for action on innovation and access

A. Public health policy

As the epidemiological data presented in the previous chapter highlights, low- and middle-income countries (LMICs) are facing a double burden of infectious and non­communicable diseases. Internationally and nationally, the human rights framework, specifically the right of everyone to the enjoyment of the highest attainable standard of physical and mental health (in short the right to health), has provided an important mechanism to further the public health policy goals of ensuring and improving access to medicines for those who are most in need. Additionally, the MDGs provided a much needed international platform for action on key concerns ranging from alleviating poverty to improving access to medicines.

The policy context for innovation and access to medical technologies needs to consider the frameworks that currently exist at the intersection of public health, innovation and access. The following section focuses on the right to health under international human rights law, the health-related MDGs, developments in the WHO on public health, access and innovation, national health policies, and regulation of medical technologies.

1. Health and human rights

The human rights dimension has provided an important legal and policy vantage point for consideration of public health and pharmaceutical issues. International human rights law defined under customary international law and international human rights treaties create binding obligations on member states. The WHO Constitution was the first international instrument to state that "the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition" (see Preamble). The right to health is a central element of the international human rights system. It is part of the Universal Declaration on Human Rights, adopted in 1948, the 1966 International Covenant on Economic, Social and Cultural Rights (ICESCR), as well as of regional human rights instruments and many national constitutions. By 2009, 135 countries had incorporated aspects of the right to health in their national constitutions (Perehudoff, 2008; Hogerzeil and Mirza, 2011). It also constitutes the basis for the overall objective of the WHO – laid out in Article 1 – which is "the attainment by all peoples of the highest possible level of health". The Declaration of Alma-Ata, adopted in 1978, provided a more global perspective on tackling the inequities in access to health care systems in general linking the social dimension of achieving the highest attainable level of health and access to essential medicines.

The scope and content of the right to the highest attainable standard of health under Article 12 of the ICESCR has been interpreted by the Committee on Economic, Social and Cultural Rights (CESCR) in General Comment No. 14.1 The CESCR specifies that the parties' obligations under the ICESCR include "the provision of equal and timely access to basic preventive, curative, rehabilitative health services and health education; regular screening programmes; appropriate treatment of prevalent diseases, illnesses, injuries and disabilities, preferably at community level; the provision of essential drugs; and appropriate mental health treatment and care". General Comment No. 14 further explains that the four elements of availability, accessibility, acceptability and quality are essential to the enjoyment of the right to health by all. The CESCR lays down the general obligations of states, which are defined in the framework of "respect", "protect" and "fulfil":

• The obligation to respect includes, but is not limited to, requiring states to refrain from interfering with the enjoyment of the right to health.
• The obligation to protect, among other things, requires states to adopt measures to prevent other parties from interfering with the enjoyment of the right to health.
• The obligation to fulfil requires that sufficient recognition be given to the right to health through legislative implementation and adoption of positive measures and policies to enable individuals to enjoy the right to health.

Although obligations under the ICESCR are subject to progressive realization, the CESCR has set out minimum core obligations which ought to be implemented by countries without delay. These obligations include ensuring non-discriminatory access to essential medicines.2 The CESCR also expressed its view on the impact of intellectual property rights (IPRs) on prices of essential medicines in its Comment No. 17 on the right of everyone to benefit from the protection of the moral and material interests resulting from any scientific, literary or artistic production of which he or she is the author.3 The CESCR notes that this right cannot be isolated from other rights guaranteed in the ICESCR. Parties are therefore obliged to strike an adequate balance, whereby the private interests of authors should not be unduly favoured but adequately balanced with the interest of the public in enjoying broad access to their productions. The CESCR states that, ultimately, IP is a social product and has a social function and parties thus have a duty to prevent unreasonably high costs for access to essential medicines.

In the context of neglected diseases where innovation in medical technologies has not kept with the needs of developing countries, the right to health includes an obligation for states to promote R&D of new medical technologies.4

In April 2002, the United Nations Human Rights Council (HRC) established a mandate for a Special Rapporteur on the right of everyone to the enjoyment of the highest attainable standard of physical and mental health, in short the Special Rapporteur on the right to health. The Special Rapporteur has prepared independent reports, following consultations with many stakeholders, including the WHO. Some of these reports deal with access to essential medicines and the role of the pharmaceutical industry, as well as IP issues. In 2011, the HRC requested the Special Rapporteur to prepare a study by 2013 on the existing challenges with regard to access to medicines in the context of the right to health, ways to overcome these challenges and good practices.5 These intersections and their linkages to human rights have also been the focus of several reports and resolutions of the HRC and its predecessor, the UN Commission on Human Rights (see Table 2.1).

Resolutions of the HRC call upon member states to promote access to medicines for all, including through the full use of the TRIPS Agreement and the flexibilities it provides. In promoting such access, member states are asked to bear in mind that protection of IP is important for the development of new medicines. They are also asked to bear in mind concerns about the effect that providing such IP protection has on prices.6 A 2011 resolution adopted by the HRC in the context of the HIV/AIDS epidemic also reaffirms the right of use, to the fullest extent, of the provisions of the TRIPS Agreement, the Doha Declaration and the WTO General Council Decision of 30 August 2003.7 In relation to access to medications for HIV, TB and malaria, the Commission on Human Rights has also stressed the need for member states to make full use of the flexibilities under the TRIPS Agreement in their national legislations.8

With respect to the HIV/AIDS epidemic, the UN General Assembly has passed several resolutions pertaining to protecting the human rights of people living with HIV and improving access to HIV treatment. The most recent political declaration made by the UN General Assembly included a commitment to remove obstacles that limit the capacity of LMICs to provide HIV/AIDS treatment, including through the use of the flexibilities contained in the TRIPS Agreement, as confirmed by the Doha Declaration, and to ensure that IPR provisions in trade agreements do not undermine the flexibilities (United Nations, 2011a).

2. Access to essential medicines: an indicator for the fulfilment of the right to health

The UN High Commissioner for Human Rights created sets of indicators for 12 aspects of human rights, including the right to housing and shelter, the right to education, the right to freedom of expression and the right to health. The indicators for the fulfilment of the right to health refer to five aspects which are often subject to inequity and discrimination:

• sexual and reproductive health
• child mortality and health care
• natural and occupational environment
• prevention, treatment and control of diseases
• access to health facilities and essential medicines.

Access to essential medicines is a vital component of fulfilling the right to health. A lack of equity in the supply of essential medicines, high prices, informal payments and out-of-pocket payments for the medication required exclude the poor and vulnerable, and do not facilitate the realization of the right to health. The segments of the population most in need of basic essential medicines are mainly the poor, women, children, older people, internally displaced people, those with disabilities, minorities and prisoners. It is the obligation of governments, as part of their human rights commitments, to ensure that these vulnerable segments of the population have access to essential medicines. Different approaches exist to promote the fulfilment of governments' constitutional and international obligations with regard to the right to health including human rights impact assessments as well as rights-based litigation (Hogerzeil et al., 2006).

3. Universal access and the UN Millennium Development Goals

The MDGs are a set of eight international development goals to be achieved by 2015. All of them relate in some way to improving physical, mental and social well­being. The WHO World Health Report 2010 focused on strategies for, and progress in, providing universal health coverage through member states' health financing systems as a means of promoting and protecting health, but without prohibitive costs (WHO, 2010h). In the area of medical technologies in particular, not only the price but also the ultimate availability, quality and appropriateness of resources are reflective of a long chain of policy decisions, market forces and other factors. Therefore, access to medical technology needs to be considered from the standpoint of a comprehensive framework of determinants that ultimately relate back to product innovation, IP protection, trade and distribution.

MDG 8 calls for enhanced global partnership for development issues (see Box 2.1). Target 8.E therefore focuses specifically on global collaboration for access to essential medicines, of which universal access is guaranteed as a right, stating: "In cooperation with pharmaceutical companies, provide access to affordable essential drugs in developing countries". Since the adoption of the MDGs, some countries have made substantial progress towards increasing access to essential medicines to fight HIV/AIDS, malaria and TB. In its 2012 report on the attainment of the MDGs, the United Nations noted that availability and affordability of essential medicines remain a challenge. Yet, new funding was pledged for the Global Fund to Fight AIDS, Tuberculosis and Malaria and the GAVI Alliance, which have demonstrated effectiveness. The report also noted that TRIPS flexibilities facilitating local manufacturing and importation of essential medicines appeared to be more broadly incorporated in national laws, but that the use of these flexibilities may be hampered by bilateral and regional free trade agreements (FTAs). Quality of medicines appeared threatened by counterfeit and substandard products, a problem compounded by the limited capacity of national regulatory agencies (United Nations, 2012). Overall access to essential medicines in developing countries is still insufficient.

4. Public health, innovation and access in the WHO

The WHO policy framework for public health, innovation and access has been developed over many years and consists of a large number of WHO resolutions that reflect the growing consensus among member states regarding the distinct role of the WHO in this area.

(a) Resolutions dealing with public health, intellectual property and trade

Immediately after the TRIPS Agreement came into effect, member states in the WHO discussed its potential impact on public health and requested the WHO Director-General "to report on the impact of the work of the World Trade Organization (WTO) with respect to national drug policies and essential drugs and make recommendations for collaboration between WTO and WHO, as appropriate".10 Since then, the interface of public health, IP and trade has been subject of many debates and resolutions that reflect a growing consensus over the years (see Box 2.2). The 52nd World Health Assembly (WHA) provided the WHO Secretariat with a mandate to work with WHO member states on the monitoring of the impact of the TRIPS Agreement and other trade agreements and to help member states develop adequate health policies to, if necessary, mitigate the negative impact of trade agreements.11 The implementation of the resolution included the establishment of a WHO network for monitoring the implications of the TRIPS Agreement on public health.

The WHA recognized the importance of IPRs in fostering R&D in both innovative medicines and essential medicines, but also urged member states "to consider, whenever necessary, adapting national legislation in order to use to the full the flexibilities contained in the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS)".12 Many subsequent resolutions contain similar language. With regard to the area of HIV/ AIDS, member states highlighted in the same year "the difficulties faced by developing countries in effective use of compulsory licensing in accordance with the Declaration on the TRIPS Agreement and Public Health (Doha Declaration)".13

The WHA also mandated the WHO Secretariat, to support member states – at their request and in collaboration with the competent international organizations – in their efforts to frame coherent trade and health policies14 as well as to provide, on request and in collaboration with other competent international organizations, technical and policy support to countries on TRIPS flexibilities (see Box 2.2 for a list of the relevant WHA resolutions).15

Thus, while in the beginning, the resolutions focused on monitoring and assessing the impact of trade agreements, they became more specific over the years – specifically mentioning IP and TRIPS flexibilities. The mandate of WHO was extended to include, on request, technical and policy support on formulating coherent trade and health policies and the implementation of TRIPS flexibilities while, at the same time, making it clear that this should be done in collaboration with other relevant international organizations.

Based on this mandate, the WHO has provided guidance to its member states by publishing a wide range of material on: (i) how to make use of TRIPS flexibilities for improving public health, including improved access to HIV treatment (UNAIDS/WHO/UNDP, 2011); (ii) how to develop a public health perspective on the examination of pharmaceutical patents (ICTSD/UNCTAD/WHO, 2007); (iii) remuneration guidelines for the non-voluntary use of patents on medical technologies (WHO, 2005a); and (iv) how to implement the WTO General Council Decision on Paragraph 6 of the Doha Declaration (Correa, 2004).16

A major development in this regard was the establishment of the Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH) and the subsequent adoption of the WHO Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property (GSPA-PHI).17

(b) The Commission on Intellectual Property Rights, Innovation and Public Health

In 2003, the CIPIH was established "to collect data and proposals from the different actors involved and produce an analysis of intellectual property rights, innovation, and public health, including the question of appropriate funding and incentive mechanisms for the creation of new medicines and other products against diseases that disproportionately affect developing countries".18 The CIPIH reviewed the interfaces and linkages between IPRs, innovation and public health, and examined in depth how to stimulate the creation of new medicines and other products for diseases that mainly affect developing countries.

In April 2006, the CIPIH published its final report that focused on the overarching question of how to promote innovation and improve access to medical technologies in developing countries through the different stages of the development of medicines – discovery, development and delivery. The report made 60 recommendations addressed to governments of developed and developing countries, the WHO, and other intergovernmental organizations and stakeholders. Recommendations covered the whole innovation cycle and included R&D policies, procurement and health delivery systems, the role of patents and protection of clinical test data, management of IP, TRIPS flexibilities, competition policy, the regulation of quality, safety and efficacy of medicines as well as the impact of FTAs on access to medicines.

The report recommended that the WHO develop a global plan of action to secure sustainable funding for developing accessible products for diseases that affect developing countries, and also continue to monitor the public health impact of IPRs on the development of new products and access to medicines in developing countries. Based on the report, the WHA established an intergovernmental working group to draw up a global strategy and plan of action19 to provide a framework for securing an enhanced and sustainable basis for needs-driven, essential health R&D relevant for diseases that disproportionately affect developing countries.20 This process led to the adoption of the GSPA-PHI in 2008.21

(c) The Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property

The adoption of the GSPA-PHI was a major step forward towards a global consensus on practical action on public health, innovation and IP (see Table 2.2). The overarching objectives of the GSPA-PHI are to promote new thinking on innovation and access to medicines, as well as, based on the recommendations of the CIPIH report, to provide a medium-term framework for securing an enhanced and sustainable basis for needs-driven, essential health R&D relevant to diseases which disproportionately affect developing countries, proposing clear objectives and priorities for R&D, and estimating funding needs in this area. The GSPA-PHI states that while IPRs are an important incentive for the development of new health care products, this incentive alone is not sufficient to trigger the development of the health products needed to fight diseases in a scenario where the potential paying market is small or uncertain.22 The lack of financing for R&D into diseases disproportionately affecting developing countries was subsequently addressed by two subsequent WHO expert working groups.23

Overall, member states agreed that the GSPA-PHI should "encourage and support the application and management of intellectual property in a manner that maximizes health-related innovation, especially to meet the research and development needs of developing countries, protects public health and promotes access to medicines for all, as well as explore and implement, where appropriate, possible incentive schemes for research and development" (see Table 2.2).24

The GSPA-PHI also reaffirms and broadens the mandate of the WHO to work at the interface of public health and IP. The GSPA-PHI has been summarizing, updating and expanding the various mandates in the area of public health and IP which were given to the WHO through the resolutions adopted since the TRIPS Agreement came into effect. On the other hand, this mandate is linked to the clear aspiration of member states to ensure closer collaboration between relevant intergovernmental organizations and their respective work on public health and IP-related issues. Element 5 of the plan of action therefore requests governments and international organizations to "strengthen efforts to effectively coordinate work relating to intellectual property and public health among the secretariats and governing bodies of relevant regional and international organizations in order to facilitate dialogue and dissemination of information to countries".25 This provision, together with the text of the resolution itself which requests the WHO Director-General "to coordinate with other relevant international intergovernmental organizations, including WIPO, WTO and UNCTAD, to effectively implement the global strategy and plan of action"26 also provides the basis for the trilateral cooperation established by the Secretariats of the WHO, WIPO and the WTO.27

(d) Other developments in the WHO

Other developments in the work of the WHO with bearing on access and innovation include:

• The Pandemic Influenza Preparedness (PIP) Framework for the Sharing of Influenza Viruses and Access to Vaccines and other Benefits, which addresses IP issues and was adopted by the WHA in May 2011.28
• The new global health sector strategy on HIV/ AIDS, 2011-2015, which guides the health sector's response to HIV and was endorsed by the WHA in May 2011.29 Its goals are consistent with "Getting to Zero", the UNAIDS strategy for the same period.
• A new mechanism for international collaboration among WHO member states to prevent and control substandard and spurious/falsely-labelled/falsified/ counterfeit (SFFC) medical products, established by the WHA in 2012.30

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5. National health policies and health systems

Countries develop national health policies and strategies for guiding health development, taking into account the international legal and policy framework. Conceptually, these policies and strategies are based on and draw their strength from a national vision for social development and relevant polices. For example, a country's social protection policy would influence that country's policy-making about providing universal health coverage for its people and establishing a social health insurance policy.

Health policy refers to decisions, plans and actions which are undertaken to achieve specific health care goals within a society. It may be in the form of a formal document backed up by institutionalized processes and reviewed periodically, or it may be dispersed among a number of different documents, including notices, plans, strategies, decisions and directives. Health laws, rules and technical guidelines are also considered to be components of health policy.

Various health subsectors often have their own policies, and these also form part of national health policy. For example, national medicine policy is usually a well-defined document about ensuring people access to safe and effective medicines. However, it draws its guidance and inspiration for this policy from overall national health policy.

In order to understand the scope and vision of a national health policy, it is important to accept the idea of a health system. The health system is a broad concept and it covers all organizations, people and actions where the primary intent is to promote, restore or maintain health (WHO, 2000a). Using this definition, the term health system covers all health subsectors – public, private, not-for-profit and international cooperation. It also covers all activities taking place in a country to promote health, prevent morbidity and provide curative and rehabilitative services. In addition, it covers relevant policy-making and planning, stewardship and intersectoral collaboration to tackle socio-economic determinants of health which are outside the general understanding and purview of the health sector and ministry of health.

The WHO approach to national health policy is explicitly enshrined in its Constitution, which
came into force in 1948:

    "Governments have a responsibility for the health of their peoples which can be fulfilled only by the provision of adequate health and social measures."

In 1978, the WHO member states also agreed on a primary health care approach towards health care systems which is captured in Article 6 of the Declaration of Alma-Ata.

    "Primary health care is essential health care based on practical, scientifically sound and socially acceptable methods and technology made universally accessible to individuals and families in the community through their full participation and at a cost that the community and country can afford to maintain at every stage of their development in the spirit of self-reliance and self-determination. It forms an integral part both of the country's health system, of which it is the central function and main focus, and of the overall social and economic development of the community. It is the first level of contact of individuals, the family and community with the national health system bringing health care as close as possible to where people live and work, and constitutes the first element of a continuing health care process."

Both the WHO Constitution and the Declaration of Alma-Ata have inspired national health policies in many WHO member states. National health policy is aimed at organizing and strengthening the national health systems in such a way that they effectively help in achieving the objectives of the policy. The WHO has been working towards strengthening health systems to make them efficient, effective and responsive to the unmet and changing needs of populations. A conceptual framework for a health system has been developed and promoted by the WHO, and comprises six building blocks, intermediate goals and ultimate health outcomes.32

6. Regulation of medical technologies

Regulation of medical technologies is intended to ensure the quality, safety and efficacy of medicines (including vaccines and other biological medicines), or, in the case of medical devices, the safety, effectiveness and performance of such devices (WHO, 2003a). Regulation also plays an important role in determining access to new products. Regulatory measures are established and enforced to ensure that products given to patients are safe, effective and are of acceptable quality. However, unjustified regulatory measures, coupled with lack of transparency in the regulatory process and slow procedures, can become an obstacle to access. Regulation can also have an effect on prices. Higher safety standards and other additional regulatory requirements may require manufacturers to generate more (clinical) data to prove the safety of products, or they may require manufacturers to further invest in production facilities and thus reach the necessary quality standards. As a consequence, higher regulatory standards can increase the level of investment needed and can contribute to higher prices for end products.

Regulatory systems also have a decisive impact on innovation. New and innovative medicines, vaccines and medical devices must comply with safety standards. Many innovative products do not make it to the market, as they fail to meet safety standards, or due to lack of product efficacy. Regulators have to balance the benefits of an early release of new treatments with safety concerns and the rights of patients in the context of acceptable levels of risk.

This section reviews the concept of regulation of medical technologies, with a specific focus on medicines.

(a) Why regulate medicines?

While people have been taking remedies of different origins to ease pain, discomfort and disease symptoms for millennia, ideas about how to ensure that medicines are of the requisite quality are relatively more recent. The era of modern medicines and medical technology regulation began after various breakthroughs in chemistry, physiology and pharmacology in the 19th century. Later, however, government response to various medical catastrophes effectively served to accelerate the development of regulation. Briefly, the US Federal Food, Drug, and Cosmetic Act, with its 1938 requirement for premarket notification for new drugs, was introduced following the deaths in the United States of more than 100 people as a result of ingesting diethylene glycol, which was used as a solvent in a sulfanilamide elixir, a raspberry-flavoured antibiotic syrup. The second major push for increased governmental oversight was the thalidomide disaster. Thalidomide, a sedative, was also targeted at expectant mothers experiencing morning sickness. Between 1958 and 1960, thalidomide was introduced in 46 different countries worldwide, resulting in an estimated 10,000 babies being born with severe birth defects (Rägo and Santoso, 2008).

These disasters created a concerted push for more oversight precisely because medicines are not ordinary consumer products and because no medicine is completely safe. Consumers lack the knowledge to make informed choices about when to use a particular medicine, which medicines to use and how to use them. They do not have sufficient information to weigh potential benefits against the risk of side-effects. In most countries, therefore, professional advice from prescribers or dispensers is required. Even so, information asymmetry exists between manufacturers, prescribers, dispensers and consumers. In addition, vaccines, blood products such as immunoglobulins and anti-venom products, and medical devices are unlike other consumer goods in that they also seek to meet an important policy objective of improving public health. Medicines that are not effective or are of poor quality can lead to therapeutic failure, worsening of disease or resistance to the medicines. If such ineffective or poor quality products are widely distributed, patients lose confidence in the health care system. Furthermore, patients can actually be harmed by the use of such products. Consequently, products must conform to prescribed standards, and their quality should be controlled rigorously.

Governments have to ensure that the manufacture, distribution and use of medical products are regulated effectively to protect and promote public health (Rägo and Santoso, 2008). The objective of medicines regulation is to ensure that:

• products are of the required quality, safety and efficacy
• products are appropriately manufactured, stored, distributed and dispensed by licensed manufacturers, wholesalers and health professionals
• illegal manufacturing and trade are detected and adequately sanctioned
• health professionals and patients have the necessary information to enable them to use products (particularly medicines) in a rational manner
• promotion and advertising is fair, balanced and aimed at rational use
• access is not hindered by unjustified regulatory barriers (such as applying different standards for imported and locally manufactured products, lengthy processing time for registration and marketing authorization applications, and duplication of the work of other regulators without delivering added value)
• side-effects, pharmacovigilance and the use of the medicines are appropriately monitored.

The quality, safety and efficacy of new medicines is in large part determined through extensive pre-clinical and clinical research and trials, while, for a generic medicine, only therapeutic equivalence and interchangeability with originator products has to be proved by bioequivalence or other appropriate studies.

(b) Clinical trials

Clinical trials are research studies in which large groups of human participants are enrolled to evaluate the safety or effectiveness of new medicines or new medical devices by monitoring their effects in human subjects (both patients and healthy volunteers can be involved). However, the first use of new medicines by human beings is always carefully carried out on only a very limited number of trial subjects. It is also important to note that clinical trials have a vital role in evaluating the safety of interventions, as many safety parameters can be controlled by quality. Clinical trials may also be referred to as interventional trials. The researchers measure how the subjects' health changes when compared with no treatment (placebo) or standard treatment. Interventions may include medicines, cells therapies and other biological products, but they can also extend to surgical procedures, radiologic procedures, devices, other treatments, diagnostics or preventive methods (e.g. vaccines).

Most clinical research that involves the testing of new medicines progresses in an orderly series of steps called phases. This allows researchers to ask and answer questions in a way that results in reliable information about the product's safety and efficacy, and it also protects patients. Most clinical trials are classified into one of four phases:33

• Phase I trial: the first studies in healthy volunteers evaluate the safety of the medicine, including the appropriate dosage and side-effects; how a new medicine should be given (by mouth, injected into the blood or the muscle); how often it should be given; and what dose is considered safe. A Phase I trial usually involves only a small number of healthy volunteers or patients (20-80).
  
  
• Phase II trial: a phase II trial continues to test the safety of the medicine and begins to evaluate how well the new medicine works (efficacy). Phase II studies usually focus on a particular condition or disease in a larger group of people (several hundred).
  
  
• Phase III trial: these trials investigate the efficacy of the medicine in large groups of human subjects (from several hundred to several thousand and more) by comparing the intervention against a "standard" or placebo, as appropriate. Phase III trials also serve to monitor adverse effects and to collect more information on safety.
  
  
• Phase IV trial: after a medicine is approved for market, the purpose of Phase IV trials is to evaluate further the side-effects, risks and benefits of a medicine over a longer period of time and in a larger number of people than in Phase III clinical trials. Phase IV trials involve several thousand people.
  
  

(c) Research ethics

Clinical trials not only involve issues around safety of the tested products, they also touch on different ethical questions. Among the most important questions to be addressed by research ethics committees before allowing a clinical trial to proceed are:

• the benefit-risk ratio
• the protection of the dignity of potential participants, which includes the validity of the informed consent process (quality of information provided and absence of coercion of participants) and the protection of privacy (confidentiality of personal data)
• the equitable access to expected benefits of the research (new knowledge or new products )
• the special attention given to vulnerable groups and the absence of discrimination.

Many international and national bodies have developed guidance for the ethical conduct of research over a period of almost 40 years. In 1964, the World Medical Association (WMA) adopted the Declaration of Helsinki. It has been reviewed regularly in the interim, with the most recent version adopted in 2008. The International Ethical Guidelines for Biomedical Research Involving Human Subjects, published in 2002 by the Council for International Organizations of Medical Sciences (CIOMS, 2002), constitutes another globally recognized ethical guidance. One essential ethical condition for comparing two treatments for a disease with a randomized controlled trial (where participants are allocated at random to receive one of several clinical interventions) is that there must be a good reason for thinking that one treatment is actually better than the other.

Following a resolution of the WHA adopted in 2006,34 an important tool designed to improve clinical trial transparency was developed by the WHO – the International Clinical Trial Platform, which provides public access to information about clinical trials which are under way around the world.35

(d) Key stakeholders in the regulation of medicines and medical technologies

A functioning regulatory system is a prerequisite for ensuring the quality, safety and efficacy of products on the market. National governments are responsible for establishing national or regional regulatory authorities which have a clear mission, sound legal basis, realistic objectives, appropriate organizational structure, adequate number of qualified staff, sustainable financing, access to up-to-date evidence-based technical literature, equipment and information, coupled with capacity to exert effective market control. These regulatory authorities must be accountable to both the government and the public and their decision-making processes should be transparent. Monitoring and evaluation mechanisms should be built into the regulatory system in order to assess attainment of established objectives. Most countries have a regulatory authority and formal requirements for providing marketing authorization for medicines. However, they tend to have fewer such provisions in place for other regulated medical technologies, such as medical devices.36

The role of the WHO in strengthening drug regulation involves the issuance of recommended norms and standards through its expert committees, the assessment of regulatory systems and support of regulatory capacity-building at the national level, in addition to the prequalification of essential medicines (such as ARVs to treat HIV/AIDS or medicines to treat malaria and TB), vaccines and certain medical devices so as to facilitate the procurement of adequate quality products internationally.37

(e) International convergence of regulatory procedures and harmonization efforts

Conveying the importance of convergence of regulatory procedures across countries is a challenge. National and sub-national registration authorities follow their own administrative rules and technical requirements, and they have established their own processes and procedures for medicines registration. Even within countries, there is often no clear indication at a national level of the length of time registration takes or the maximum period of time permitted for regulators to assess and register medicines. Furthermore, limited transparency may apply before or during the registration process. Different national-level interpretations and implementation of technical requirements for registration set out in international guidelines are often due to factors such as different governmental structures, cultural norms, levels of technical competence and availability of human resources, or they may be due to particular business environments. In addition, there is often a time lag between the publication of international/regional/subregional technical regulatory guidelines and their implementation by individual countries. Regional differences still exist in terms of how individual countries go about ensuring compliance with current international good manufacturing practices (GMPs), as well as numerous other regulatory requirements for ensuring quality, safety and efficacy of products. Such distinctions can influence costs and the speed with which a company obtains marketing approval.

Convergence of the different national systems, in conjunction with harmonization of technical requirements, can remove many of the transactional and human resource costs associated with multiple regulatory submissions in each country, including multiple testings. Thus such convergence can result in saving scarce resources for countries as well as companies. Regulatory convergence and increasing trust in regulatory decisions made by other competent authorities should lead to: (i) more efficient resource use (e.g. international and regional sharing of scientific resources and "best practices"); (ii) better quality applications to register medicines from manufacturers; (iii) cost savings both at the company and government level; and, as a consequence, (iv) quicker access to quality essential medicines that are safe and efficacious.

One of the roles of the WHO in terms of improving regulation is to provide a platform for regulators to discuss common challenges and identify areas where further guidance for regulators needs to be developed. The WHO has convened the International Conference of Drug Regulatory Authorities (ICDRA) every two years since 1980 to build collaboration between regulators globally, to promote harmonization and exchange of information, to identify good practices and to seek common approaches to problems that medicines regulatory authorities face.38 The ICDRA recommendations serve as a guide to the WHO and interested stakeholders in determining priority actions in national and international regulation of medicines, vaccines and other regulated medical products.

There are also a number of regional and interregional regulatory harmonization initiatives on the regulation of medicines and medical devices:

(i) East African Community

The East African Community (EAC) launched a project on the harmonization of medicines registration in all five EAC member states. The objective of the project is to improve public health by increasing rapid access to good quality medicines through the harmonization of technical requirements and procedures for medicines registration, so as to achieve shorter registration periods for priority medicines to treat communicable and non-communicable diseases. The project also seeks to increase collaboration between the authorities, thereby resulting in joint assessments and inspections, and leading to mutual recognition and the avoidance of duplication.

(ii) European regulatory system and the European Medicines Agency

The European Medicines Agency (EMA) is responsible for the scientific evaluation of applications to market certain categories of medicines in Europe for both human and veterinary medicines. It is based on EU-wide harmonization of certain areas of pharmaceutical legislation, including technical requirements for marketing authorization. Under a centralized procedure, companies submit a single marketing authorization application to the EMA. The EMA has the power to execute its functions and grant centralized marketing authorizations. Once granted, a centralized (or "Community") marketing authorization is valid in the European Economic Area (EU member states, Iceland, Liechtenstein and Norway).

The EMA centralized procedure applies only to certain categories of medicines, including all medicines for human and animal use derived from biotechnology and other high-tech processes, and also including medicines for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases. In addition to the above, there are many other medicines which do not fall within the scope of the EMA centralized procedure and thus are registered at the national level.

These harmonized regulatory requirements also enable companies to apply for simultaneous authorization of medicines in different EU member states (decentralized procedure). Furthermore, mutual-recognition procedures allow companies to apply for an authorization of a medicine to be recognized in other EU member states.

(iii) Gulf Cooperation Council

The Gulf Cooperation Council (GCC) drug registration was established in 1999. Members comprise the Kingdom of Bahrain, the State of Kuwait, Oman, Qatar, the Kingdom of Saudi Arabia and the United Arab Emirates. The GCC registers pharmaceutical companies, pharmaceutical products; inspects companies for GMP compliance; approves quality control laboratories; reviews technical and post-market surveillance reports; and is responsible for bioequivalence studies as a component of quality assurance procedures. Certain countries which have established regulatory systems rely on their own competencies for registration (Pateriya et al., 2011).

(iv) Pan American Network for Drug Regulatory Harmonization

The Pan American Network for Drug Regulatory Harmonization (PANDRH), a continental forum, was established to deal with medicines regulatory harmonization. It comprises representatives of all drug regulatory authorities in the Pan-American region. It set up the Pan American Forum of Drug Regulatory Agencies to discuss and explore solutions to common problems. National authorities participate in and lead this process. The main aim of PANDRH is to support harmonization processes through the analysis of specific aspects of such processes, and to adopt recommendations on priority subjects and harmonized regulatory guidelines.

(v) Other regional initiatives

Further regional initiatives on medicines regulation include:

• the Andean Quality System, which was established in 1995
• the Southern Common Market (MERCOSUR)
• efforts by the Association of Southeast Asian Nations (ASEAN) to create a harmonized medicines regulatory process
• the African Medicines Regulatory Harmonization (AMRH) initiative, of which the EAC project is the first subregional project.

There are also a number of interregional regulatory harmonization initiatives for technical requirements.

(vi) International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and related initiatives

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 and brings together the regulatory authorities and pharmaceutical industries of Europe, Japan and the United States to discuss scientific and technical aspects of medicines registration, specifically focusing on new innovative medicines. The harmonization of technical requirements for the registration process can avoid unnecessary costs generated as a result of differences in national registration processes. Harmonization also helps to avoid the duplication of clinical trials, and speeds up the development and registration process for new medicines. Streamlining the regulatory assessment process can thus have a positive impact on both innovation and access by facilitating authorization and reducing duplication of efforts and related costs.

In response to increasing globalization in the development of medicines, the ICH also involves regulatory authorities from countries that are major producers of active pharmaceutical ingredients or clinical trial data. The ICH topics are divided into four category-assigned codes: Quality (Q) Guidelines; Safety (S) Guidelines; Efficacy (E) Guidelines; and Multidisciplinary (M) Guidelines. M Guidelines consist of cross-cutting topics which do not fit neatly into one of the other three categories. One such example is the Common Technical Document (CTD), covering the preparation of registration dossiers through a harmonized structure and content. This has been adopted by all partners in the ICH, as well as by Australia, Canada and Switzerland. Prior to the adoption of the CTD, each country had its own format for new drug applications. A company seeking to register a product for sale in more than one country was required to submit the application in the relevant country's format, which lead to a considerable duplication of effort, with a corresponding waste of time, energy and money. The WHO is following the ICH CTD format in its prequalification programme, and it has provided numerous CTD training sessions for regulators and industries alike to promote the use of CTD for multisource (generic) medicines registration applications outside ICH regions.

(vii) Global Harmonization Task Force: international harmonization in the regulation of medical devices

The Global Harmonization Task Force (GHTF) is a response to the need for international harmonization in the regulation of medical devices. It was created in 1992 to achieve greater uniformity between national medical device regulatory systems. The GHTF was founded by Australia, Canada, the European Union, Japan and the United States as a voluntary group of representatives from national medical device regulatory authorities and the regulated industry. The aim of the GHTF is to further the convergence of regulatory practices related to medical devices. It also promotes technological innovation and facilitates trade in medical devices by contributing to more harmonized regulatory requirements. The GHTF publishes documents on regulatory practices, which provide a model for the regulation of medical devices and can be used by national regulatory authorities. The arguments in favour of the harmonization of regulatory standards for the safety, effectiveness, performance and quality of medical devices are substantially the same as those favouring the harmonization of regulatory standards for medicines. Different national standards for the regulation of medical devices lead to duplications, increased costs incurred by regulators as well as companies and, ultimately, the jeopardy of patient safety. Harmonized standards open up possibilities for countries, enabling them to rely on foreign authorizations of more advanced regulatory systems to approve medical devices. Countries with weaker regulatory systems can thus allocate scarce resources to other areas – thereby facilitating access to needed medical devices through shorter regulatory processes (WHO, 2003a).

(viii) International Medical Device Regulators Forum

Based on the work of the GHTF, the International Medical Device Regulators Forum (IMDRF) was established in 2011 to discuss future directions in medical device regulatory harmonization. The IMDRF comprises a group of medical device regulators, and currently includes representatives from Australia, Brazil, Canada, the European Union, Japan, the United States and the WHO. China, India and the Russian Federation have been invited to join. As a result, IMDRF membership is expected to become more internationalized than GHTF membership. The mission of the IMDRF is "to strategically accelerate international medical device regulatory convergence to promote an efficient and effective regulatory model for medical devices that is responsive to emerging challenges in the sector while protecting and maximizing public health and safety". Regulatory convergence refers to the voluntary alignment of regulatory requirements and approaches across countries and regions.

(f) Future of regulation

It is a complex task to balance the benefits of the early release of new products with safety concerns and to find an acceptable level of risk. Regulators face the complicated challenge of using the best science available to balance the various different interests of the public in general, patients and producers of regulated medical technologies while ensuring that products are safe and efficacious. Optimizing the use of the scarce resources available to regulators will assume ever-increasing importance in the future. In this environment, new products will inevitably create new regulatory challenges.

Increasingly, complex new advanced therapy medicinal products include new medical products based on genes (gene therapy), cells (cell therapy) and tissues (tissue engineering). These advanced therapies may offer revolutionary treatments for a number of diseases or injuries, such as skin injuries in burn victims, Alzheimer's disease, cancer and muscular dystrophy. They offer huge potential for patients and industry. In addition, new technologies such as nanotechnology offer new horizons for treatment. For example, one particular application of nanotechnology in medicine that is currently being developed involves employing nanoparticles to deliver medicines, heat, light or other substances to specific types of cells (such as cancer cells). Particles are engineered so that they are attracted to diseased cells, thereby enabling direct treatment of these cells. This technique reduces damage to healthy cells in the body and allows for earlier detection of disease.

Nanoparticles that deliver chemotherapy medicines directly to cancer cells are currently in development, and testing on the targeted delivery of chemotherapy medicines is under way, with final approval for their use on cancer patients pending. New biological medicines, including follow-on ("biosimilar") biological products, represent another challenging area (see Box 2.3). The future of medicines regulation and other regulated medical technologies is increasingly reliant on highly sophisticated scientific skills and the capacity of regulators, combined with a greater degree of collaboration and cooperation. In the future, regulators are more likely to function as a network, benefitting from each other's work as opposed to relying on individual duplicative efforts. The regulatory system, supported by relevant legislation, is an important component of a functioning modern health system and is essential in order to facilitate innovation and access to new safe and effective medicines.39

Besides regulation, many other health policy aspects impact innovation of and access to medical technologies. The supply of medicines and medical technologies within health systems, as well as procurement, price regulation, and the funding of health systems are covered in Chapter IV, Sections B and C.

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UN document E/C.12/2000/4.  back to text

Ibid.  back to text

UN document E/C.12/GC/17.  back to text

OHCHR/WHO, "The Right to Health", Fact Sheet No. 31, 2008.  back to text

UN document A/HRC/RES/17/14.  back to text

Ibid.  back to text

UN document A/HRC/RES/16/28.  back to text

UN document E/CN.4/RES/2004/26.  back to text

Source: United Nations (2012).   back to text

WHA, Resolution: WHA49.14: Revised drug strategy   back to text

WHA, Resolution: WHA52.19: Revised drug strategy.   back to text

WHA, Resolution: WHA56.27: Intellectual property rights,
innovation and public health 

WHA, Resolution: WHA56.30: Global health-sector strategy for HIV/AIDS.  back to text

WHA, Resolution: WHA59.26: International trade and health.  back to text

WHA, Resolution: WHA60.30: Public health, innovation and
intellectual property   

For a list of relevant WHO and other intergovernmental organization publications, see www.who.int/phi/publications/category_ip_trade/en/index.html.  back to text

See Section 4(c) below.  back to text

WHA, Resolution: WHA56.27: Intellectual property rights, innovation and public health.  back to text

WHA, Resolution: WHA59.24: Public health, innovation, essential health research and intellectual property rights: towards a global strategy and plan of action.  back to text

For more on the CIPIH, see Chapter II, Section A.4(b).  back to text

WHA, Resolution: WHA61.21: Global strategy and plan of action on public health, innovation and intellectual property.   back to text

WHA, Resolution: WHA61.21: Global strategy and plan of action on public health, innovation and intellectual property, Annex, para. 7 .  back to text

See Chapter III, Section C.3.  back to text

WHA, Resolution: WHA61.21: Global strategy and plan of action on public health, innovation and intellectual property, Annex, para. 14 (e).  back to text

Ibid, Annex Element 5.1(h).  back to text

WHA, Resolution: WHA61.21: Global strategy and plan of action on public health, innovation and intellectual property, para. 4(5).  back to text

See Chapter I, Section B.4.  back to text

WHA, Resolution: WHA64.5: Pandemic influenza preparedness: sharing of influenza viruses and access to vaccines and other benefits. See also Chapter III, Section E.  back to text

WHA, Resolution: WHA64.14: Global health sector strategy on HIV/AIDS, 2011-2015.  back to text

WHA, Resolution: WHA65.19: Substandard/spurious/falsely­labelled/falsified/counterfeit medical products.  back to text

UN document A/RES/66/2. See also WHA, Decision WHA65(8): Prevention and control of noncommunicable diseases: follow-up to the High-level Meeting of the United Nations General Assembly on the Prevention and Control of Non-communicable Diseases.  back to text

WHO (2007). See also Chapter IV, Section B and Figure 4.4.  back to text

See: NIH (2001); and www.who.int/ictrp/glossary/en/index.html. For information on the role of clinical trials in the drug development process, see Chapter III, Section B.5.  back to text

WHA, Resolution: WHA58.34: Ministerial Summit on Health Research.  back to text

See Chapter III, Section B.5. back to text

See Sections (e)(vii) and (viii) below. back to text

See Chapter IV, Section B.5. back to text

See www.who.int/medicines/areas/quality_safety/regulation_legislation/icdra/en/index.html. back to text

The supply of medicines and medical technologies within health systems, as well as procurement, price regulation and the funding of health systems are covered in Chapter IV. back to text

The EMA has issued a number of scientific guidelines on biosimilar medicines. See www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. back to text

See Anleitung für die Zulassung ähnlicher biologischer Arzneimittel (Biosimilars), www.swissmedic.ch/rechtstexte/00626/index.html?lang=de. back to text

See www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. back to text

See 42 U.S.C. § 262 Regulation of biological products. back to text