Luc Besançon and Zuzana Kusynová, International Pharmaceutical Federation

Submission by: Luc Besançon and Zuzana Kusynová
Organization: International Pharmaceutical Federation (FIP)
Country: The Netherlands

Abstract

Access to effective medicines is crucial for successful prevention and treatment; therefore, it should be a basic human right.
Research and development (R&D) models are turning towards transparency and public support, through the sharing of information, capabilities, and intellectual property (IP), including between competitors. Models as ‘open innovation’ should involve partners from developing countries to participate at the research, as their knowledge of the environment can identify and meet the concrete access needs in these countries. The integration of medicine use considerations in earlier stages of R&D is crucial.

Pharmaceutical sciences are key for innovation and access to new medicines and technologies. In its recent publications, FIP reviewed the achievement and impact of the large spectrum of pharmaceutical sciences over the last 50 years, and identified the major challenges for the pharmaceutical sciences in the next 5 – 10 years. Pharmaceutical sciences enhance all aspects of R&D important for improved access, including those suitable for low resource setting: maximising the lifetime of a medicine, reducing phases for R&D of generics (e.g. biowaivers), using predictive computer simulations and systems pharmacology models, building know-how for development and assessment of generics for treatment of NCDs, developing easy administration routes, etc.

Economic models and incentives, such as EU-sponsored Innovative Medicines Initiative (IMI), collaboration between the United Nations Population Fund (UNFPA) and the Institute for Pharmaceutical Sciences (MIPS) at Monash University, etc. stimulate R&D.
Access to medicines is impaired by non-affordability, lack of education on health, and shortage of trained healthcare personnel. Pharmacy organisations, both national and international, promote to governments and other stakeholders, the need to take effective action to improve policy, practice, science and education in relation to access to medicines. There is a wide range of technical expertise amongst pharmaceutical scientists and pharmacists worldwide that can be mobilised for this purpose.

Submission

ACCESS TO MEDICINES AS A HUMAN RIGHT
Medicines are crucial for successful prevention and treatment of many illnesses. Access to effective medicines should, therefore, be considered to be a basic human right. However, one-third of the world’s population lacks access to essential medicines. In the poorest parts of Africa and Asia, this figure rises to one-half of the population. [1]

COMPLEXITY OF ACCESS
Access to medicines is complex and has been described by the World Health Organization (WHO) as having four main components: rational selection, affordable prices, sustainable financing and reliable systems for purchase, storage, and distribution. Non-affordability, lack of education on health, weak public distribution systems for medicines and shortage of trained healthcare personnel, all adversely affect the ability to access medicines in developing countries. [1]

Pharmacy organisations, both national and international, have a vital role to play in taking responsibility for promoting, to governments and other stakeholders, the need to take effective action to improve policy and practice in relation to access to medicines. There is a wide range of technical expertise amongst pharmacists worldwide that can be mobilised for this purpose. [1]

As the focus of the High-Level Panel is on research, development, and innovation, emphasis will be given to these aspects.

INNOVATIVE R&D MODELS
Developing a new medicine involves a great deal of time, effort, scientific research and expense. Unfortunately, the traditional closed R&D business model has been failing to generate optimal results and bears a high risk. Consequently, R&D is now turning towards new approaches that aim to enhance transparency and attain broad (public) support of medicine development through the sharing of information, capabilities, and intellectual property (IP) between organisations, including competitors. Unlike more traditional collaboration models, this approach can also allow collaborators to exploit a new technology in other, non-competing areas. [2] Moreover, open innovation involves more partners, including from developing countries, to participate at the research. Since they are familiar with the situation and the needs of the developing countries, they can for example integrate the concrete considerations such as medicine use and administration in earlier stages of R&D. This can directly improve the access to the medicine once it reaches the market.

PHARMACEUTICAL SCIENCES ARE KEY FOR INNOVATION AND ACCESS TO NEW MEDICINES AND TECHNOLOGIES
In 2012 FIP looked back over the last 50 years in reviewing the achievements and impact of the pharmaceutical sciences over the spectrum of its activities, including drug discovery, drug absorption, distribution, metabolism and excretion, pharmacokinetics and pharmacodynamics, formulation science and drug regulation. [3] This review accompanied an outline of how the pharmaceutical sciences might look in 2020 [4], and identified the major research activities which are likely going to drive drug discovery and development, as well as the enabling technologies, together with the paradigm shifts foreseen in drug discovery, development. This analysis also lead to the development of scenarios analysis on the evolution of pharmaceutical sciences. [5] More recently, an FIP position paper has been published also looking forward, specifically identifying the major challenges for the pharmaceutical sciences in the next 5 – 10 years. Areas covered are drug design and discovery, natural products, formulation design and pharmaceutical technology, pharmacokinetics/pharmacodynamics and systems pharmacology, translational and personalized medicine, biotechnology, analytical sciences and quality control, and regulatory science. [5]

INNOVATIVE SOLUTIONS ARE NEEDED FOR LOW-PROFIT AREAS
There is often a disconnection between the value, price and cost of medicines, and real outcomes should be measured in terms of lives saved and public health needs. For example, the emerging global health threat of antimicrobial resistance (AMR) leading to significant gaps in the treatment of infectious diseases is calling for the R&D of new medicines. However, for a number of reasons including financial ones, the development of antimicrobial, including antibiotics and other anti-bacterial agents, has not been fully recognised by the pharmaceutical industry as a priority area. Indeed, only two types of new antimicrobials (oxazolidinones and lipopeptides) have come to market over the past 30 years. [6] Any compound in the pipeline is likely to generate low profit, at least initially, because of limited use as a last-ditch treatment. As a consequence of this failure in development, there is an urgent need to ensure economic incentives combined with innovative R&D initiatives to stimulate interest in new antimicrobials. [7] This includes the development of alternative economic and pricing models, the refinement of public-private partnerships with open access to relevant information across national borders, and, in common with all aspects of drug development, a strict oversee of data integrity and scientific honesty. [5]

PATENT POLICY
The revision of patent policy in order to make it more flexible could help to resolve the conflict between the profit motives of companies and the public interest in maintaining the effectiveness of antimicrobial therapy. Collective action with involvement of all stakeholders, including those representing pharmaceutical expertise, is necessary, as exemplified by the multilateral initiative on malaria research. [8, 9, 10] In line with SDG 3b, the provision of Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) already includes some flexibility in intellectual property (IP) regulation, allowing greater scope for countries to accommodate their own patent and intellectual property systems and developmental needs. This should go some way to de-linking R&D costs from price to be paid by health care systems. [11]

PUBLIC-PRIVATE INITIATIVES AND INCENTIVES
There are successful examples of initiatives that aim to tackle bottlenecks in R&D in addressing high-priority healthcare needs, while improving the drug development process through more efficient discovery to develop better and safer medicines for patients. [12]
The world’s largest public-private partnership in health, called The Innovative Medicines Initiative (IMI), seeks to accelerate the development of better and safe medicines for patients. IMI is a joint undertaking between the European Union and the pharmaceutical industry association EFPIA. [12] With a total budget of €2 billion – €1 billion each from the European Union and the pharmaceutical industry through EFPIA, it brings together European stakeholders to pool their resources and knowledge in a collaborative effort to address some of our most pressing and complex health issues. Set up in 2008, IMI is currently overseeing some 40 projects, dealing with issues from superbugs to cancer. The initiative is already delivering results, covering early to late stages of medicines development from biomarkers for vaccine safety to understanding chronic pain and developing anti-tuberculosis drug combinations. [12]
Collaboration is pursued within IMI by sharing data, pooling resources, and exchanging expertise, and the model should be applied more widely. [12]
IMI also includes considerations to the education of current and future pharmaceutical scientists. This is very much aligned with the SDG 9.5 to “Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries, in particular developing countries, including, by 2030, encouraging innovation and substantially increasing the number of research and development workers per 1 million people and public and private research and development spending.” Within this objective, it would be reasonable to include a sub-objectives specifically focusing on pharmaceutical scientists, so that the efforts made to reach SDG 9.5 would also lead to increased capacity in R&D in the field of health, ultimately supporting the achievement of the SDG this High-level panel is focusing on. Indeed, meeting these goals require not only a sufficient but also competent pharmaceutical sciences workforce. To reach this dual objective, FIP has set an ambitious 2 million USD programme called FIPEd to facilitate the reform of pharmacy and pharmaceutical sciences education based on locally determined needs.[13]

RESEARCH TO ENHANCE ACCESS TO EXISTING PRODUCTS
The injectable uterotonic, oxytocin, is a MNCH (maternal, newborn and child health) life-saving medicine for post-partum bleeding. Because it needs cold storage, the access to this medicine can be limited especially in lower income countries. In this context, FIP has served as a facilitator in the collaboration between the United Nations Population Fund (UNFPA) and the Institute for Pharmaceutical Sciences (MIPS) at Monash University in measuring the impact of disruption of cold storage on the safety and efficacy of injection of oxytocin. The objective was to maximise the lifetime of this medicine in developing better storage conditions in the presence of elevated temperatures. Clearly, if a product has a longer expiry date this will improve access to it, in turn improving MNCH as outlined in SDG 3. This example illustrates how research can have an impact on accessibility of existing pharmaceutical products.

BIOWAIVERS
Innovative ways should also be considered to reduce the costs and time of the development of a new medicine and its generic versions. For example, for over a decade, FIP has been working in collaboration with the World Health Organization on the concept of biowaivers, so that the in-vivo tests of bioequivalence can be waived based on dissolution tests. The application of this concept enables to preserve the safety of drugs approval while minimising the need for full in vivo or clinical investigation.

The FIP Special Interest Group on Regulatory Sciences is stimulating the development of this approach through the publication of biowaiver monographs (over 40 to date) based on literature reviews. Issues discussed in these reviews include solubility and permeability, dissolution of dosage forms, pharmacokinetics, the therapeutic use and therapeutic window of the API, data on excipient interactions and problems with bioavailability and/or bioequivalence. This project is supported by WHO and takes published guidance from WHO, FDA and EMA into consideration as well as scientific developments in this field. The collected information is critically reviewed, published in the Journal of Pharmaceutical Sciences and made available on the FIP Website (http://www.fip.org/bcs). Although the monographs have no formal regulatory status, they are accepted by medicines regulatory agencies for drug approval as they represent the best scientific opinion currently available and, as such, facilitate the availability of cheaper medicine alternatives, thereby enhancing access. [14]

ORAL ADMINISTRATION OF MEDICINES TO REMOVE BOTTLENECKS TO ACCESS
The easiest way to administer a drug is by the oral route as a tablets or capsule. However, designing these pharmaceutical products in such a way that the active ingredient is absorbed at an appropriate rate and to an appropriate extent from the gut is far from easy. More research needs to be done in this regard, to facilitate access to medicines especially in low resource settings.
The ORBITO project, [15] sponsored by the EU, is an example of a collaborative approach between academia and industry to facilitate understanding of the many factors that affect the absorption of medicines from the human gastrointestinal tract. New experimental methods and approaches using predictive computer simulation are being evaluated using the extensive data based available in the pharmaceutical industry. Crucially, the project will set up a framework to guide the use of these new tools in drug development. Several members of the FIP Special Interest Group on Regulatory Sciences participate in this important European initiative to streamline pharmaceutical development.

SYSTEMS PHARMACOLOGY MODELS
Systems pharmacology seeks to develop quantitative computational models that integrate discrete pieces of data on biomolecules, organelles, cells and tissues to predict therapeutic and toxic effects of medicines, thereby guiding the development of new medicines in making critical decisions. Importantly, it is a bridge between greater understanding of disease mechanisms and therapy and in vitro and in vivo investigation. Best practices are now in the process of elaboration. [5]

DEVELOPMENT OF GENERIC PRODUCTS FOR BIOLOGICAL PRODUCTS
The advent of patent expiry on biological drugs poses the question as to what the impact on access to these medicines will be. Central to this issue is the concept of comparability, requiring the demonstration that 2 products of the same biologic are essentially similar with regard to efficacy and safety (and quality). Comparability is usually assessed during the development of a new biological drug and also needs to be considered with regard to the demonstration of the biosimilarity of generic and reference products. However, it is widely acknowledged that current comparability techniques are not capable of characterizing biological products completely. Accordingly, the continuing challenge is to progress this assessment in preclinical evaluation involving the development of better methods to characterise the content of different products of the same compound and relevant pharmacokinetic studies in appropriate animal species. [5] In this context, access to these medicines and their biosimilars needs to be looked at not only from the IP point of view, but also from a know-how perspective.

UHC via RESPONSIBLE USE OF MEDICINES
We will not expand on the important issue of improved access and universal health coverage via responsible use of medicines, as it is not included in the focus. But we would like to stress on the fact that while many resources are invested in the development of new medicines, the issue of responsible use of medicines is crucial to ensure that the full value of these new medicines are made available to patients.


ABOUT THIS CONTRIBUTION:
Founded in 1912, the International Pharmaceutical Federation (FIP) is the global organization gathering 137 national associations of pharmacists and pharmaceutical scientists. FIP represents 3 million pharmacists and pharmaceutical scientists and in an NGO in official relations with the World Health Organization (WHO).

While this contribution has been prepared by Luc Besançon and Zuzana Kusynová, it is based on the inputs from many experts who are members of FIP.

Bibliography and References

[1] International Pharmaceutical Federation (FIP). FIP Statement of Policy on Improving Access to Medicines in Developing Countries. Cairo, 2005. [cited 2016 February 12]. Available from: http://www.fip.org/statements

[2] Deloitte. Executing an Innovation Model: Cooperation is key to competition for biopharmaceutical companies. [Online]. 2015. [cited 2016 February 12]. Available from: https://www2.deloitte.com/content/dam/Deloitte/us/Documents/life-sciences-health-care/us-lshc-open-innovation.pdf

[3] Rowland M, Noe CR, Smith DA, Tucker GT, Crommelin DJ, Peck CC, Rocci ML Jr, Besançon L, Shah VP. Impact of the pharmaceutical sciences on health care: a reflection over the past 50 years. J Pharm Sci. 2012 Nov;101(11):4075-99. doi: 10.1002/jps.23295. Epub 2012 Aug 21.

[4] Shah VP1, Besancon LJ, Stolk P, Tucker G, Crommelin DJ. The pharmaceutical sciences in 2020: report of a conference organized by the board of pharmaceutical sciences of the International Pharmaceutical Federation (FIP). Pharm Res. 2010 Mar;27(3):396-9. doi: 10.1007/s11095-009-0048-3. Epub 2010 Jan 27.

[5] Crommelin D, Stolk P, Besançon L, Shah V, Midha K, Leufkens H. Pharmaceutical sciences in 2020. Nat Rev Drug Discov. 2010 Feb;9(2):99-100. doi: 10.1038/nrd3087.

[6] Tucker G. et al. Current Challenges and Potential Opportunities for the Pharmaceutical Sciences to Make Global Impact: An FIP Perspective. 2015. Journal of Pharmaceutical Sciences. [cited 2016 February 12]. doi:10.1016/j.xphs.2015.12.001 Available from: http://www.sciencedirect.com/science/article/pii/S0022354915001811

[7] European Medicines Agency (EMA) and European Centre for Disease Surveillance in Europe (ECDC). The Bacterial Challenge: Time to React. [Online]; 2009 [cited 2016 February 12]. Available from: http://bit.ly/1JuxvlT

[8] Harrison PF, Lederberg J. The National Academy Press, Open Book: Antimicrobial resistance: Issues and Options. [Online]; 1998 [cited 2016 February 12]. Available from: http://bit.ly/1Mxd5KS.

[9] Ramanah L, Powers JH. Antibacterial R&D incentives. Nature reviews- Drug Discovery. 2011 October; 10.

[10] Butler D. Time to put malaria control on the global agenda. Natura. 1997; 386: p. 535-6.

[11] Buse K, Walt G. Global-public private partnerships: Part II. Bulletin of the World Health Organization. 2000; 78: p. 699-709.

[12] Report of the Consultative Expert Working Group on Research and Development: Financing and Coordination, April 2012, WHO. Geneva. [cited 2016 February 12]. Available from: http://www.who.int/phi/cewg/en/

[13] The Innovative Medicines Initiative (IMI). [Website]. 2016 [cited 2016 February 12]. Available from: http://imi.efpia.eu/achievements

[14] FIP Education Initiative. More information and publications: http://www.fip.org/educationreports

[15] International Pharmaceutical Federation. Biowaver monographs 2004-2012: Bringing essential medicines to those who need them most. The Hague, the Netherlands: International Pharmaceutical Federation, 2012. [cited 2016 February 12]. Available from: http://www.fip.org/centennial/files/static/press/FIP_centennialbook_biowaiver_webversion.pdf [15] Project Orbito. [Website]. 2016 [cited 2016 February 12]. Available from: http://www.orbitoproject.eu/