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Nbsapforum.netEFPIA Submission in response to CBD COP 8 DECISION VIII / 17 The contents of this paper are drawn from two seminars organised by EFPIA in 2005 and 2006. While the contents of this report remain the sole responsibility of EFPIA, we would like to thank the following for their contributions to the seminars and to this report: David Rosenberg and Marcus Dalton of GSK, Paul Denerley and Martin Todd of AstraZeneca, Axel Braun of Roche, Frank Petersen, René Amstutz and Anna Brodowsky of Novartis, and Simon Munt of PharmaMar. We would also like to thank the representatives of the European Commission and Member States for their participation. This document was drafted by Brendan Barnes and Lorraine Gallagher, EFPIA Cover Jabiru Dreamstime.com p4 Peonia p9 Pufferfishy Dreamstime.com p10 PharmaMar, SA p15 PharmaMar, SA p16 Sangiorzboy p17 Angels Gendre p19 AstraZeneca p23 Vincent Go Dreamstime.com p26 PharmaMar, SA TABLE OF CONTENTS 1 > INTRODUCTION 5 2 > UNDERSTANDING THE CURRENT RESEARCH 2.1 The current context and challenges faced by industry . . . . . . . . . . . 6 3 > THE R&D PROCESS AND ITS USE OF GENETIC 3.1 Understanding the use of Genetic Resources and the R&D process . . . . . . . 103.2 The Process of Product Development . . . . . . . . . . . . . . 113.3 Probability that Use of Genetic Resources lead to a Drug Compound . . . . . . 143.4 R&D Investment and the Need for Legal Certainty . . . . . . . . . . . 15 4 > GOOD BUSINESS PRACTICE & SUCCESSFUL PARTNERSHIP: CASE STUDIES 16 4.1 Industry codes of conduct and commitment to CBD objectives . . . . . . . . 164.2 Partnerships and Benefit Sharing . . . . . . . . . . . . . . . . 174.3 CASE STUDY 1 AstraZeneca and Griffith University, Queensland, Australia. . . . . . . . . 18 PharmaMar - Advancing Cancer Care with Marine Resources . . . . . . . . 20 Novartis - Collaboration and Collective Gain . . . . . . . . . . . . . 25 5 > MOVING FORWARD: WHAT SORT OF REGIME? 33 LIST Of ABBREVIATIONS ABS . . . . Access and Benefit Sharing
CBD . . . . Convention on Biodiversity
CNA . . . . Competent National Authority
COP . . . . Conference of the Parties
GR . . . . . Genetic Resource
GMP . . . . Good Manufacturing Practices
HTS . . . . High Throughput Screening
ICC . . . . International Chamber of Commerce
IP . . . . . Intellectual Property
IR . . . . . International Regime
IUCN . . . . International Union for the Conservation of Nature & Nat. Resources
MAT . . . . Mutually Agreed Terms
NP . . . . Natural Product
PIC . . . . Prior Informed Consent
TRIPS . . . Trade Related and Intellectual Property Rights
1> INTRODUCTION In february 2004, the Seventh Conference of the Parties to the Convention on Biological Diversity (in (COP) (Decision VII/19D)) mandated the Ad Hoc Open Ended Working Group on Access and Benefit Sharing It is through a greater understanding of the relevant issues, which includes an appreciation of the practical "…to elaborate and negotiate an international implications for the research-based pharmaceutical regime on access to genetic resources and industry, that a solution satisfying all involved benefit sharing with the aim of adopting an stakeholders is most likely to be found. It is critical instrument/instruments to effectively implement that pragmatism and practicality remain central to the [key provisions of the CBD]." The German Government (and indeed other European Any ABS framework or policy tool proposed must governments), which hosts the Ninth Conference in be evaluated in terms of its usefulness to safeguard 2008, is keen to see significant progress towards CBD objectives and its ability to facilitate access to such a regime. As a critical stakeholder in the debate genetic resources. EfPIA would like to emphasise the surrounding access and benefit sharing (hereafter fol owing regarding the position of the industry: ABS), the research-based pharmaceutical industry is pleased to respond to the call by the secretariat of the CBD to develop and promote the business case for biodiversity.
p The research-based pharmaceutical industry
fully supports the aims and objectives of the
Convention of Biological Diversity and is
committed to the sustainable use of biological This submission aims to advance the debate diversity and the fair and equitable sharing regarding how best to achieve the objectives of the of the benefits arising out of the utilization of CBD. Previous debate on the issue of access and genetic resources."1 benefit sharing (hereafter ABS) has at times been marked by a polarisation of standpoints and a lack of p Industry should be, and wants to be, involved
understanding of the practical complexities, subtleties in all stages of the development of the regime and implications of the issue. It is important that policy makers and stakeholders involved in the debate p Without research investment, there will be no
are ful y aware of what is actual y at stake for various benefits or commercial rewards to share with
stakeholders and indeed for society in general. countries of origin nor technology to transfer to those countries EfPIA considers that the contribution that pharmaceutical research could make in advancing p Companies and others who invest in research
the goals of the Convention will be put at risk if the must have legal certainty as to what is needed
International Regime is over-prescriptive or inflexible in to ensure the security of their investment. the way it deals with business. This paper, therefore, aims to increase awareness of the issues at stake from a commercial point of view and present case studies of good business practice built on partnership in order to move the discussion forward.
This document will provide an overview of the issues surrounding the use of genetic resources by the research-based pharmaceutical industry and will be divided into three main sections: Understanding the business case for biodiversity Case studies: successful and responsible busi-ness practice (iii) Moving the debate forward - recommendations
1 CBD, Article 1 2> UNDERSTANDING THE CURRENT RESEARCH ENVIRONMENT 2.1 THE CURRENT CONTExT AND CHALLENGES fACED BY INDUSTRY Research using natural products
Anti-Cancer Agents Natural products have a strong track record as Paclitaxel (TAXOL) Roots of the bush Taxus pharmaceuticals. In times when scientific capabilities were more restricted, they were the main source of Vincristina (ONCOVIN) Leafs of Catharanthus roseus new pharmaceutical concepts. One study suggests that over 42% of the 1184 new chemical entities that Irinotecan o CPT-11 Leaf of the plant Camptoteca reached the market over the last 25 years have their origins in nature (Newman et al, J. Nat. Prod, 2007). Etoposido (VEPESID) Roots of the plant The full analysis in the paper classified the source of all New Chemical Entities as follows: Bacterium Streptomyces All new chemical entities, 01/1981-06/2006,
Many believe that molecules isolated from natural by source (N) 1184).
sources often contain structural features that are outside the scope of combinatorial or synthetic medicinal chemistry, for example they are often larger, more rigid and more chirally complex (Feher M. and Schmidt J.M., J. Chem. Inf. Comput.Sci.43, 2003). Such novel chemical structures often result in new modes of action and open up the potential of new ways to treat cancer and other diseases.
Despite this, the attraction of using natural products for pharmaceutical research has diminished within B . . . Biological the industry. Within modern drug discovery, natural N . . . Natural product product approaches have been deprioritised by the ND . . Derived from a natural product and is usually a industry (Koehn and Carter, Nat. Rev. Drug Discov. 4, S . . . Totally synthetic drug, often found by random 206, 2005). Concerns include: screening, modification of an existing agent S* . . . Made by total synthesis, but the pharmacophore is/ p Discovery timelines - typically slower than synthetic was from a natural product NM . . Natural product mimic p Sourcing logistics - scientific or political hurdles make many species inaccessible One of the most valuable contributions of the above p Reproducibility - organisms change their chemistry survey is that it highlights very clearly that, although with season, age, etc a very limited number of natural products are actually approved as medicines, natural products make a much p Identification - complex extracts containing many wider contribution to the research process as a whole.
nuisance compounds This track record is even stronger in cancer, and well- p Production - about 80 % of natural structures are known examples include Taxol (from the roots of the intractable to synthesis, and large-scale production bush Taxus brevifolia) and Doxorubicin (produced by the of most is impossible.
bacterium Streotomyces peucetius). These examples, and many other examples of commercial medicines in Important technological changes underlie the shift in other therapeutic areas, attest to the value of naturally research strategies and this has created competition derived molecules in medicine.
between different research strategies. The overall Reasons for the decline in pharmaceutical industry natural products research
in the last decade2
1. Introduction of high-throughput screening against defined molecular targets
(and the move from natural products extract libraries to ‘screen-friendly' synthetic 2. Development of combinatorial chemistry, which appeared to offer more drug-like
screening libraries of wide chemical diversity; 3. Advances in molecular biology, cellular biology, and genomics, which increased
the number of molecular targets and prompted shorter drug discovery timelines; 4. Declining emphasis among major pharmaceutical companies on infectious disease
therapy, a traditional strength of natural products; 5. Possible uncertainties with regard to collection of biomaterials as a result of
the Convention on Biological Diversity.
effect has been to place the understanding of resources and their efforts to ensure ABS compliance, disease at the centre of research to a greater degree namely the following: than before.
(a) Incomplete frameworks at national level Advocates of natural products research will point to the (b) Legal uncertainty and inconsistency historical track record and the low current productivity of the pharmaceutical R&D and argue that these changes have not brought positive results. Others will 2.1.1 Incomplete frameworks at national level
argue the contrary. Where there is consensus is that pharmaceutical R&D is a socially vital but difficult and complex process, which largely depends on the legal The regulatory framework for industry working with and regulatory environment for its viability.
genetic resources and ABS is far from comprehensive. Following the entry into force of the Convention Unfortunately, the post-CBD regulatory environment of Biodiversity in 1993, the adoption of the Bonn has not been a positive influence and it is easy to Guidelines in 2002 was designed to accelerate the conclude that the overall effect has been to deter implementation of ABS provisions. However, out of exactly the type of research that the CBD should the 188 Contracting Parties to the CBD, only 26 have promote. 15 years after the signing of the CBD, which adopted ABS laws and procedures and these existing originally aimed to create simple, workable legal and ABS measures are often ‘sectoral and patchy'.4 regulatory frameworks for ABS, providers and users of genetic resources are ‘increasingly estranged, and Where laws exist, they may not be adequate. A the environment in which bio-prospecting takes place 2005 report on the commercial use of biodiversity is often characterized by misunderstanding, mistrust, commissioned by the secretariat of the Convention and regulatory confusion'.
for the Ad Hoc Open-ended Working group on ABS5, concluded that there remain many gaps in national This section will highlight some of main challenges legislation despite the explicit aims of the 2002 Bonn faced by industry regarding the use of genetic Guidelines. These gaps pose significant challenges 2 Koehn, FE and GT Carter (2005), The Evolving Role of Natural Products in Drug Discovery, Nature Reviews, Drug Discovery, vol 4, March 2005. 3 Laird, S & Wynberg, R (2005): The Commercial Use of Biodiversity: an update on current trends in demand for access to genetic resources and benefit-sharing, and industry perspectives on ABS Policy and implementation - UNEP/CBD/WG-ABS/4/INF/5, page 5. Report commis- sioned by the CBD for the fourth meeting of the Ad Hoc Open-ended Working Group on ABS - available here 4 Ibid., p.36, 5 Ibid. for industry wishing to negotiate ABS with a provider invention if an incorrect determination is made. country and must be addressed in any discussion These barriers are more than sufficient to make a regarding a potential ABS framework. Likewise, a scientifically valid research strategy commercially gap analysis is vital to establish what is needed in order to fill the gaps at national level highlighted in There are three areas in particular, where legal the following points: certainty is lacking: p The 2002 Bonn Guidelines recommend that each (i) The nature of the material subject to regulation country designate a competent national authority
(ii) Requirements regarding in-situ and ex-situ ma- (CNAs) or national focal point for ABS. Most
countries have yet to designate or clearly define the (iii) The nature and regulatory treatment of "deriva- tasks of CNAs, and industry regularly experiences difficulties locating government officials that can clearly explain and authorise access to genetic Each of the issues highlighted below, and several resources (GR) for collections and research.
others, need to be carefully addressed in devising national access and benefit laws and the international p Many governments remain ill-informed about the
regime, which the Ad Hoc Open Ended Working Group scientific and commercial realities of bio-prospecting is mandated to elaborate.
and industry often faces undue bureaucracy and delays before receiving permits; p Without implemented regulatory regimes, it is (i) Nature of the material subject to regulation
effectively impossible to prove compliance in many
The meaning of terms such as ‘genetic resources' and ‘biological resources' is not clearly or adequately p There is often a lack of "political will" within
addressed in national legislation and in proposals governments to improve this situation and industry for a disclosure requirement. In addition there is a may often face unrealistic expectations and need to distinguish between human and non-human excessive transaction costs.6
Some other unanswered questions regarding genetic 2.1.2 The need for legal certainty
p Would an international regime include only GRs or a Given that allocation of significant resources is broader class of "biological resources"? needed for any R&D investment, ensuring a secure p Will human GRs be excluded? investment is paramount for industry. In the field p Will non-human GRs found in humans be excluded? of natural product research, the legal framework at e,g. concerning HIV, H5N1 virus, malaria parasite national level is often inadequate and, as underlined p What is "associated traditional knowledge"? above, the tendency has been to explore other forms Each of these issues, and several others, will need of research, which involve natural products to a to be addressed as part of the process of building an lesser extent. Those who do use natural products International Regime. for research are faced with many challenges in understanding the nature of any national legal obligations, e.g. the inconsistent and variable use of core concepts, which may render it impossible for (ii) Requirements regarding in-situ and ex-situ
a potential developer or user of genetic resources to know if the ABS requirements in force in any particular country have been met.
Regarding the definition of ‘origin' there appears to be various interpretations, including both in-situ and ex- Researchers are left to guess whether obligations situ sources.
they are subject to are satisfied in each country because requirements are often opaque and Many genetic resources, some of which may be imprecise. Many applicants face increasing valuable for pharmaceutical research, have long since delays, fines, or even loss of the right to patent his been removed from their original natural environment 6 Mathur, E, C Constanza, L Christoffersen, C Erickson, M Sullivan, M Bene, and JM Short (2004), ‘An Overview of Bioprospecting and the Diversa Model', IP Strategy Today. No 11 - 2004, 1 -21.
(examples include vectors, plasmids, cell lines and scenario, a genetic resource is used as a tool in the other genetic resources that have been used for development process but the final product does not decades). Many have become commodities or staple incorporate a genetic resource.
commercial products in the trading system.
National laws and any international regime must National laws, and any international ABS regime, must clearly define the nexus between the end product and address how such materials are to be dealt with.
the genetic resource, which triggers legal obligations in order to ensure legal certainty for any user of genetic resources. In addition, in order to comply with the (iii) The nature and regulatory treatment of
CBD, this should be done in such a way as to facilitate access for environmentally sound reasons. Potential scenarios, which highlight the need for such clarity, The CBD seeks to promote the "fair and equitable are presented in the Annex 6.3.
sharing of the benefits arising out of the utilisation of And to the extent that any legal obligations will have an genetic resources". impact on trade in genetic resources and "derivatives" Products "arising out of the utilisation of genetic (however defined), the number of transactions that resources" are commonly referred to in the debates might be affected must be considered. The number of as "derivatives".
transactions involving materials that incorporate GRs - including legal transactions (trading) and functional National laws and any international regime need to transactions (use) - runs into many millions per day, address whether and how to define, and whether and every day. If derivatives (however defined) are included, how to regulate use of and trade in, "derivatives" and, the numbers of legal and functional transactions are in doing so, the practical effect of decisions on such multiplied. Indeed, every time a loaf of bread or bottle issues must be appreciated.
of wine is purchased, a legal transaction occurs using a derivative of a GR.
It must be acknowledged that, taken literally, derivatives could include such things as loaves of bread and bottles In the face of these multiple uncertainties, EFPIA of wine as each "arise(s) out of the utilization of genetic believes that an understanding of the pharmaceutical resources". Is it really intended that national laws and R&D process is crucial in order to increase any international regime should regulate the sharing comprehension of what is at stake and to counteract of benefits made by those who manufacture and sell unrealistic expectations and misguided claims that wine or bread. If not, what should and should not be a particular genetic resource has directly led to a final product with commercial value. The reality of pharmaceutical R&D is much more complex than is It is vital to consider carefully the nexus or connection commonly appreciated. The next section of this paper that is needed between the final product which deals with the R&D process. Readers are encouraged generates commercial value and a genetic resource to recognise both the role that natural products can that might have been used in the development process play in R&D, but also the role of other inputs.
that must exist to trigger any obligation under national law or an international regime. At one end of the spectrum of possible uses of genetic resources is the use that the CBD was intended to capture. Such a situation arises when a genetic resource - for example, a leaf - is obtained from a CBD member, a compound is isolated from that leaf and the compound - without modification - becomes the active ingredient in a drug.
At the opposite end is the situation in which a company uses purely synthetic mechanisms to develop novel small molecule compounds, but tests the utility of those compounds with commonly available or staple genetic resources, such as cell lines. Under such a 3> THE R&D PROCESS AND ITS USE OF GENETIC RESOURCES 3.1 UNDERSTANDING THE USE Of GENETIC RESOURCES AND THE R&D PROCESS Among providers and users, one notes that there p Uses of GR and derivatives by the pharmaceutical
exist radically different understandings of the value of genetic resources to commercial product discovery and development7 and indeed one of the greatest The following list highlights the main possible uses challenges regarding ABS is to match expectations of of GR in the R&D process, which is subsequently value with commercial realities. In this regard, it is vital that the following key points are understood about v Use of GRs/derivatives as a starting point in devel- the nature and complexity of the R&D process: oping active compound(s) p Not all "uses" of a genetic resource (GR) are driven
v Use of GRs/derivatives as elements of vaccines by a commercial motivation. Many researchers
v Use of GRs/derivatives as inactive parts of final never intend to use accessed genetic resources to develop commercial products. In such situations, v Use of GRs/derivatives as a tool in the research uses of genetic resources could occur that would yield "benefits" - including scientific knowledge - that could theoretically be shared with the country v Use of GRs/derivatives as a tool in the production of origin. Yet, the uses will not be linked in any way to a commercial exploitation. Some uses of GR with As the rest of this section will highlight, the value- a commercial purpose and value will be kept secret creation chain from GR to final product generally and will not be published. This might be the case with involves a number of diverse steps and players and, a particular mixture of herbal medicines. In other indeed, there may be numerous transactions from GR cases, many years may pass between the initial work to consumer.
on developing a product and any commercialisation.
p Very few uses of genetic resources will ever
directly result in a commercial product. Typically,
many thousands or even hundreds of thousands of samples must be screened to identify potential leads for investigation. Once identified, those leads rarely yield compounds that merit serious investigation, fewer still yield compounds that possess attributes that could merit the filing of a patent application and even fewer lead to a commercial product.
7 Laird, S & Wynberg, R (2005), op cit. note 6 3.2 THE PROCESS Of PRODUCT DEVELOPMENT Step 1: Target Identification
the symptoms of disease. In this approach, natural products and traditional remedies were significant because they provided evidence of treatment and Target Identification is the first formal stage in effect. The modern approach is inherently more direct, the Drug Discovery and Development process. To since it addresses itself directly to the nature of the understand what is involved, imagine a disease as a disease though that too presents its own challenges.
series of physical events that ultimately lead to the disease showing its outward symptoms. Each step is a The sort of issues in the scientist's mind are to find molecular event with its own specific characteristics. a point of intervention that will be specific to the disease, but will not affect other metabolic processes that might be affected by the same chemical pathway. Drug Discovery anD Development
Natural products and traditional knowledge can play a role here. Research based pharmaceutical companies 1. Target Identification
have to choose strategies to reduce the overwhelming What we need to achieve in this phase: number of potential avenues of research. Opinions vary ✓ Identify a link to disease in animals within the industry, but for some companies, the use of particular plants and traditional remedies is still a ✓ Link a biological mechanism (target) to a key biological process useful way of discovering original compounds and of Enzyme, receptor, ion channel, ion pump directing the search for effective medicines.
✓ Identify a link to disease in animals ✓ Identify a link to disease in man The output from this stage is an idea about how a ✓ Select a target balancing effect vs. risk diseases process might be modified. Typically, this will lead to the isolation of a molecule or part of a molecule existing in the body, which is implicated Lead Lead opti- Concept Devt for tenance and Life in the hypothesis. Many molecules in the body are Ident Ident misation Testing Launch Launch Cycle Support extremely large. The target may be a very small part of the molecule that is thought to be key to the molecule's role in disease. The action of the target Each step produces some biochemical change in the may be modified through pharmaceutical intervention. human body. There are many such processes going on The search then turns to whether other molecules can in the body at any point - repairing damaged tissues, be found which will interact with the target, since any maintaining functioning, etc. The disease-creating drug must interact with the target if it is to be effective. steps may only differ in quantitative terms, for example Chemicals, which interact with the target are known when the body is producing too much or too little of an essential enzyme. Alternatively, the change may lead to wholly detrimental changes, as would be the case with the steps leading to the proliferation of tumour Step 2: Hit Identification
A target is a point of intervention in the sequence of A modern pharmaceutical company will attempt molecular events that lead to disease. Imagine a chain wherever possible to preserve and develop its of fifty people of varying types, who are asked to pass a piece of paper from one to the other and each add one word to the paper while remaining grammatical. rug Discovery anD Development
The input of one of the fifty people might be considered as a target for intervention with the aim of modifying 2. Hit Identification
what is written on the paper when it reaches the end What we need to achieve in this phase: of the chain. Not only is the contribution of the target ✓ Identify chemicals that interact with target changed, but so is everything downstream.
✓ Develop test systems to measure effect Target Identification is based on the company ✓ Screen mil ions of compounds for potency and selectivity- scientist's knowledge and intuition about the pathways compound libraries,natural products (peptides, products of individual diseases. Advances in the number of from fungi, bacteria, animals, humans, plants), natural research tools available to scientists mean that it is product fragments increasingly possible to understand these pathways at a molecular level. This can be contrasted with a more Target Lead Lead opti- Concept Devt for traditional approach where product development Ident Ident misation Testing Launch Launch tenance and Life relied on observation of the effects of substances on knowledge base concerning biochemical interactions. Modern technology has enabled companies to present Knowledge of what doesn't work can be as important to these libraries for screening in a highly efficient way. a scientist as what does work. It has become popular to Companies also need to prepare appropriate test think of the interaction between a drug and the target as systems to ensure that the results of the screening a lock and key. The analogy is a good one for explaining exercise can be used to take clear decisions. Assuming the end of a successful development process. At the that the screening process produces some hits, these beginning of any process, the companies have their will then provide the raw material for the next stage, collection of keys - usually over a million of them. but it is often the case that the "hits" are sufficiently Some look like they should work given ideas about diverse in their structure and in the degree of affinity certain locks, others have worked in the past, others that they show for the target, that the researchers do are known not to work reliably, but can provide useful not have an ideal therapeutic molecule so much as a information on what would work.
series of clues about what such a molecule might look like. Not all screening exercises deliver the expected As well as physical "libraries" of these compounds, results. This stage of the process may trigger re- companies have accumulated knowledge of their evaluation of the underlying hypothesis - an iterative chemical behaviour, which is carried both in the heads aspect of drug research that continues through later of its researchers and in the companies' records of past discovery efforts. Every researcher carries his/her own library of hypotheses and knowledge, which may of course include knowledge of traditional remedies. Step 3: Lead Identification
In addition to their own resources, companies may source external libraries of compounds that they consider potentially relevant to the hypothesis about The Lead Identification process narrows the field. the target. These libraries may contain genetic The molecules that have shown affinity for the target resources or compounds, which have been produced can now be more closely examined. Nevertheless, it using genetic resources in some way.
is important to address a common misconception that the screening process identifies a preferred The composition of the libraries used differs between lead molecule, which then goes into development. It companies. Complete randomness is avoided. The is rather the case that researchers start with a brief construction of the library is a knowledge-building to identify molecules, which could lead to successful process aligned with the companies overall research medicines. The Lead Identification process provides strategy. One company may include a significant vital input, specific to the hypothesis at hand. Hence, number of biological molecules and genetic close attention will be paid to better understanding resources in its libraries. Another may consider the nature of the interaction between lead and target. that, in light of the well-established challenges This may be particularly important if, for example, the in turning such molecules into medicines, they target molecule is relatively large.
prefer to limit the library to synthetic derivatives of key fragments of such molecules, which have However, there is another input to Lead Identification been modified to align them more closely with the through which the researchers bring a range of design size and structures familiar to existing medicines. These choices are the essence of competition in a knowledge-based industry. For companies that are Drug Discovery anD Development
more heavily engaged in research involving GRs and their derivatives, it is likely that the starting point 3. Lead Identification
will have been an insight regarding the properties What we need to achieve in this phase: of a plant, organism or traditional remedy. For these companies, it is necessary to take the starting ✓ Design compounds with multiple properties Potent – at selected biological target material, which will usually contain hundreds of Selective – predicted and measured different chemicals, and identify those active in Risk free structures toxicity – predicted relation to the disease in question. However, even for Risk free structures – absorption/metabolism these companies, it is highly likely that the molecules Chemical y attractive for synthesis identified would become the basis for a specific synthetically-designed sub-library for screening, rather than being tested alone. As in many other Lead opti- Concept Devt for instances, the interaction between material covered Ident Ident misation Testing Launch Launch tenance and Life by CBD and human intervention is complex.
Step 4: Lead Optimisation…and beyond
Drug Discovery anD Development
Lead optimisation introduces a greater level of specificity regarding the required characteristic of a 3. Lead Identification
medicine. It is also the first time that the lead compound We carry out chemical design to produce leads based on is used in animal studies. Prior to this, the only evidence mil ions of fragments of information, hit screening, drug prop- that the company can have of effectiveness has been erties, competitor patents, physical sciences, safety sciences. gained in artificial circumstances. The behaviour of a This is our core skill and one of our key IP steps.
large organic molecule in isolation may be different from its behaviour in a functioning organism. These early animal tests are the only way that the researchers can assess the specificity of action of the compound (does it affect only the target or the target and several other related molecules, which may have different and Lead opti- Concept Devt for tenance and Life important functions in the body?). They also provide Ident Ident misation Testing Launch Launch Cycle Support an opportunity to examine how the lead compound is absorbed, metabolised and excreted in an organism. parameters to bear on their challenge. Many of these By this stage, the company has made the fundamental parameters are predictive in the sense that they are choices about the chemical structures, which it is to based on accumulated knowledge of the characteristics pursue. It is unlikely that the lead compounds include of successful medicines. The parameters are a mixture naturally-derived products, but it is possible that of generally accepted principles (e.g. that structure X such products will be used as tools in the process of is toxic) and company-specific guidelines.
identification and optimisation.
Regarding the role of materials relevant to the It also important to emphasise what the company does Convention on Biological Diversity, it is possible that not know. It does not know if the preferred compound the molecules of interest identified in the previous will be effective or safe in human subjects, nor stage are derived from genetic resources. This is what dose will be required to produce a therapeutic highly likely if the company has a commercial niche, effect. As this shows, the knowledge-development which depends entirely on identifying biologically- process is far from over when the process of chemical active and naturally-occurring molecules.
manipulation is finished. From this point on, the use of natural products (if any) is likely to be limited to their However, the need to design a drug is paramount. As use in bulk production of precursors of the medicinal a result, for many companies, regardless of how the hits were sourced, this is the point in the research process at which interest in such "natural" materials is Patenting will normally have taken place by the time replaced by a focus on molecules, which offer greater that lead compounds have entered lead optimisation. certainty regarding safety and ease of manufacture.
Though multiple uncertainties regarding commercial return still surround the lead compounds, unless the company has secured the rights, it will have no commercial basis to take the molecule(s) into further Drug Discovery anD Development
4. Lead Optimisation
Quite aside from the progress of the specific research projects, the knowledge development process will What we need to achieve in this phase: continue in parallel. Some of the results of the ✓ Design a compound with required profile research will be disclosed through publication in Potent at selected target scientific journals, while internally within the company, Selective for target mechanism knowledge acquired through the process will feedback into other relevant projects.
Safe in short term animal tests Lead Iden- Concept Devt for Ident Ident tification Testing Launch Launch tenance and Life 3.3 PROBABILITY THAT USE Of GENETIC RESOURCES LEAD TO A DRUG COMPOUND While the previous section has traced the steps of R&D, it is also vital to understand the truly minute From leaD series to market
probability that a natural product will contribute to drug discovery and to underline the enormous failure rate involved in drug research and development. In the following diagrams, a hypothetical, but typical Typical result of lead optimization:
scenario is presented. Starting first with the company's ✓ Synthesis of 10'000 analogues collection of compounds that are normally screened ✓ Max. 1 lead series fulfill criteria (High Throughput Screening - HTS) for activity with the ✓ Max. 1-2 compound(s) fulfill criteria for ✓ Final y selected compound incorporates From Hts to leaD series
various structural elements that were not present in HTS hits 700‘000 compounds (incl. 2000 natural products) Typical result of Clinical Development:
Typical result of high throughput screening
✓ Only 1 out of >10 compounds that enter development reaches the market.
✓ Not all compounds that are launched are profitable ✓ 500 compounds identified as actives ("hits"),✓ Grouped in 20 clusters ate', For example, let us say that the company has past Typical result of filtering of HTS hits1:
experience which leads it to be concerned about the toxicity ✓ Only 1-5 clusters selected to explore of "tin". It is believed that the active element of the lead is ✓ Synthesis of 50-200 analogues (= "lead "ate", which is unfortunately chemically unstable. The lead optimisation strategy is to identify a range of candidates, all of which must be between 5 and 9 letters in length, Typical result of lead generation:
not include "tin" and all of which must contain a structure ✓ Only 1-2 hit cluster full fill lead series very similar to "ate" somewhere. As indicated above, in all likelihood, the optimum development candidate will be completely different from any of the hits identified in filtering criteria: chemical tractability, selectivity, PK, pys. chem. prop.
2 lead criteria: similar to filtering criteria, but more stringent.
the screening process. The major difference between compounds and words is that there is no finite dictionary of compounds. The only limit is human ingenuity.
target, we can see that approximately only 2000 of a total library of 700,000 are of natural origin. The rest of the slide describes how hypothetical results of the initial screening are further refined resulting in two p Probability that a compound in the library is the lead series.
starting point for a lead series is in the range of 1/350'000 - 1/700'000 (cf. 2 lead series from a HTS.) The next steps of this hypothetical scenario are illustrated in the slide From Lead Series to Market. In p Probability that such a compound is a natural this example, two clusters of molecules are selected product: considerably lower due to usually very low as the basis of lead optimisation. The chemical chemical tractability; i.e. less than 1/1 Mio.
characteristics of these clusters are analysed and p Probability that no lead optimization is required for a a set, a so-called ‘library' of 10,000 analogues8 is natural product: best guess 1/1000.
created. All of these molecules are new creations. They have never been described before, and with an p Probability that a development compound originating extremely high probability, they never existed on our directly from a natural compound reaches the market: planet before.
even lower due to the general attrition rate during clinical development, i.e. less than 1/10,000 Mio.
To illustrate the optimisation process, imagine this as p Taking the number of natural compounds ( 2000) creating a library of words. It may be that lead Identification in the library into account: the probability that a produced the word "procrastinate", which showed affinity development compound, originating directly from for the target but is considered too large to be a feasible the collection of natural compounds, reaches the compound to take into development. The company can market: in the range of 1/10 Mio.
make certain other assumptions about ‘pro-cras-tin- 8 Analogue: a chemical compound that is structurally similar to another but differs slightly in composition 3.4 R&D INVESTMENT AND THE NEED fOR LEGAL CERTAINTY The business case for biodiversity can only be understood if the R&D process (as described earlier) is understood as a commercial venture, where choices are made regarding the allocation of resources and the likely returns on investment. Risk calculation is a fundamental factor influencing decisions regarding the investment of resources and companies who invest in research must have maximum certainty in order to ensure the legal security of any investment. Likewise, legal risk should be minimal and legal certainty must There are many common misunderstandings regarding the actual value of genetic resources for R&D. There is no straightforward means by which the association can be made. The industry argues that that the diversity of possible contributions, coupled with the overarching objective to promote responsible research, renders a detailed taxonomy of "nexus" both impractical and unnecessary. Higher expenditure and greater risk associated with drug development compared to drug discovery, coupled with the low probability that any one GR sample will lead to a commercial product9, are two such issues that are poorly understood. In addition, the internal competition between genetic resources research programs and other research programs within companies is often poorly appreciated10.
9 Laird, S., Wynberg, Rl, op.cit., note 6. It is estimated that one in 10,000 samples makes it into a commercial pharmaceutical product, and Cragg et al (in press) estimate that less than 4% of patented pharmaceutical drug candidates become commercial drugs. 10 Kaiser, R, 2004, Ibid. As one researcher said of bioprospecting for fragrances: "…if it becomes too difficult to do this research from a legisla- tive perspective then it will stop, which would be a terrible shame." 4> GOOD BUSINESS PRACTICE & SUCCESSFUL PARTNERSHIP: CASE STUDIES Successful progression towards an effective and fair system of ABS, while facilitating innovation will depend on the understanding of various issues. As a critical stakeholder and user of genetic resources, the research-based pharmaceutical industry can contribute its knowledge, experience and skills and hopes that this submission will further the discussion in with a view to ensuring both access and benefit sharing of genetic resources. The research-based pharmaceutical industry is committed to working in partnership with all stakeholders in order to find a solution that is accepted by all and which will promote the CBD objectives, enabling a sustainable and beneficial use of global biodiversity. This section p Introduces industry regulatory approaches p Identifies the benefits that have been derived from existing partnerships and, p Describes some important real-life examples 4.1 INDUSTRY CODES Of CONDUCT AND COMMITMENT TO CBD OBjECTIVES Following CBD negotiations, the 1. Guidelines for IFPMA Members on Access to Ge-
netic Resources and Equitable Sharing of Benefits
shown itself to be committed to the Arising out of their Utilisation11
objectives of the Convention and has worked to encourage best practise. 2. Guidelines for BIO Members engaging in Bio-
Evidence of the industry explicitly prospecting as defined by the biotechnology
aligning policy and practice with the three objectives of the CBD is found in two relevant code of conducts, which aim to encourage best practice and ensure equitable sharing of benefits among industry.
INDUSTRY COMMITMENT TO RESPONSIBLE ACCESS & BENEFIT SHARING (ABS)13
1. To obtain prior informed consent (PIC) to the acquisition and use of genetic resources controlled by a
country / indigenous people and provided to the company in accordance with local law.
2. In obtaining PIC, to disclose the intended nature and field of use of the GR
3. To gain necessary approval to remove materials found in situ, and to enter into formal contractual benefit-
sharing agreements reflecting the MAT on the use of the GR obtained through that removal. These agreements may contain conditions on permissible uses of the genetic resources, transfer of the genetic resources to third parties, and appropriate technical assistance and technology transfers.
4. To respect existing use(s) of the genetic resources in the manner it has been used in the source or any
5. To agree that any disputes as to compliance with the clauses contained in formal contractual benefit-
sharing agreements are dealt with through arbitration under international procedures or as otherwise agreeable between the parties.
11 IFPMA Guidelines are available at: http://www.ifpma.org/pdf/ABS_Guidelines_26Jan07.pdf12 In June 2005 BIO, the world's largest biotechnology industry association issued Guidelines for Bioprospecting for its members (www.bio.org/ 13 Taken from Guidelines for IFPMA Members on Access to Genetic Resources and Equitable Sharing of Benefits Arising out of their Utilisation 4.2 PARTNERSHIPS AND BENEfIT SHARING Pharmaceutical companies see benefit sharing as an used to develop blockbuster drugs is simply false and integral part of business and as the following case misleading. Most industries products rarely, if ever, studies will underline, partnership with provider achieve this status16. However, what is realistic is countries and institutions is the most common model the enjoyment of potential benefits by both user and for genetic resource use by the pharmaceutical provider as the following list shows: industry14. By developing partnerships with source country institutions mutual benefits are enjoyed by both the user and provider and ABS negotiations are Benefits for companies
generally much more fruitful.
Through partnership, numerous benefits for both p Enables companies to access local expertise and parties are made possible. Depending on the case in resources in areas question, benefits to the provider country or institution may be both monetary and non-monetary and could p Greater insurance to companies that the resources include the following examples: they access are legally obtained p Research capacity may be built more affordably in provider countries p Assistance with local bureaucracies and national PIC requirements17 Milestone payments Royalties on net sales Research exchanges Licensing agreements Supply of equipment Benefits for provider country institutions
Technology transferJoint publications15 p Oversight of the collection and use of genetic Importance of non-monetary benefits
p Construction of scientific and technological capacity for research in provider country As highlighted in the UNEP study, groups with the most experience in benefit sharing, stress the importance p Technology and knowledge transfer through of non-monetary benefits and ‘front-loading' benefit- scientific collaboration sharing packages. ‘Front-loading' benefit-sharing packages ensures that provider countries receive p Exchange opportunities to work and train in the user a stream of benefits through both the discovery and development phases.
p Greater opportunity to monitor the ways samples As highlighted in section two of this document, are collected and used, i.e. companies often do not the probability of any one partnership yielding a need to go back to providers to re-collect promising commercial product based on genetic resources is truly minute, and likewise the chance of GR-based products generating royalties is extremely small. The p Employment opportunities for scientists to work and simplistic claim that genetic resources are widely learn in their home country and stem brain drain 14 Laird, S & Wynberg, R (2005), op.cit., note 615 As part of their roughly 125 agreements since 1993, the ICBGS (International Co-operative Biodiversity Groups) have provided formal training for 2,800 individuals from 12 countries, with 90% of these from developing countries. Associated with training and research efforts, a sub- stantial amount of equipment and infrastructure enhancement for both US and developing country institutions is carried out, and capacity- building to undertake research. Other benefits address the direct needs of collaborating communities, and include water tanks, fencing for gardens, shade cloth, boats, and refrigerators (Rosenthal and Katz, 2004 - In Laird & Wynberg (2005)). 16 As noted in Section 2.1, even within the pharmaceutical industry, companies are moving away from the ‘blockbuster' model to smaller niche markets with still significant sales (Lewis et al, 2005-In Laird & Wynberg (2005)). 17 The US National Cancer Institute (NCI), for example, found that it is most effective for local partners to obtain all necessary permits and PIC from relevant government authorities as well as local communities (Cragg et al, in press - - In Laird & Wynberg (2005)). ASTRAZENECA AND GRIffITH UNIVERSITY, BRISBANE, QUEENSLAND, AUSTRALIA AstraZeneca is one of the world's leading the active ingredient(s) and identify the chemical pharmaceutical companies with over 12,000 people working on the Research and Development of new medicines for treating human health. AstraZeneca The active ingredient is usually not suitable to develop scientists investigate new treatments for cancer, as a medicine but is a lead for creating different infection, pain and cardiovascular, respiratory, chemical structures for extensive pharmacological inflammation, gastro-intestinal and central nervous system diseases as well as others.
Since the collaboration commenced, the Natural Griffith University, Brisbane and the Queensland Product Discovery laboratory has tested over 35,000 State Government entered into an agreement with specimens from plant and marine environments. These AstraZeneca in 1993. This set up a Natural Product specimens have been collected via contracts with Discovery laboratory in Brisbane; specifically the Queensland Herbarium and with the Queensland located to take advantage of the intellectual strength Museum as well as from other sources.
in Brisbane and the proximity to the unique natural environment of Queensland - the rainforest and reef. Australia is one of the twelve mega-diverse countries Benefits for Griffith University,
and is a party to the Convention on Biodiversity.
Queensland and Australia
The agreement was set up in compliance with the Biodiversity laws of the State of Queensland and The agreement and associated funding has established the Australian Federal Government18. These laws a world-leading research facility in the area of encourage the Conservation of Biodiversity and natural product discovery. This facility has lured the sustainable use of natural products, and they several leading Australian researchers back to their further encourage Access and Benefit Sharing. Some general principles include: p Give effect to CBD & other international obliga- p Facilitate ecologically sustainable access and usep Enable fair and equitable sharing of benefitsp Ensure use of traditional knowledge undertaken with cooperation and approval of holders of such p Enhance biodiversity conservation and valuep Facilitate continued non-commercial researchp Integrated into biotechnological development poli- cies and strategies Under the agreement, Griffith University retains Natural Product Research Institute, Brisbane. intellectual property rights with AstraZeneca having the first right to develop a product arising from the collaboration. Sale of any resultant product would These researchers have maintained contact with lead to a royalty for the University. AstraZeneca has global developments in pharmaceutical research, placed more than A$120 million funding into Griffith not only through their academic contacts but through University since the collaboration started.
very close interaction with research scientists of many different scientific disciplines throughout AstraZeneca. The Natural Product Discovery laboratory collects These interactions maintain Australian knowledge of specimens from the Queensland rainforest and cutting edge science.
from the Great Barrier Reef. These specimens are then screened at the laboratory against a wide Over 50 people work at the Natural Product Discovery variety of medicinal targets using High Throughput laboratory and their general knowledge and skills feed Screening (HTS). If a specimen shows an interesting into the Australian academic community. Technology result, the chemists at the laboratory then isolate transfer is enabled. The work of the Natural Product 18 Australian Federal and State Government Biodiversity policies, available at: http://www.environment.gov.au/biodiversity/science/access/ Discovery laboratory directly supports the collecting has added different and diverse approaches to facility of the Queensland Herbarium and Queensland AstraZeneca's drug discovery over the years of the Museum, as well as supporting other suppliers.
The difficulty of drug discovery, selecting a promising Benefits for Biodiversity
molecule for development and then taking that molecule successfully through development has meant that to date, although the collaboration has The laboratory has over 35,000 specimens in its been very successful, no new drugs arising from this library. The vast majority of 7,500 marine specimens collaboration have been developed to the market have been collected in Queensland and represent about 4,000 species, the majority of which are new.
Many of these specimens and organisms are totally new to science. The work of the laboratory has led to a massive expansion in knowledge, especially of marine This collaboration between AstraZeneca, Griffith University and the State of Queensland builds on Australia's strong intellectual and academic p Phylum Cnidaria - soft corals, gorgonians, jelly- prowess, its unique natural environment and the Government's policy on implementing the p Phylum Porifera - sponges Convention of Biodiversity. The collaboration has p Phylum Chordata - tunicates, ascidians strengthened Australia's scientific base and has p Phylum Bryozoa - moss animals, lace corals given AstraZeneca a wider scope in drug discovery The laboratory has amassed a large biota library.
efforts. Finally, the collaboration has stimulated and has enabled a greater understanding of the The work of the laboratory and the Museums has led natural environment, including the discovery of to a much greater understanding of the biodiversity of many new marine species. Queensland, such as in distribution of plant species and, in particular, in the biodiversity of the Great Barrier Reef. This knowledge of marine biogeography and mapping of the ‘hot spots' of biodiversity over the years is of great benefit for active management of the Reef for future generations. Benefits for AstraZeneca and Medical Science
The Research and Development of a new medicine is a long process involving hundreds, if not thousands, of skilled scientists (chemists, biologists, pharmacists, doctors, etc). It can take 15 years from idea to market with the first few years spent investigating the idea and the last 8-12 years spent developing a specific molecule through the scientific, safety and clinical challenges. The challenges are great as over 90% of developments fail, even though compounds are carefully selected before they enter development.
The Pharmaceutical industry is always investigating new ideas and new leads for drug discovery, as there is considerable unmet medical need in society. The work of the Natural Product Discovery laboratory PHARMAMAR - ADVANCING CANCER CARE WITH MARINE RESOURCES Case study number two focuses on PharmaMar, a biopharmaceutical company whose mission is to advance cancer care through the discovery and development of innovative marine-derived medicines. The sea provides the starting point for research at PharmaMar.
More than 99% of marine biodiversity is as yet still un-explored and over millions of years marine life forms have evolved towards great biological and chemical diversity and the new chemical entities isolated from the marine organisms typically have entirely novel structures and often show great structural complexity.
These novel chemical structures often result in new modes of action against tumour cells that opens up the potential of new ways to treat cancer and it is hoped that this rich bio-diversity and chemical diversity provides qualitative advantages when discovering new drugs.
Over the last 20 years, PharmaMar has built up a unique collection of over 42,000 marine invertebrates and micro- organisms and approximately 7000 new chemical entities have been discovered and 30 new families of compounds identified. In additional, the company has a full pipeline of emerging products, including five compounds in clinical development and a portfolio of different molecules at different stages of pre-clinical development.
Only after 20 years of research and significant investment, has PharmaMar reached a position where it is able to plan commercial launch of its first marine-derived medicine. This attests to the length and complexity of the drug development process and the high up-front and sustained investment required to bring nature-inspired medicines The following text attempts to highlight the role natural resources can play in yielding bioactive molecules and the complexity and uncertainties involved in converting these molecules into medicines.
1. Challenges & risks with Natural Product research
The use of biodiversity for drug discovery is just one of many different possible options. These include knowledge-based approaches (using literature and patent-derived molecular entities, endogenous ligands or biostructural information) and purely serendipity- based methods (such as screening), as well as the These combined hurdles represent an additional barrier to developing new medicines using biodiversity. The positive side is that despite the higher risk there may be greater opportunity to be 2. Complexity of R&D
PharmaMar's business model has many similarities with those of most pharmaceutical companies. In particular, the outline of the research process presented earlier is very much the same.
companies in that all the new molecules developed by the company are derived from marine invertebrates or micro- organisms is an essential part of the drug discovery However, the creation of a natural product library is only the starting point. Without significant further work, it is impossible to know whether any individual natural product sample has any value for drug discovery.
To understand the role of biodiversity in the drug discovery process, it is important to understand the differences between a bioactive molecule, a drug-like molecule and a medicine.
2.1 Bioactive Molecules
The drug discovery process starts with the search for bio-active molecules.
Each natural sample is extracted and purified by chromatographic techniques in order to isolate a pure sample of the different molecules present. A few grams of natural sample is all that is required to provide sufficient quantity of the different molecules present to allow elucidation of their chemical structures and an initial assessment of the in vitro activity.
Even though most natural product samples contain a tremendous array of different molecules, the majority of the molecules present in such samples do not show in vitro activity. It has been estimated by the US National Cancer Institute (NCI) that just 1 % of samples from marine organisms tested in the laboratory reveal anti-tumour potential (which compares favourably with just 0.01% of samples of terrestrial origin).
The isolation and characterisation of a new molecule with in vitro activity, a bioactive molecule, from the natural source is an important early milestone in the drug development process.
Once a new bio-active molecule has been identified, PharmaMar follows all the usual steps required for any new medicine including a full programme of pre-clinical testing (to design a drug-like molecule) and clinical development (to produce a medicine).
2.2 Drug-like Molecules
Even though a compound from the natural source may possess in vitro activity, it is highly unlikely that it will also possess all the other characteristics (physiochemical and biological) required to become a successful medicine.
All bio-active molecules require significant further effort in order to optimise their properties and produce a drug- like molecule for the start of clinical trials. This process of optimization is critical for the downstream success.
Structural modifications may be introduced (using chemical, enzymatic or biological methods) to enhance certain aspects of the molecules properties. The new molecules thus obtained have chemical the original naturally but are not themselves using such compounds are best described as inspired by nature rather than natural medicines.
For administration to patients, all molecules need to be formulated. The resulting presentation (freeze-dried vial, capsule, tablet, cream etc) contains not only the active molecule (whether as found in nature or after modification) but also different excipients and other components to ensure the suitability of the formulation. Many sophisticated drug delivery technologies are also available to further optimise drug performance.
The conversion of a bioactive molecule into a medicine is a long and risky process. For example, following structural elucidation and identification of taxol as a new bioactive molecule, it took over 20 years to achieve FDA approval to market a medicine containing this molecule.
Furthermore, the chance of a bioactive molecule successfully negotiating all the hurdles and reaching the market are typically about 1 in 100.
2.4 Responsible Use of Natural Resources
The approach used permits the isolation of novel molecules from small samples of marine material. Once the anti- tumour activity of these chemical entities has been recognized and characterized, a synthetic process is established to produce further quantities for development and for commercial supply and to avoid dependence on the natural source and damage to the marine environment.
Invariably, the natural source would not be considered as an appropriate or viable source of larger quantities of the bioactive molecules, which are usually present in only minute amounts in the marine organisms.
3. Monetary and non-monetary benefits used
3.1 Partnership, collaboration and mutual benefits
Drug discovery at PharmaMar starts with the selective collection of small quantities of marine invertebrates and micro-organisms around the world. This work is carried out by experienced in-house marine biologists and in collaboration with worldwide local research institutions.
PharmaMar supports the protection, conservation and sustainable use of the precious resources from the sea and the fair and equitable sharing of the benefits.
Ensuring the survival of existing biodiversity is essential for future business survival.
The PharmaMar approach to drug discovery not only contributes to the development of possible new treatments from just a few grams of marine sample, but also furthers knowledge and conservation of marine ecosystems. Such information is shared with local communities and teaching institutions and benefits both the local institutions and PharmaMar who uses the knowledge gained to optimise future exploration activities.
PharmaMar is supported by an extensive worldwide network of collaborators of all types who provide expertise and support throughout the drug discovery and development process from bio-prospecting and drug discovery through to clinical development, regulatory and marketing activities.
The opportunity to work with an international network of first class collaborators is essential in ensuring the success of the overall drug discovery process and is an important part of ensuring that the company remains at the forefront of all the best-practice within the Each of the external collaborations is designed to complement in-house collaborations are only possible through the fair of any benefits that may NOVARTIS - COLLABORATION AND COLLECTIVE GAIN The importance or impact of technologies and research concepts are permanently balanced in industry. The same is true for the natural products programs in the pharmaceutical industry. There are many good reasons to leverage the unusual diversity of evolutionarily selected molecules in drug discovery efforts. On the other hand, the use of these molecules means facing intrinsic hurdles or challenges, which some companies may not be willing to take on. Novartis is strongly com- mitted to natural products based research. A key as- pect of this commitment is the creation of external partnerships with coun- tries of high biological diversity. Currently No- vartis focuses on collabo- rations with China and Thailand and in parallel is constantly evaluating other opportunities in or- der to diversify the access to biological sources.
Partner institutes chosen by Novartis are interna- specialists in the field of microbial and plant re- lated natural products research. An integral part of current partner- ship agreements is the exchange of know-how by on-site training sessions, the education of scien- tists in the laboratories of the Novartis Institutes of Biomedical Research and the financing of technol- ogy related investments. In the cooperation con- tracts, success related milestones or royalty pay- ments are also defined.
The project and investment goals are mutually defined in joint steering com- mittee meetings, which are an important instru- ment to monitor project progress and, if neces- sary, to redirect collabo- rations. In the microbial sourcing collaborations, Novartis is responsible for the implementation of specific microbiology skills at the site of partner institutes, guaranteeing the high quality criteria of microbial strains as start- ing points for Novartis' in- ternal project activities.
A particularly success- ful cooperation with the Shanghai Institute of Ma- teria Medica should be mentioned here. Over a period of 6 years, Novartis received more than 1500 isolated molecules from plants used in Chinese traditional medicine from its Chinese partner. From its side, Novartis contrib- uted significantly to the implementation of tech- nological innovations at the Shanghai based insti- tute. There are currently several compounds be- ing considered for closer preclinical investigation at Novartis.
Although the Rio-Conven- tion came into force more than 10 years ago, legal uncertainties regarding entitlement of institutes to start bioprospecting endeavours with indus- trial partners remain; sibilities and authorities of national government and local administration, lack of official contact points within a country and the much discussed Access and Benefit Shar- ing framework. However, this issue is by no means an exclusive problem of biodiversity rich coun- tries: the majority of the Western nations have also failed to implement suitable modus operandi.
The most advanced No- vartis project benefiting from traditional knowl- edge is related to a tra- ditional Chinese medi- cine. Artemisia annua is a plant, which has been used in China to fight ma- laria for over 2000 years.
The active ingredient, ar- temisinin, was isolated in China in 1977 and demon- strated potent and highly selective activity against Plasmodia. The multi drug resistant Plasmodium fal- ciparum can be effectively killed with the unusually structured natural prod- uct. In a joint development project with Chinese gov- ernmental institutes, an artemisinin derivative to- gether with another plas- modicidal drug substance were combined in one tab- let and were introduced successfully as Coartem(r)/ Riamet(r) onto the pharma- ceutical market in 1999. In 2001, the WHO added the anti-malaria drug to its es- sential medicines list.
In the following years, No- vartis implemented full supply chain management. were made in seed develop- ment; horticulture capacity was expanded in Africa and China and manufacturing infrastructure was put in place. Together with Chi- nese industry partners, the syntheses of the drug sub- stances were developed to production scale and GMP (Good Manufacturing Prac- tices) conform processes were established in China. 5> MOVING FORWARD: WHAT SORT OF REGIME? 5.1 IMPORTANT POINTS TO CONSIDER In considering any proposals for an ABS regime, the those countries.
following points should be used to assess the value and effect of any potential element of an ABS frame- The Regime must also confront the realities of the industrial processes which it is seeking to regulate. Pharmaceutical research is a "many-to-one" process, 1. What is the objective to be achieved or promoted
in which an enormous number of inputs contribute to by the requirement? a single new drug. Many of the inputs are attributable 2. To what extent does the requirement achieve or
to sources outside the firm. Some are invisible, in that promote that objective? they are purely intellectual and exist in the minds of researchers. Some are substitutable; some are not. 3. To what extent does such a requirement have un-
Some are expensive; some are commodities. From the desirable consequences and do these outweigh research companies' point of view, there is a strong the advantages of the requirement? preference for knowing the cost of inputs in advance. 4. Will this requirement help achieve the CBD objec-
For that reason, the industry favours solutions, which tives and facilitate both access and benefit shar- focus primarily on the point of acquisition of the genetic resource. The post-hoc attribution of value defers rewards to the source country for a long period of time It is necessary to address lack of clarity and to dispel and will inevitably be subject to debate.
myths in order to establish valid objectives. In section 2, examples of differences of opinion about fundamental concepts that underpin discussion of ABS were given. Underlying these differences is a lack of global consensus on almost every aspect of what might be termed the appropriate "regulatory philosophy." The preferred regulatory instruments depend in turn on one's perception of the problem. Those who believe, like some NGO's, that a generalised theft of genetic resources is taking place and who place the lack of ownership above the recognition of innovation will approach the question of regulation from a different point to those who believe that the core issue is to promote responsible use. An approach that is purely seeking to prohibit need deal only with the identification of certain actions, whereas as one that seeks to be facilitative must proceed from a deeper understanding of the processes involved.
The decisions made regarding ABS policies and laws, their clarity and workability will clearly affect the readiness of industry to invest in certain types of resource research and development. As legal certainty decreases and risks increase, the likelihood of investment in development of genetic resources will in parallel decrease. Any ABS framework must facilitate both access and benefit sharing and aim to ensure legal certainty. Without research investment, there will be neither commercial rewards to share with countries of origin nor technology to transfer to 5.2 AVOIDING THE WRONG PATH The example of "biopiracy" shows what happens when responsible use of NP and fair benefit sharing. To policy is developed from the wrong base. While some jeopardise such collaboration and partnership would would claim that bio-piracy is a major problem, there is be misguided and would benefit no-one.
in fact little evidence that a significant practical problem exists and industry believes that this misconception The emphasis that has been placed on biopiracy is somewhat due to political rhetoric and misguided shifts the attention of policy-makers away from the perceptions of biopiracy. It is important that debate on key points of reference in the search for equity. It has the issue is grounded in fact-based analysis.
also delayed consensus regarding the key concepts, because in a situation of imagined threat there is a EFPIA considers that the scale of biopiracy has tendency towards blanket regulation, rather than the been systematically and sometimes deliberately more considered approach that the issue needs.
exaggerated. A 2005 IUCN report on bio-piracy pointed out a recurring observation made throughout Just as the issue of "biopiracy" has assumed an interviews carried out for this report: "to some people, importance, which is not justified by rigorous, evidence- any ABS negotiation is ‘biopiracy'"19. One of the based analysis, so to has the patent system been perverse realities of the current situation is known as misused as a scapegoat to be blamed for contributing ‘punishing the compliant' and this describes a situation to "biopiracy". A limited number of cases of invalid where ABS claims are scrutinised and allegations of patents relating to use of genetic resources have been biopiracy are made regarding those who make the cited as evidence that biopiracy is widespread and effort of meeting all government requirements.
facilitated by the patent system.
Regarding the extent of misappropriation claims These cases have been used to build political support made, several persons have suggested that there are for a disclosure requirement which industry believes actually very few substantiated claims20. The above would create significant legal and commercial report suggests that the frequency of claims could uncertainty and will provide no practical benefits. very well diminish if a set of objectively determinable Indeed, there is no measure more likely to accelerate standards for ABS compliance (including clarification withdrawal from natural products research and deter on when ABS compliance is required) were agreed at investment in mega-diverse countries than a badly international and/or national levels21. Most claims designed patent disclosure requirement. It is an "end- reviewed in the 2005 IUCN report arose at least in part of-pipe" solution which discourages natural products from uncertainty regarding ABS requirements and a research because of its unavoidable arbitrariness, lack of objective standards for determining whether a whereas the interests of both acquirer and source user is authorised to utilise genetic resources.
country are much more closely aligned by a focus on the development of local research capabilities, around Yet another report for the 2005 Ad Hoc Open-ended the point of sample acquisition.
Working Group on Access and Benefit-sharing, noted that the bioprospecting environment is often The types of cases, which have been referred to in characterised by ‘misunderstanding, mistrust and this debate, could generally have been dealt with by regulatory confusion.'22 The same study reported better search examination procedures. It is clear that widespread concern expressed by researchers in both a disclosure requirement would not help prevent the academia and industry that traditions of trust and grant of patents in cases such as these because in partnership among scientists has been undermined. several of the cases cited, the source of the genetic However, as the case studies in section four show, there material was in fact disclosed and yet the patent was are numerous examples of good business practice, 19 IUCN Canada (2005), "Analysis of Claims of Unauthorised Access and Misappropriation of Genetic Resources and Associated Traditional Knowledge." This paper was commissioned by the Secretariat of the Convention in response to decision VII/19E, paragraph 10 (c) of the Conference of the Parties and co-financed by Environment Canada. UNEP/CBD/WG-ABS/4/INF/6 - 22 December 2005 20 This point is based on discussions of ABS issues in COP-7, including Working Group 1, and the ABS Contact Group meetings throughout that Conference. A review of recent literature will turn up numerous articles regarding the paucity of actual ABS-related claims. 21 IUCN, op.cit., note 17, p.3522 Laird, S & Wynberg, R (2005), op.cit., p.38 Successful progression towards an effective and fair p User-friendly: If it is to be binding, the IR must
system of ABS, while facilitating innovation will depend define rights and obligations which are sufficiently on the understanding of many issues. As a stakeholder attractive and clear to encourage use of GRs - and user of genetic resources, the research-based must avoid over-regulation/uncertainty - "user pharmaceutical industry can contribute its knowledge, experience and skills and hopes that this submission will further the discussion in with a view to ensuring both p Promoting all CBD Objectives: care must be
access and benefit sharing of genetic resources. The taken that obligations do not run counter to CBD research-based pharmaceutical industry is committed objectives, i.e. facilitate both access and benefit to working in partnership with all stakeholders in order to find a solution that is accepted by all and which will promote the CBD objectives, enabling a sustainable p Added value: detailed cost/benefit analysis of any
and beneficial use of global biodiversity.
certification scheme must be undertaken The following are elements, which are seen as critical p Practicable and transparent: any framework
to any proposal or framework by the industry: should be practicable, transparent, and efficient and avoid arbitrary treatment, consistent with the p Flexible and Facilitative: any international regime
provisions of the convention (IR) must be sufficiently flexible to enable countries to establish national regimes appropriate to their needs within the context of facilitating access - "provider flexibility" In summary, EFPIA suggests that the following points should guide the design of the Interna-
p National laws are key and that should be the focus of discussions. In order to manage access to and use of genetic resources, national mechanisms must be created to regulate these activities and equitable benefit sharing should be achieved through contractual arrangements. Failure of countries to fulfil CBD obligations will automatically lead to non-fulfilment of ABS objectives.
p An international regime will not remedy a legislative gap given that many parties of the CBD have yet to implement adequate legislation. Therefore the promotion of national laws, which are appropriate for each country is vital, as is capacity building at national level.
p The international element of the Regime must be built around consensus standards of national implementation p It is critical to define the legal meaning of key concepts that will underpin any proposed mechanisms. Questions raised in this document should be answered in order that the debate can move forward in certainty of the parameters being discussed.
p Companies and others who invest in research must have legal certainty as to what is needed to ensure the security of their investment.
p Without research investment, there will be no benefits or commercial rewards to share with countries of origin nor technology to transfer to those countries.
p Provider flexibility and user friendliness are key to any international ABS regime that can be effective p Industry should be, and wants to be, involved in all stages of the development of the regime.
p Nature is a valuable source of novelty and complexity and so access should be promoted and facilitated so that the benefits of nature can be shared out in an equitable and faire manner.
FACILITATE - NOT RESTRICT - ACCESS p BIO (2005), Guidelines for BIO Members Engaging in p Lewis, G, S Class, and E Edery (2005), Growth, in Bioprospecting, available at: http://www.bio.org/ip/ moderation, Scrip Magazine, pp 2-4, February 2005. p Bonn guidelines (2002): Bonn Guidelines on access to p Mathur, E, C Constanza, L Christoffersen, C Erickson, genetic resources and fair and equitable sharing of M Sullivan, M Bene, and JM Short (2004), ‘An the benefits arising out of their utilization - Decision Overview of Bioprospecting and the Diversa Model', VI/24, available http://www.biodiv.org/decisions/ IP Strategy Today. No 11 - 2004, 1 -21.
p Rosenthal, JP and FN Katz (2004), Natural products p Cragg, GM, DGI Kingston, DJ Newman (eds) (2005), research partnerships with multiple objectives Anticancer Agents from Natural Products, Taylor in global biodiversity hot spots: nine years of the and Francis Group, CRC Press, Boca Raton FL.
International Cooperative Biodiversity Groups Programs. In Bull, AT (ed) (2004), Microbial Diversity p Feher M, Schmidt JM. (2003), Property distributions: and Bioprospecting. ASM Press, Washington DC, pp differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 43:218-227, 2003.
p Newman, D.J.; Cragg, G.M. (2007), ‘Natural Products as Sources of New Drugs over the Last 25 Years', p ICC Discussion Paper on Access and Benefit Journal of Natural Products, 70 (3), 461-477. Sharing: Special Disclosure Requirements in Patent Applications, Document 212-11, May 25th 2005.
p IFPMA (2004), Guidelines on Access to Genetic Resources and Associated Traditional Knowledge and Equitable Sharing of Benefits Arising out of their Utilisation, available at: http://www.ifpma.org/pdf/ p IUCN Canada (2005), "Analysis of Claims of Unauthorised Access and Misappropriation of Genetic Resources and Associated Traditional Knowledge" prepared by IUCN-Canada. This paper was commissioned by the Secretariat of the Convention in response to decision VII/19E, paragraph 10 (c) of the Conference of the Parties and co-financed by Environment Canada. UNEP/CBD/WG-ABS/4/INF/6 - 22 December 2005 p Kaiser, R (2004), Vanishing Flora - Lost Chemistry: The Scents of Endangered Plants around the World. Chemistry and Biodiversity, vol 1, pp 13 - 27.
p Koehn, FE and GT Carter (2005), The Evolving Role of Natural Products in Drug Discovery, Nature Reviews, Drug Discovery, vol 4, March 2005. www.
p Laird, S & Wynberg, R (2005): The Commercial Use of Biodiversity: an update on current trends in demand for access to genetic resources and benefit- sharing, and industry perspectives on ABS Policy and implementation. Report commissioned by the CBD for the fourth meeting of the Ad Hoc Open- ended Working Group on ABS - UNEP/CBD/WG- ABS/4/INF/5 available here 6.2.1 Scientific Terms used
1. Company A is informed that rubbing a bruise with a leaf
p Analogue: a chemical compound that is structurally from the XYZ tree in Brazil alleviates bruising. It obtains similar to another but differs slightly in composition the seeds (with appropriate consents) and grows p Genetic resource: means genetic material of actual sufficient quantities to enable it to extract and purifies or potential value23 the oils which it sells. It patents the purified oils, their p Lead: a chemical which has significant biological use and the process of extraction and purification. activity at a target and properties which make it Would the disclosure requirement apply? attractive to design and synthesise analogues to 2. Company A is informed that rubbing a bruise with a optimise the desirable properties and remove any leaf from the XYZ tree in Brazil alleviates bruising. unwanted properties It obtains quantities of the leaves (with appropriate p Target: a biological mechanism like an enzyme, consents) and isolates and synthesises the active a receptor or ion channel which is implicated in a ingredient, which it develops and sells. It patents the active ingredient and its use. Would the disclosure requirement apply? 6.2.2 Problematic or undefined Terms
3. Company A obtains (with appropriate consents) leaves from 100 species of trees in Brazil. It knows nothing about their properties. Using various assay p Bio-piracy: activities relating to access or use of genetic techniques, it discovers that one ingredient of one resources in contravention to national regimes based of the leaves is medically useful. It isolates and on the CBD. Accordingly, a legitimate claim of ‘biopiracy' synthesises the active ingredient, which it develops will involve unauthorized access to a controlled genetic and sells. It patents the active ingredient and its resource and using that resource in a manner that use. Would the disclosure requirement apply? contravenes the national regime. In practical terms, this means that (a) the activity in question occurred 4. Under 3, does it make a difference to the applicability after the CBD came into force (December of 1993), and of any disclosure obligation if the medical use was (b) the acts consist of a party gaining access without known to a community in Brazil but not disclosed to the consent of the source country, or in contravention Company A either at the time of collection or before to laws or regulations governing access to or use of application for the patent? genetic resources that the country has established24.
5. Company A does either 2 or 3 but finds that the ingredient it has isolated and synthesised has unacceptable toxicity. It finds a hitherto unknown analogue of it in the same class of compounds and patents and commercialises that analogue. Would the disclosure requirement apply? p Traditional Knowledge 6. Company A does 2, 3 or 5 but does not commercialise the product. On the basis of the patent disclosures 6.3 Potential scenarios involving GR and un-
of Company A, Company B develops, patents and commercialises a compound in a different class of compounds from those patented by Company A. Is As a result of discussions concerning the proposed there a need for Company B to disclose the origin patent disclosure obligation, the following illustrative of the leaf used by Company A? Does it make a scenarios were produced. They are all hypothesised but difference if Company A had disclosed its origin? plausible examples of different levels of association or nexus between genetic resources and a final product. Scenario 2
While the text explains the intellectual property issue, the questions raised by the scenarios can be applied to any One of the thousands of compounds synthesised by situation where the production of a final product is used Company A as part of its combinatorial chemistry as a regulatory ‘trigger point' for some sort of obligation program is Compound X. Its screening processes on the producer.
disclose that this novel compound has a medical use. It 23 CBD, Article 224 This is merely one definition of biopiracy - that used by the International Chamber of Commerce, available at: http://www.iccwbo.org/collec- patents the compound and its use. However, Company exclusively licenses Company D to make and sell the A cannot develop a cost-effective method of producing enzyme in washing powder? (iii) Company D did not commercially viable quantities of the compound and publish, but gave Company E the information under a does not commercialise it.
contractual obligation to pay royalties to Company D Company B is aware of the patent disclosure. It should a commercially viable enzyme be marketed.
obtains access to a large number of micro-organisms 4. Under 2 or 3, does it make a difference to the from Brazil and discovers (it is not told) that one of applicability of any disclosure obligation if Company them naturally produces Compound X , but not on a D never discloses to Company E the source of the commercially efficient scale or with adequate purity.
plant, and the plant is also found to be native to the Based on this discovery, it analyses a similar micro- country of Company D and Company E.
organism which is native to Europe and finds that that micro-organism produces Compound X more efficiently Scenario 4
than either the micro-organism from Brazil or the synthetic route disclosed in Company A's patent.
1. Company F is informed that a plant virus is wiping out Company B genetically modifies the European micro- a cash crop native to Bolivia. The company obtains organism to improve production efficiency still further. the plant (with appropriate consent) and discovers It patents the micro-organism and compound X as a receptor which the virus uses to infect the plant. produced by the micro-organism.
The DNA sequence of the receptor is found and the receptor is cloned and used to screen compound Company C genetically modifies the European micro- libraries for chemical antagonists which would prevent organism still further to improve purity of Compound viral infection. A patent application is filed on: the X and obtains relevant patents.
new receptor, its gene sequence, methods of finding Companies A,B and C cross-licence each other under antagonists, the chemical antagonists themselves, and the patents to enable sale of the commercial products.
their use. Would the disclosure requirement apply? Does Company A, B or C have to disclose the Brazilian 2. Under 1, does it make a difference to the applicability of any disclosure obligation if the receptor was found by the Bolivian Agricultural Department, and its Scenario 3
sequence published, and i) Company F was given the vector comprising the gene for the receptor by the 1. Company D is informed that people wash clothes Bolivian Agricultural Department and the antagonists with a plant extract in Chile. It obtains the plant were found and patented? or ii) Company F synthesised (with appropriate consent) and discovers a new the published gene sequence to discover and patent lipase enzyme. It isolates the gene for the enzyme and patents the isolated enzyme, its DNA sequence, its use in laundry detergents and a process for its recombinant production. Would the disclosure Scenario 5
requirement apply? Consider all of the above cases and assume that, for 2. Company D is informed that people wash clothes with a whatever reason, relevant patents are held invalid. plant extract in Chile. It obtains the plant (with appropriate Producers of generic/unpatented products make large consent) and discovers a new lipase enzyme, isolates its amounts of money selling the products. Are those gene, and determines its DNA sequence. The company producers obliged to share the benefits of their sales finds, however, it cannot withstand normal laundry with the countries, which provided the materials? temperatures, and publishes the work. Company E reads the publication and undergoes extensive R&D to mutate the gene to make the gene more heat stable. The Scenario 6
new gene shares only 40% sequence identity with the In order to make a wheat crop hardier, plant breeders original gene. Company E patents the mutated enzyme, crossed a conventional wheat variety with a variety its gene sequence, its use in laundry detergents and obtained from Russia (with appropriate consent). a process for its recombinant production. Would the Plant Breeders Rights were obtained (under UPOV) disclosure requirement apply? for the new variety. Would the disclosure requirement 3. Under 2, does it make a difference to the applicability apply? What if several breeding steps were required to of any disclosure obligation if (i) Company D worked generate the new plant variety, and the Russian variety with Company E to generate the new enzyme and a had been used 20 steps previously to the new variety joint patent application was filed? (ii) Company E later Leopold Plaza Building, Rue du Trône 108,B-1050, Brussels, Tel: +32 (0)2 626 25 55 Fax: +32 (0)2 626 25 66 Produced Sept. 2007
SIA Standards Committee ISC West – Las Vegas, NV Committee Meeting Wednesday, April 1, 2009 10:00 a.m. to 12:00 noon Room 507 (Venetian) DRAFT AGENDA 1. Administrative a. Call to Order . Knight b. Attendance / Roll Call . Rigano c. Membership . Rigano d. Rigano 2. Approval of the Draft Agenda…. Knight 3. Approval