9.2 General principles
9.3 Scale of need and scale of investment
9.4 A case history: GLA from evening primrose oil
9.5 Development of the evening primrose as a commercial crop
9.6 Future roles for novel crops
Until the 1950s, almost all products used as human pharmaceuticals were either of natural origin or were synthetic or semi-synthetic copies of natural compounds. There then began a chemical revolution in the pharmaceutical industry which ensured that for the next 30 years, with the exception of antibiotics, almost all new drugs developed were hitherto unknown new chemical compounds. As a result, a generation of managers grew up in the industry which completely forgot that, historically, most medicines have been derived from natural products.
Four separate influences have combined to begin to reverse this trend. First, many of the new synthetic drugs turned out to have unacceptable side effects. Second, several important disease areas proved stubbornly resistant to the new synthesised drugs and so some scientists began to look back to traditional remedies for ideas for new compounds. Third, the enthusiasm and financial hype associated with the biotechnology industry began to make natural products respectable again, even in mainstream medical and pharmaceutical professions. Fourth, the rise of the `green' and environmental movements made patients and consumers much more interested in natural products.
For the first time in 40 years the climate is now therefore ripe for the introduction of new health care products derived from plants. Scotia Pharmaceuticals has been in the forefront of this development and this chapter outlines some of the opportunities and problems.
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The main problem is that the development of a drug or nutritional product derived from a crop requires the expenditure of very large sums of money, of orders of magnitude which are not normally available to the agricultural community. Because of this it is important to be reasonably confident that, at the end of the day, a secure market will emerge.
In practice this means that there must be the possibility of a licensed drug which has some form of intellectual property protection, so enabling the drug to command a price which will allow the research and development costs to be recouped. Although in theory an unprotected unlicensed health food product might achieve such high sales that its research costs would be justified, in practice the risks of developing such a product would be such that no organisation could incur them. Health food products in this field are likely to be ones which are carried along by the pharmaceutical market because the product has a dual role as both a drug and as a nutritional supplement. This has been the case with evening primrose oil, for example.
Fortunately the intellectual property issue has developed in favourable directions in the past decade. Except in the USA, it was once impossible to patent new uses for known chemicals. Thus, if a chemical found in a plant was known for any reason, its use as a pharmaceutical could not be protected. In practice, by various devices, most of the developed world has now come into line with the USA. It is now therefore possible to patent entirely new uses for known chemicals. For example, Scotia now has over 20 patents in most Western countries covering different aspects of the pharmaceutical use of gamma-linolenic acid (GLA), the key ingredient of evening primrose oil.
Western governments have also recognised that there is a need to stimulate the development of drugs which may be very valuable but which for one reason or another may not be patentable. For example, it is not rare for work by academic researchers to be published freely at an early stage so destroying any possibility of patenting. Unfortunately this also often destroys the possibility of commercial development since few organisations will invest in a product which cannot be protected against imitators who have spent no money on research. Most Western countries therefore now specify situations where an unprotected product which wins a drug licence can be protected in the market-place. The most generous provisions are in the EC where, if an unpatented product wins a drug licence in any one EC country, imitators of that product cannot be marketed throughout the EC for 10 years (6 years in Denmark).
These changes in patent and marketing law have given considerable impetus to the development of drugs from natural products. Even so, the problems facing a would-be developer are considerable. If they are to be overcome a medical need must be identified and a crop must be found which provides the opportunity to meet that need. The development of the medical need and of the crop opportunity must proceed in parallel. Both can be conveniently divided into four stages.
Demonstration of medical need and crop opportunity
This is the first step. A disease must be identified where there is reasonable evidence that a particular chemical will provide an effective treatment. At the same time a plant must be identified which contains that chemical and whose initially observed characteristics suggest that turning the plant into a crop may be feasible.
Creation of the medical need and of the crop opportunity
Clinical studies on a small scale need to be carried out to provide convincing evidence that the chemical does indeed work. At the same time, genetic and agronomic investigations on the crop must be performed to confirm the initial impression that the plant can be cultivated in a way which will allow substantial and reliable amounts of the required chemical to be produced. Methods for extracting and purifying the chemical from the crop must also be developed.
Fulfilment of the medical need and the crop opportunity
The clinical studies must be extended to several hundred or indeed thousands of patients and a systematic programme of pre-clinical and toxicological investigations must be performed. The aim must be to develop a licensing dossier which will allow the drug to be approved as effective and safe in most countries. The dossier must also be sufficient to convince doctors that the drug should be prescribed. Simultaneously, the experimental plant must be turned into a genuine crop by demonstrating that it can be grown by ordinarily competent farmers in quantities sufficient to meet the likely demand.
Maintenance of the medical need and the crop opportunity
There must be a continuous ongoing programme of clinical research and development and of marketing to ensure that the drug is used in the best possible way and that doctors use it as much as is sensibly possible. Without continual refinement of the drug, its formulation and its method of use, it is likely to be replaced by new and better treatment. On the agricultural side there must be relentless attempts to improve efficiency and quality and to exert downward pressure on costs. One can be confident that any successful crop chemical will provoke attempts to synthesise it or to make it by other routes such as fermentation. Without constant improvement of the crop, it may be vulnerable because of alternative sources of the chemical.
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At an early stage in the development process it is important to estimate the likely world use for a particular chemical. This requires first an estimate of the number of people in the world with the disease. Second, an estimate must be made as to the likely daily dose. Third, it must be worked out whether the treatment is likely to be short term (e.g. 5–10 days for antibiotic treatment of infection) or long term (e.g. life for the management of diabetes). Fourth, an estimate must be made as to how much patients, insurance companies or governments will be willing to pay. A cure for cancer will obviously demand a far higher price than symptomatic relief of some minor ache or pain.
The estimated scale of need must then be balanced against the likely scale of investment required. The pharmaceutical industry estimates that development of a new drug to the level where it can win licences from governments costs around £150 million on average, spent over 6–15 years. This figure masks a great deal of inefficiency, but even the most effective organisations are unlikely to be able to put together a convincing dossier for less than £15–25 million. On the crop side expenditure is not quite so high but is nevertheless likely to be of the order of £1–5 million, perhaps spread over 10–20 years. Finally, once licences have been obtained, at least equivalent sums - and most would say considerably higher ones - must be spent to market and sell the product, since otherwise all the research and development effort will be wasted.
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Although there had been earlier suggestions of possible medical uses for GLA, it was not until the late 1970s and the early 1980s that the development of GLA from evening primrose oil began in earnest. At that time, researchers from Scotia, building on academic research whose commercial importance had not been fully appreciated, recognised that there were diseases which might benefit from the use of GLA. in particular they focused on atopic eczema and on diabetes, diseases which involve at least 20 million people in Western Europe and North America.
Outline of linoleic acid metabolism.
Linoleic acid is an essential fatty acid (EFA), a vitamin-like substance which must be provided in the diet. But in order to be used properly within the body it must be metabolised by the sequence of reactions shown in Fig. 9.1. The first step is critical: linoleic acid must be converted to gamma linolenic acid (GLA). We suspected and then confirmed that in certain diseases, notably eczema and diabetes, the body might not make enough GLA. For example, in eczema the blood levels of linoleic acid are elevated whereas those of GLA and its further metabolites are below normal, indicating an impaired ability to form GLA.
It was known that the seed oil of the evening primrose (EPO) contains GLA and that the characteristics of the evening primrose did not preclude the possibility of converting the plant into a fully commercial crop. A simultaneous programme of medical and agricultural research was therefore initiated. The principles and problems of the seed research are outlined in section 9.5.
On the medical side we were initially naive enough to think that because EPO is a natural product which contains nothing not normally found in the human body we would not be required to carry out a full toxicology programme. We were soon disabused by discussions with the relevant government departments in various countries. We were told in no uncertain terms that in order to have any hope of winning a drug licence we would have to carry out a full toxicology programme including performing full 2–year carcinogenicity tests on two species. Paradoxically, the same governments usually recognised that EPO was safe and had no problems about its sale as a nutritional supplement without making drug claims. But in order to make a drug claim there was no way of avoiding the standard tests.
At the same time we performed large-scale clinical studies, in many medical schools in several countries, on the clinical effectiveness of EPO. We concentrated on atopic eczema and on the nerve damage (neuropathy) which is associated with diabetes and which is responsible for many amputations and for such problems as impotence or diabetic ulcers. In 1988, almost exactly 10 years after the research programme started, we obtained our first drug licence in the UK for atopic eczema under the trade name of Epogam. Epogam now has licences in the UK, Ireland, Germany, Denmark, Italy, South Africa and Australia. No licences have yet been granted for diabetes but we expect the first one in the relatively near future. There can be no doubt, on the basis of the clinical trials, that Scotia's EPO is effective in treating both eczema and diabetic nerve damage.
The scale of investment has been considerable. At present Scotia has spent a total sum of just over £25 million on medical and agricultural research and development. Equivalent amounts will be spent on sales and marketing. Fortunately for us, as a result of patent and marketing protection, we have been able to develop a protected market for the drug uses of EPO, although not for the nutritional uses. Also, it looks as though the sales will justify the expenditure and eventual drug sales of Scotia's EPO are likely to reach £200 million per year or more. In both Germany and the UK, where Epogam has been on the market for only a relatively short period, it is now the best-selling drug for atopic eczema. This demonstrates that, provided the research and development back-up is there, both patients and doctors find the concept of natural drugs to be very acceptable.
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Some of the main requirements for an ethical pharmaceutical product are that there should be a reliable supply, that the product should comply with a tight quality specification and that it should be consistent from batch to batch (all of which must be achieved at a reasonable unit price). When the raw material is produced chemically or through fermentation, there is not normally any difficulty. However, when the raw material is produced agriculturally, and particularly where the source species is new to agriculture, compliance with these needs is much more difficult to achieve. We shall discuss some of the problems which can arise, and the ways in which they can be tackled, using evening primrose as an example.
Evening primrose is the common name given to a group of 12 species of the genus Oenothera and it is so called because the flowers are primrose-yellow and open in the evening (the common primrose Primula spp. is not related). The evening primrose originated in North America but is now distributed worldwide in the temperate regions of both northern and southern hemispheres. The pharmaceutical interest lies in the seed oil which contains an unusual fatty acid, gamma linolenic acid (GLA).
In ecological terms, the plant is a `primary coloniser' and will exploit areas of bare ground where the vegetation has been cleared (by fire, or soil movement, for instance) or where the soil is too poor for other species to survive (e.g. on sand dunes). However, it is a poor competitor in a mixed stand, and is rapidly crowded out by other species in fertile ground.
In the wild the plant normally grows as a biennial. Seed is shed in the autumn, lies dormant overwinter and then germinates in the spring. During the first year, the plant forms a rosette of leaves, flat to the ground, which may grow up to 30 cm across by the autumn. This is a particularly effective form of plant architecture which maximises the chances of overwinter survival in severe climates, as the plant will be covered by even a light fall of snow which will insulate it from severe low temperatures.
In the spring of the second year, the plant bolts, producing a central stem with a variable number of branches, and will reach an eventual height of 1.3–2.0 m. Flowering normally starts in July, with fresh flowers being produced each day, and lasts for several months. Most evening primroses are self-pollinated but some do outcross, primarily through the agency of moths.
The seed is small (1000 seed weight is about 500 mg) and is produced in capsules attached directly to the stem. These mature from September to October and, as the capsules become ripe, they split open and the seed is shed progressively through movement of the plant in the wind and the attention of small birds, which find the seed very attractive.
As can be appreciated from this description, there are a number of characteristics of wild evening primrose which are difficult to cope with in an agricultural situation. Attention therefore was given from the earliest days to find ways to change or circumvent the major problems.
One of the main problems of material sourced from the wild is that the quality is likely to be extremely variable. This is primarily because the plants have a wide range of genetic compositions. One of the first tasks therefore in domesticating a new crop is to produce genetically uniform varieties for cultivation. This may be done initially by selecting from the wild populations, but the required combinations of characters are unlikely to be found in a single line and a hybridisation programme will be required if further progress is to be made.
The wild evening primrose has a life cycle of 24 months which, if transposed to the farming situation, would mean only one crop every 2 years. Initially, to overcome this, we began planting in late July/early August. This permitted the crop to grow large enough to survive the winter and flower and set seed in the following year. Whilst the life cycle still occupied the ground for 14 months, there was sufficient time for the grower to harvest an early maturing crop (such as winter barley, vining peas or early potatoes) prior to sowing the evening primrose. More recently, it has become possible to sow in the spring, using special varieties which bolt readily and come to harvest in the same year. In practice, we now use a combination of autumn and spring sowings which gives us the best balance of reliability, cost and flexibility.
Wild evening primrose seed can stay in the soil for up to 20 years before germinating. The precise mechanism of this dormancy is uncertain but there is some evidence that it is determined by factors present in the seed coat (testa) and that it can be overcome by chilling the imbibed seed. This effect, however, is lost if the seed is redried, so conventional seeding is ruled out following treatment. Techniques such as transplanting and fluid drilling of chitted seed have been used successfully but are expensive. In the long term the most effective solution is to breed varieties that have low seed dormancy and this has now been done; all current Efamol varieties can be grown without pretreatment.
No chemical company could justify in commercial terms the development of a new product for a minor crop like evening primrose. The only way forward, therefore, is to screen existing chemicals in order to find suitable products. As a result of public concern, we are experiencing a continual tightening of the regulations governing agrochemical use, in order to control the level of residues present in food. This will place an increasing burden on those developing new crops as the amount and standard of data required to satisfy the regulatory authorities increases. We have been fortunate with evening primrose, as the best chemicals we have found are of low toxicity and are normally applied early in the lifecycle of the crop.
Evening primrose is normally sown in July, but does not produce a full canopy until May of the following year. It is therefore necessary to keep bare ground free of weeds for 9 months, which is not an easy task. However, after an extensive screening programme, we now have a sufficient range of herbicides which, when used together with some mechanical cultivation in spring, is able to achieve this in most cases.
The main disease problem in evening primrose is Septoria oenotherae which attacks the leaves of the rosette during winter and can result in crop loss in severe attacks. We are currently investigating a range of control measures, including the use of both fungicides and cultural practices.
The evening primrose plant matures over a period of several months as a result of its flowering pattern, in which just a few flowers open every evening. In wild material, this is combined with pods which split open as they mature. Thus, if a grower leaves the crop until it is fully mature before harvesting then most of the seed is lost, but if he harvests as soon as the first seed is shed then he will lose a high proportion of seed which is still immature. There is, in fact, an optimum time to harvest, but even then a significant amount of seed is lost. One of the main thrusts of our research over the last 15 years has been to develop indehiscent varieties. Using these varieties the farmer can wait until all the pods are ripe and harvest when the weather is suitable. As a result, he will get a higher yield, his crops will be more reliable and the quality of the seed will not be reduced by moulds or immature seed. All of the main varieties grown by Scotia currently have indehiscent pods, and there are a number of exciting new indehiscent varieties in multiplication.
Evening primrose therefore, in common with most novel crops, has a number of major defects which need to be overcome before it can become a successful agricultural crop, and the primary factor in its development has been research. This, in turn, requires funding. However, it is important to understand that the level of funding is less critical than its consistency. Any novel crop is likely to require a plant breeding input for success, and for this a time-scale of 10–20 years has to be allowed before the fruits of the work are fully commercialised. In many areas of research there can be trade-off between the funding available and the time taken, but traditional plant breeding is resistant to short cuts.
In the commercial world, it would be a rare company which could wait for the fruition of a breeding programme before seeing any financial return from its investment. Accordingly, there is usually a pressure to produce crops of species which are, at best, only partially domesticated. The manager of the production programme is therefore in the position of having to guarantee a supply of raw materials of reliable quality from a crop plant which is prone to failure from many causes. There are a number of factors which can help him to achieve this.
A farmer always has a choice of crops to grow. Whilst the mainstream crops may not offer large return, they are reliable and allow the farmer to plan his cash flow. If he is to grow a novel crop, then the pay back in good years has to be sufficient to cover the risk of failure. In particular, contracts which reduce the price per kilo above a certain yield should be avoided. Nothing encourages growers more than the chance to win the jackpot.
Support the growers
Novel crops are usually difficult to grow. It is therefore essential that technical advice is given freely, together with frequent crop visits by experienced staff. A new grower for Efamol is likely to receive 10–15 visits during the life of his crop, and even experienced growers will receive 5–10 visits.
Treat the growers fairly
In view of the investment required to train a new grower, it is important that he should not be tempted to grow for a competitor. It should go without saying that fair trading should always be followed, but it is surprising how many companies involved with novel crops do not always adhere to that rule.
Vary the growing season
By growing in northern and southern hemispheres and by planting in both autumn and spring, flexibility can be built into the production programme.
Diversify source of supply
By growing in a range of different countries, one can minimise the risks from climatic problems (such as droughts, severe winters, etc.) and from over-reliance on one supplier who might be tempted to exploit that position commercially.
Maintain a good inventory
Efamol has a policy of maintaining at least 18 months supply in store at any time. In that way, even if all crops in all countries failed in a given year, there would be sufficient seed to last until the following harvest.
In summary, the production of novel crops such as evening primrose for pharmaceutical uses imposes a number of requirements which can be met by both technical and managerial practices, and these needs are likely to be similar for a wide range of species.
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In spite of the difficulties, we believe that there will be important future roles for novel crops, especially for novel crops based on observations in traditional medical systems. The increasing interest in naturally occurring drugs and the likely efficacy and relative lack of toxicity of appropriately selected candidates will ensure substantial interest from both the public and the medical profession.
However, an essential requirement of successful development will be combined and simultaneous agricultural and medical research programmes. This combination might be found within a single company or as a result of collaboration between two companies, one operating mainly in the agricultural field and one in the medical field. What must not be underestimated are the time and money which such developments may cost.
We have identified about six candidates as possible follow-ups to our development of Oenothera biennis. These have activities in cardiovascular diseases, in psychiatry, in cancer, in inflammatory disorders, in allergic reactions and in obesity. Not all of them will come to fruition but we are very confident that our crop-derived drugs will have a major role to play in the future.
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There are formidable difficulties confronting any organisation which wishes to develop a sustained market for a drug from a plant source. However, provided that valid early assessment is made, and provided that there is adequate investment in research and development, these problems can be overcome. No one should underestimate the time and the costs involved.
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|© Peter Lapinskas 1999-2012||Email Peter Lapinskas||Last updated: 3 July 2012|