Next month, the Shanghai Innovative Research Center of Traditional Chinese Medicine, a research and development institution for the modernization of traditional medicine, will apply to conduct clinical trials in Finland for its new antidepressant medicine extracted from herbs.
If the drug is approved, the center will be among a handful of companies that are launching therapeutic drugs derived from TCM onto the global market. “After seven years of study, we have extracted a single active ingredient from ginseng herbs. The pre-clinical trial has showed that this drug is safe and effective,” says Jiang Hongquan, an official with the center.
“The efficacy of this drug is very close to Eli Lilly’s Prozac, or fluoxetine, but the cost is much lower,” notes Jiang, adding that the active ingredient extracted from ginseng herbs is a brand new ingredient that had not been previously identified. The development is a breakthrough for herbal medicine innovation and modernization, according to Jiang, who says that the center is also considering applying to the U.S. Food and Drug Administration (FDA) for clinical trial approval. Meanwhile, given the renewed global interest in TCM-derived drugs, the new medicine remains a closely guarded business secret.
The Shanghai Innovative Research Center is not alone in its effort to introduce Chinese herbal medicines into the mainstream market. Other companies have been doing the same thing for years, including Hutchison MediPharma (the R&D subsidiary of London AIM-listed Hutchison China MediTech), and Tasly Pharmaceutical Co., one of China’s largest TCM manufacturers.
The market for pharmaceuticals is huge, but in the past few years, with few new drugs in the pipeline, the industry has hit a lull and is looking for a new direction. Enter Traditional Chinese Medicine (TCM), long a source of therapy for the Chinese, and more recently a source of pharmaceutical ingredients for Western drug makers.
However, on top of the efforts noted above, another new approach is now evident, thanks to a landmark 2004 ruling by the U.S. Food and Drug Administration, which combines the Eastern and Western approaches by allowing pharmaceutical drugs derived from plants – called botanical drugs – to contain more than one active ingredient. Drug companies around the world have taken notice.
TCM has now expanded in this bold new direction – using botanical drugs that mimic Western drugs because they have verifiable and measurable effects, but behave like Chinese drugs, because they combine several active ingredients into their therapies. It’s a third way forward for the world’s drug manufacturers, and they are beginning to take action.
Meanwhile, in China, the ancient home of herbal medicine and a country where some 600 time-honored therapeutic herbs are widely used, TCM is undergoing a transformation of its own. The government has tightened production standards, set new regulations for the growth of medicinal crops and made other moves to push TCM into the world of modern medicine. “Together, these two trends promise to provide new cures for consumers and new business horizons for both Chinese and Western drug companies,” according to an industry expert.
East Is East and West Is West
TCM modernization has been a hot topic in recent years, both in China and abroad. The accepted definition of TCM modernization is the identification of an active ingredient or several active ingredients from an herbal remedy that results in mass production and marketing of a drug with a detailed pharmacokinetic profile. Essentially, it is the process of introducing Chinese herbal medicines to the world as therapeutic, Western-style drugs, rather than as food and dietary supplements.
The key to modernizing an herbal medicine is to prepare it as a Western drug – that is, to conduct laboratory tests and analyze its active ingredient or ingredients. However, due to the very different theories espoused by Western medicine versus herbal medicine, that makes the modernization of herbal medicines exceedingly difficult.
Western medicine uses precise, molecular-level studies to make accurate drug profiles, and sets up diagnostic and efficacy standards for their use with different diseases. Western medicine and theories are products of laboratory tests, which can be measured and repeated. As a result, Western medicine is rigorously scientific.
However, as a clinical pursuit, Chinese herbal medicine stresses a holistic understanding of the body and how the parts relate to each other, in contrast to the Western emphasis on disease causes and pathology.
While Western medicines concentrate on causing a specific effect on targeted areas of the body, Chinese herbal medicines are explained by concepts like ‘temperature’ and ‘taste’, the two major dimensions of Chinese herbs. These temperature characteristics and taste properties are used to adjust the overall ‘balance’ of the patient.
The two systems are very different. The Western approach – identifying specific targets and using particular drugs to achieve certain results – is not regarded as applicable by TCM practitioners. In TCM, the body is seen as a complex and open system, and the symptom-specific Western approach is viewed as too narrow. TCM practitioners point to the toxicity and side effects of some Western medicines as a demonstration of this point.
This difference in approach makes the TCM modernization process more difficult, as it is not easy to make traditional herbal TCM more controllable by pinpointing and evaluating active ingredients. Yet the effort is ongoing: “Pharmaceutical researchers from all around the world are exploring ways to establish a scientific evaluation system to make the development of herbal medicines controllable, to pinpoint the active ingredients and to ensure safety,” says Ye Yang, the head of the herbal medicine research department at the Shanghai Institute of Materia Medica.
One of the solutions is to market TCM drugs as herbal remedies. However, herbal remedies have been pigeonholed as food and dietary supplements. For centuries, these remedies have been used as traditional therapies, but in mainstream markets like the U.S and Europe, they are only recognized as food and dietary supplements. These supplements include vitamins, minerals, and herbs or other plants, and they can be in pill, capsule, tablet, or liquid form. Common dietary supplements include vitamins and minerals, botanicals such as St. John’s wort, and substances that come from a natural source, such as glucosamine.
Makers of dietary supplements cannot legally claim that the supplements can diagnose, cure or prevent disease, but they can say they contribute to health maintenance and well-being. The U.S. FDA does not regulate dietary supplements in the same way that it regulates medication, because there is a lack of global standards to evaluate their efficacy and safety. This limits their marketability.
The Western Approach — A TCM-based Malaria Treatment
A second solution is to isolate the active ingredient of a TCM, and analyze, test and market it as a Western-style drug, which is what Shanghai Innovative Research Center of Traditional Chinese Medicine has been doing.
Another institute from Shanghai — The Shanghai Institute of Materia Medica, a subsidiary of the Chinese Academy of Sciences — has also long been engaged in the development and research of plant-derived drugs, both for TCM modernization and for traditional TCM treatments. It has pioneered one notable drug: the Institute developed Artemether, a derivative of artemisinin, in the 1980s, and it is now one of the active ingredients in Novartis AG’s anti-malarial therapy, Coartem.
Coartem, first registered in 1998, contains artemether and lumefantrine, and is one of the few therapies recommend by the World Health Organization as a preferred alternative in areas experiencing resistance to conventional monotherapies against malaria, an infectious disease that threatens some 40% of the world’s population. Artemisinin, a substance extracted from the plant Artemisia annua L, or sweet wormwood, is the only Chinese-developed drug that has received international acclaim for its effectiveness in treating malaria.
The company is now working on a new, anti-aging herbal medicine. “We are collaborating with researchers from other countries on a global Phase III clinical trial on an herbal medicine for the treatment of aging-related diseases,” Ye says. “And we believe that herbal medicine has the potential to treat diseases in which the efficacy of Western medicine faces limitations.” Global Phase III trials are large-scale worldwide clinical trials, as opposed to region-specific trials.
A New Way Forward
Although turning TCMs into Western-style drugs is effective and often lucrative, it is still more West than East, and the results can’t be precisely defined as TCM. However, there is now a third way forward: botanical drugs that combine several active ingredients in the same way that time-honored TCM treatments do.
The new approach received a strong boost from a landmark June 2004 ruling by the U.S. FDA, when it published its Guidance for Industry for Botanical Drugs, a new policy that provides advice for botanical drug makers. The new policy described the application process and provided recommendations on how chemically complex products might satisfy the requirements of the FDA’s rigorous ‘new drug’ review process.
The FDA defines a botanical as a product that exclusively contains ingredients from plants, algae or fungi. In contrast to most conventional pharmaceutical drugs comprised of one single chemical, botanicals contain complex mixtures of naturally occurring chemicals. A botanical drug, according to the FDA, is an herbal medicine that has been successfully modernized and has a clear pharmacokinetic profile.
A huge breakthrough came in 2006 when MediGene, a German biotech firm, obtained approval from the U.S. FDA to market Veregen ointment, a botanical drug that is extracted from green tea leaves for the treatment of genital warts. “This is the first time that the U.S. FDA has granted approval to a polymolecular botanical drug in more than half a century. This move gives us more confidence in doing modernization on Chinese herbal medicines,” says Tom Tang, vice president of Hutchison MediPharma.
The FDA’s approval of the ointment is regarded as ground-breaking. “It is proof that the FDA can deal with botanicals, not only as foods and dietary supplements, but also as approved medicines,” says Freddie Ann Hoffman, an expert on the botanical drug process. Hoffman, a former U.S. FDA official who was quoted in the product’s news release by the American Botanical Council, said the approval paves the way for a new pharmaceutical industry.
Other companies are following a similar path. “We are encouraged by the FDA’s growing acceptance of herbal remedies,” Tang says. “Through our communication with U.S. FDA officials, we find that they have confidence in this new area of drug development.”
Hutchison MediPharma now has two botanical drugs based on Chinese herbal medicines undergoing Phase II clinical trials in the U.S. (Typically, drug trials are performed in phases: There is a pre-clinical trial, then a Phase I clinical trial, then Phase II, Phase III and Phase IV. Phase IV, conducted after the product is on the market, is an additional test of long-term safety.)
The two botanical drugs, HMPL-004 for the treatment of Crohn’s disease and Ulcerative Colitis, and HMPL-002, a treatment for head and neck cancer, are expected to be launched in the U.S. market in 2011 and 2013 respectively.
In November last year, HMPL-004 obtained clearance for its new Investigational New Drug (IND) application from the U.S. FDA for ulcerative colitis, a form of inflammatory bowel disease. The IND allows the company to begin a global Phase IIb trial; Phase IIb is a later stage of a Phase II clinical trial.
Tasly has also unveiled a botanical medicine, this one derived from Danshen (the dried root of Salvia miltiorrhiza) and two other plant ingredients. The new drug, called Compound Danshen Dripping Pill, or CDDP, is now undergoing Phase II clinical trials in the U.S., and will be used in the treatment of cardiovascular diseases. Danshen is widely used in China to quicken blood circulation and relieve chest pain.
The overall process is far from easy, says Tang. “There are many difficulties, especially in terms of quality control. Botanicals, or plant-derived drugs, are a mix of chemical entities, so it is difficult to pinpoint the active ingredient and how the drug works.”
Tightening Standards within China
TCM has a 3,000-year-old history, and the current Chinese pharmacopoeia lists more than 6,000 different medicinal substances in terms of their properties and the conditions, or disharmonies, that they can help treat. As many as 600 different herbs are now in common use in China. “It’s a great treasure for us,” says Tang.
China’s long history of TCM use should prove useful, adds Ye, of the Shanghai Institute of Materia Medica. “China has the advantage in terms of TCM culture – experienced TCM practitioners and an abundant talent pool. If you come to Zhangjiang High-Tech Industrial Zone, you will be amazed by the number of scientists who are engaged in the research and development of herbal medicines.”
The Shanghai-based Zhangjiang High-Tech Industrial Zone is home to the R&D centers of hundreds of pharmaceutical companies, including big names such as Novartis, Roche and AstraZeneca, as well as medium-sized and smaller pharmaceutical companies.
In addition to spearheading R&D efforts, the Chinese government has moved to enhance the quality and safety of herbal medicine production. As of January this year, China’s State Food and Drug Administration (SFDA) began to require all TCM ‘ready form’ makers to be GMP (Good Manufacturing Practice) certified. Ready form is an herbal medicine that is processed, and can be taken after being boiled with water.
“The technology used in the production of TCM ‘ready forms’ is still of low quality, with the result that many small and medium-sized companies are rushing into this business in the hope of turning a quick profit,” says Zhou Rui, a pharmaceutical analyst with Haitong Securities Co. Ltd., who specializes in the TCM sector. “In the past, these drug makers did not bother much with GMP standards, so this move will force unqualified manufacturers to shut down their factories.”
A few days later, the Chinese government implemented several more policies aimed at further standardizing production and research and development of Chinese traditional medicine. “Standardizing the production of TCM is a major step towards TCM modernization,” says Zhou.
A key policy is the supplementary regulation on TCM registration, which brings herbal medicines more in line with Western medicines in terms of drug registration.
“The quality of a finished TCM varies mostly as a result of factors closely linked to the raw materials used in TCM production,” says Tang Sheng’an, a researcher at the TCM R&D Center of Tasly Pharmaceutical Co. Because environmental conditio