HerbalEGram: Volume 7, Number 10, October 2010
Chinese Herbal Medicine Clears US FDA Phase II Trials
A patented Chinese herbal medicine has successfully
completed Phase II clinical trials in the United States and will soon begin
Phase III investigations, raising the possibility that it could become the
first Traditional Chinese Medicine (TCM) product to obtain drug approval from
the US Food and Drug Administration (FDA).1
The product, Compound Danshen Dripping Pill (also referred
to as Cardiotonic Pill), is produced by Tianjin Tasly Pharmaceutical Co. Ltd.
in Tianjin, China. It contains the extract of the root of Chinese salvia (Salvia
miltiorrhiza; known as danshen in Chinese), the extract of the root of notoginseng
(Panax notoginseng; known as sanchi
or tien-chi ginseng), and synthetic borneol, an active ingredient
that replaces the more expensive natural borneol found in cardamom (Elettaria
cardamomum var. cardamomum), ginger (Zingiber officinale), and other spices.1,2,3 According to
Tasly’s website, the pill is sold as a prescription drug in China, Vietnam,
Pakistan, South Korea, India, and the United Arab Emirates and reportedly is
taken by about 10 million people every year to treat angina and coronary heart
diseases.3 Last year, its international sales brought in a reported
$148 million.
Danshen has been used
in TCM for many years to improve patients’ circulation and to treat
cardiovascular diseases.3 The oldest documented record of danshen as a medical agent is found in Shen Nun
Ben Cao (The Divine Husbandman’s
Classic of the Materia Medica), dated at
about 200 CE.4 Consumers in the United States are currently able to
buy and use danshen and notoginseng
either as whole, raw herbs or in herbal dietary supplements. An FDA drug
approval would give Tasly protection of market exclusivity for the pill’s
ingredient combination, specifically in dripping pill form and for the
cardio-indication as a prescription drug, because it specifically intends to treat and prevent
disease.5 (The product cannot qualify for over-the-counter drug
regulation because the condition it intends to treat is not a self-diagnosable,
self-treatable, and self-limiting condition.)
“This product, known earlier as Fufang Danshen Pian
(tablet of salvia with other ingredients), has been used in China for many
years, and there have been efforts to get it approved for use outside China for
decades,” said Subhuti Dharmananda, PhD, director of the Institute for
Traditional Medicine and Preventative Health Care in Portland, Oregon (e-mail,
September 16, 2010).
"The biggest problem,” he said, “is that it is for
very serious cardiovascular disorders—mainly angina pectoris—and so it is
difficult to integrate it into modern medicine. There were some previous
concerns about borneol being potentially toxic, but I think that has been alleviated
in recent years. Also, the problem of inconsistency of the botanical
constituents is a big issue. In particular, notoginseng grows in southwestern China, an area with difficult
climatic conditions that can lead to considerable variability of the chemistry
in the root.”
In order to conduct human clinical trials, a product must be
designated by FDA as an investigational new drug (IND), which requires varying
levels of evidence that the product is safe for testing in humans and that the
clinical protocol is suitably designed.5 (Compound Danshen Dripping
Pill was the first TCM product to obtain IND designation in the United States in
1997.2) Then, Phase I consists of testing the drug within small
groups to determine safety, dosage range, and side effects, and in Phase II
researchers study the drug on a larger group of people to determine safety and
efficacy. In its third phase of clinical trials, Compound Danshen Dripping Pill
will be studied on large groups of people to confirm efficacy, monitor side
effects, compare it to commonly used treatments, and collect safety
information.6
If Phase III investigations are completed, Tasly can decide
to submit a new drug application (NDA) to FDA, which then considers if the drug
used for its intended purposes is safe and effective, if the benefits outweigh
any known adverse side effects, if the drug’s proposed labeling is appropriate,
and if the drug can be manufactured in a way that preserves its identity,
strength, quality, and purity.7
An FDA drug approval for Compound Danshen Dripping Pill,
which could take 10 years from the beginning of Phase III trials, might be
significant, as it entails official recognition of the safety and efficacy of
an herbal preparation in the conventional healthcare system, said William Morris,
PhD, DAOM, LAc, president of the Academy of Oriental Medicine at Austin, TX
(e-mail, September 23, 2010). “But it
could also mean that there is a trend toward ‘pharmaceutical herbs,’” Dr.
Morris added.
Additionally, of the
near 3,000 medicines currently in development stages in the United States, only
25 new drugs were approved in 2009, evidence of the extreme difficulty in
bringing a new drug to market in the United States.8 It now costs a
reported $800 million to $1.3 billion to conduct the research and development
needed to bring a new drug to the market, and generally takes 10 to 15 years
for most new drugs to go from the laboratory to market.8,9
“If the drug successfully gains approval in the US through
the NDA process, it will be the first time a multi-sourced botanical ‘new’
drug—one derived from more than one plant [or] plant part—is approved by FDA,
and the first botanical to achieve a cardiovascular indication,” said Freddie
Ann Hoffman, MD, a former FDA official and founder of HeteroGeneity, LLC, a
Washington, DC-based consulting firm that advises companies seeking to market
botanically-based drugs (e-mail, August 17, 2010). Dr. Hoffman noted that there
are approximately 450 IND and pre-IND applications for botanicals that have
been submitted to FDA.
Many botanical product sponsors experience great difficulty
in completing the FDA clinical trial process due to the complex chemical nature
of the products’ multiple plant components. To address this situation, in June
of 2004, FDA released Guidance for Industry for Botanical Drugs.10 This document advises potential
botanical drug sponsors by describing both the application process and
recommending how chemically complex products might satisfy the requirements of
FDA’s rigorous drug review and approval process. Though presenting somewhat
different regulatory policies for botanical INDs than those applied to other
drugs, including a somewhat easier process for Phase I and II trials, the
document states that botanicals are still treated like any other new drug in
order to gain full drug approval.5
According to the FDA Center for Drug Evaluation and
Research (CDER) Botanical Review Team, the most difficult issue for new
botanical drugs is how to ensure "therapeutic consistency" of all
marketing batches, which is typically easier for synthetic, purified small
molecule drugs (e-mail, C. Rice [FDA], August 17, 2010). The Botanical Review
Team noted that it thinks a comprehensive approach can address this situation.
“Besides conventional [chemistry, manufacturing, and controls] measures, the
sponsor may use clinically relevant bioassay, clinical dose-response data, and
testing multiple batches in Phase III clinical trials to demonstrate the
consistency of a botanical drug product.”
Scientists working with single-herb botanicals and TCM
products, which usually are mixtures of herbs, also face challenges in showing
evidence that each component of their complex mixtures contributes to the
product’s claimed effects. This requirement may be impossible for botanical
researchers to meet before FDA revises the related regulation, said the FDA
Botanical Review Team.
Additionally, few conventional health professionals in the
United States practice TCM, said Dr. Hoffman. “Therefore the product and
its uses must be ‘translated’ into US medical practice. This goes for claims,
dosage forms, and schedules (consumers want once- or at most twice-a-day
dosing). Although the indication may be derived from traditional use, the
pivotal clinical study (or studies) must address what will go in the drug’s
Package Insert—the prescribing information for the health
practitioner. The US approach to medicine is not individualized in the
same way that TCM is practiced.”
Though difficult, it is not impossible for botanicals to successfully
complete FDA’s drug approval process. In 2006, FDA gave drug approval to
Veregen® Ointment (Medigene AG, Martinsried/ Munich, Germany), which
contains a proprietary blend of phytochemicals produced from a partially
purified water extract of green tea leaves (Camellia sinensis, Theaceae).10 Veregen was the first
botanical approved as a drug under the 1962 federal law known as the
Kefauver-Harris Amendments, which requires drugs to be proven both safe and
effective prior to being marketed in the United States.
No botanicals have achieved drug designation since Veregen
(C. Rice, e-mail, August 17, 2010), and it is possible that Compound Danshen
will also fail to obtain FDA drug approval.
“While entering into Phase III usually means that there is sufficient
interest on the part of the sponsor to proceed—based on prior studies—the
success of the trial lies strictly with the data itself, which determines
whether FDA can approve the drug for marketing,” said Dr. Hoffman. “Even drugs
produced by large, global pharma companies, which have gone through rigorous
preclinical testing, can ‘miss the mark’ in Phase III.” Some examples include Medivation's
drug Dimebon for Alzheimer's disease,11 Merck’s HIV drug vicriviroc,12 and Inspire
Pharmaceuticals’ Prolacria for the treatment of dry eye disease.13
—Lindsay Stafford
Photo captions in order of appearance: 1) Dried root of Chinese salvia (Salvia
miltiorrhiza; known as danshen in Chinese).©2010 Jasmine Oberste. www.chineseherbgarden.com. 2) Dried root of notoginseng
(Panax notoginseng; known as sanchi
or tien-chi ginseng). ©2010 Jasmine Oberste. www.chineseherbgarden.com. References
1.
Chinese patent traditional medicine first time passes U.S. FDA crucial clinical
trials. Xinhua. August 7, 2010. Available at: www.news.xinhuanet.com/english2010/china/2010-08/07/c_13434173.htm.
Accessed August 12, 2010.
2. Xiaohui Z, Xinfeng Z, Xin Z, Shixiang W, Yinmao W, et al.
Determination of the main bioactive metabolites of Radix Salvia miltiorrhizae in Compound Danshen Dripping Pills and the tissue
distribution of Danshensu in rabbit by SPE-HPLC-MS. J Sep Sci. 2007:30;851–857.
3. Herbal medicine. Tianjin Tasly Pharmaceutical Co.
Ltd. website. Available at: www.tasly.com/en_web/Product_list1.aspx.
Accessed August 18, 2010.
4. Chen J, Chen T. Chinese Medical
Herbology and Pharmacology. City of
Industry, CA: Art of Medicine Press Inc., 2001;636-637.
5.
Amin R, Bayne H. FDA issues final guidance for industry regarding botanical
drug products. HerbalGram. 2004; 64:52-53.
Available at: www.cms.herbalgram.org/herbalgram/issue64/article2741.html.
6. Understanding clinical trials. ClinicalTrials.gov
website. Available at: www.clinicaltrials.gov/ct2/info/understand#Q01.
Accessed August 18, 2010.
7. New drug application (NDA). Food and Drug
Administration website. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm.
Accessed August 18, 2010.
8. Pharmaceutical Research Companies Receive Approval for 34
Innovative Treatments in 2009. New Drug Approvals in 2009: Presented by
America’s Pharmaceutical Research Companies. The Pharmaceutical Research and
Manufacturers of America. Available at: www.phrma.org/new_drug_approvals.
Accessed October 1, 2010.
9. Woodcock J, Woosley R. The FDA critical path initiative
and its influence on new drug development. Annu Rev Med. 2008;59:1-12.
10. FDA approves special green tea extract as a new topical
drug for genital warts; expert says development marks the birth of a “new
industry.” HerbalGram. 2007;74:62-63.
Available at: www.cms.herbalgram.org/herbalgram/issue74/article3120.html.
11.
Carroll J. Medivation's Dimebon fails Phase III for
Alzheimer's, shares collapse. FierceBiotech. March 3, 2010. Available at: www.fiercebiotech.com/story/breaking-news-medivations-dimebon-fails-phase-iii-alzheimers/2010-03-03. Accessed October 1, 2010.
12.
Horstmann A. Merck defers seeking FDA approval of Vicriviroc for
treatment-experienced HIV patients. The AIDS Beacon. February 2, 2010. Available at: www.aidsbeacon.com/news/2010/02/02/vicriviroc-not-approved-for-treatment-experienced-hiv-patients/.
Accessed October 1, 2010.
13.
Inspire Pharmaceuticals stops Prolacria development program, amends agreement
with Allergan. The Associated Press. August 25, 2010. Available at: www.finance.yahoo.com/news/Inspire-Pharma-amends-apf-3388997606.html?x=0&.v=1.
Accessed October 1, 2010.
|
|