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Perspectives: Mainstreaming Alternative Medicines: Botanicals and Other Complex Natural Products as Prescription Drugs
FDA-approved treatment options for people with epilepsy include medications and vagus nerve stimulation. Special diets, especially for children, and brain surgery may be very beneficial as well for selected patients. However, approximately 1 in 3 persons with epilepsy taking medications do not achieve adequate control of seizures and another 1 in 3 experience side effects that interfere with daily activities. Consequently, there continues to be a need for new and well tolerated treatments.
Complementary and alternative medicine
Those patients who experience suboptimal clinical responses to current treatment regimens often seek out alternative treatments. Use of "complementary and alternative medicine" (CAM) is quite prevalent in people with epilepsy.[Schachter-2008] CAM includes herbal and other natural medicines, many of which have been used historically to treat neurological disorders (see Table 1), but have not been formally tested or evaluated by the FDA to date. Although mainstream drugs often contain a single compound ("active") derived from natural products, plant extracts comprised of complex chemical mixtures have not been a part of US medicine— at least not until recently.
In the US, botanicals were historically used as drugs up until the passage of the Kefauver-Harris Act in 1962. The law amended the federal Food, Drug and Cosmetic Act to impose rigorous requirements on the US Food and Drug Administration (FDA) to affirm the safety and efficacy of all drugs marketed after 1938. To study the clinical effects of a botanical extract or food as a treatment or prevention of seizures, an Investigational New Drug (IND) application must be filed with the FDA. This requires the submission of not only a clinical section (study protocol, investigator credentials and consent form), but also detailed information about the chemistry, manufacturing and controls (CMC) of the study product.
Botanicals and herbals
For botanicals, product sponsors were stymied as to how to conform to FDA’s CMC requirements, since for some products there was no specific "active", and for others there were too many "active" constituents to characterize. As a result very few "pre-1962" botanical ingredients remain on the US market as drugs.
As a product class, botanicals did not return to the US market in any numbers until the passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994. This could be attributed in part to DSHEA’s explicit mention of "botanicals and herbals" as "dietary ingredients" for use in dietary supplements. By this time there was also the misperception that complex mixtures could no longer be marketed as drugs in the US.
The above may explain why in the US the majority of natural ingredients are sold today as foods, including "dietary supplements." In foreign countries the same products and ingredients may be classified as "herbal" or "traditional" medicines or drugs. Contrary to other regulatory systems, products are regulated in the US by their intended use. A product intended to be used to diagnose, treat, prevent, mitigate or cure a disease condition, such as epilepsy or seizures, and which exerts its effect by affecting the structure or function of the body, is considered to be a "drug," regardless of the source or nature of its ingredient(s), or how it is currently being marketed in the US.
Botanicals not intended as treatment
No prohibition exists for physicians to recommend botanicals to their own patients or for consumers to self-medicate with these products. However, such products are not intended to be used to treat or prevent disease, disease symptoms or the side effects of mainstream interventions, and rigorous evidence of their effectiveness and safety is often lacking. Further, manufacturing requirements for foods and "dietary supplements" are far less rigorous than for drugs, and unlike drugs, there is no criterion that foods or supplements must demonstrate "efficacy".
In June 2004, FDA published a "Guidance for Industry for Botanical Drug Products" in which it defines a "botanical" as any product that "contains ingredients of vegetable matter or its constituents as a finished product." The guidance provides recommendations for developing botanicals and other complex mixtures for the US market as drugs and describes the IND process for botanical drugs, focusing on the CMC and toxicological sections of the application.
According to this guidance, for a botanical drug, documentation of the product’s identity (genus, species, cultivar), sourcing (growing conditions, harvesting, processing), characterization (HPLC "fingerprint"), standardization (biomarkers, lot-to-lot consistency), potency and stability and manufacturing process validation are needed to ensure reproducibility of the clinical results. Safety data from both nonclinical (animal) testing, and prior human use (if available), and efficacy data must be collected or established in "adequate and well-controlled" trials. Data submitted to the IND eventually serve as the basis of a New Drug Application (NDA) to permit marketing of the drug. To approve an NDA, FDA must affirm that the data support the drug’s benefits and that these outweigh any risks to the intended "target" population.
To date, the FDA has received nearly 400 "pre-IND" meeting requests and IND applications for botanical drugs. FDA recently approved two NDA applications for naturally complex drugs. An omega-3 drug derived from salmon oil, [originally called Omacor®; Ross Laboratories; licensed to Reliant Pharmaceuticals, NJ; and now marketed under Lovaza®] was approved in November 2004, as "an adjunct to diet to reduce very high (≥500 mg/dL) triglyceride (TG) levels in adult patients." In October 2006, FDA approved the first complex botanical drug, a green tea extract [Veregen®, Medigene; Munich] as a topical treatment for genital warts. As approved drugs, both of these complex natural products were able to meet the legal criteria for safety and efficacy, and they are manufactured to the same quality standards as other prescription drugs in the United States.
While no complex botanical drugs have yet been approved by FDA for use in epilepsy, their polymolecular nature may theoretically be able to impact a multitude of cellular targets, and it is likely that further developments will be made in the testing and development of complex botanical drugs for the treatment of epilepsy.
TABLE 1: Complex Botanical Ingredients Traditionally Used for Epilepsy and Other Neurological Conditions (Caution: Rigorous Evidence for their Safety and Efficacy is Generally Lacking)
Source: Chart created by HeteroGeneity, LLC for epilepsy.com
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Submitted on April 20, 2008
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