Establishment Wages War On Supplements. Part2

[Guest guest]

Thu, 14 Oct 2004 20:06:12 +0200

 

" Sepp (Josef) Hasslberger " <sepp

 

Botanical Debacle? Unregulated Risk

 

The following article is on regulation of herbal products in the US,

and it goes together with one sent previously on the American Society

of Health-System Pharmacists warning against supplements.

 

Same campaign - tighter regulations for those products that compete

with pharma. Masterfully orchestrated.

 

Kind regards

Sepp

 

 

 

http://www.medscape.com/viewarticle/489431

 

Botanical Debacle? Unregulated Risk

Posted 10/01/2004

 

David A. Taylor

Abstract and Introduction

 

Abstract

 

Over the past decade, the marketplace has seen the rising popularity

of botanical dietary supplements. At the same time, the U.S. Food and

Drug Administration (FDA) has seen a rising need for better regulation

of such products. Reports have mounted describing adverse health

effects from certain products; variable quality, efficacy, and content

of products on store shelves; and questionable advertising claims made

on their behalf. As part of its mandate to regulate botanical

supplements, the FDA has undergone reorganizations to help it better

manage the myriad number of products within this class of products.

And the NIH has increased its budgets for research to eliminate the

huge gaps in the data on botanical dietary supplements.

 

Introduction

For the past decade, the U.S. medical establishment has been adjusting

to the rising popularity of herbal remedies and other dietary

supplements. The 1994 Dietary Supplement Health and Education Act

(DSHEA) created a new regulatory approach for products that included

herbal products, vitamins, and minerals. Intended to streamline the

entry of lower-risk products to the marketplace, DSHEA has since

become viewed by some as having unleashed a deluge of relatively

unregulated pharmacologically active products onto unwary consumers.

At the same time, reports have mounted describing products of variable

quality and manufacturers who lack accountability for their claims.

Today, regulatory agencies are ramping up their efforts to ensure the

safety of botanical supplements.

 

The Last Straw

 

Under DSHEA, herbal products, vitamins, and minerals were to be

regulated as foods, and were not subject to the rigors of drug or food

additive approval. Supplements that had been on the market prior to

1994 were presumed to be safe. They could be marketed without further

testing or approval from the Food and Drug Administration (FDA), even

if they were used in new combinations. [For more on DSHEA, see " Herbal

Medicine at a Crossroads, " EHP 104:924-928 (1996).]

 

According to the FDA, the number of supplement products on the market

grew more than sevenfold since DSHEA's 1994 passage, to about 29,000

in 2003. Many manufacturers entered the industry with little

investment and easy access to a growing market, and were not careful

in processing or labeling their products. Even under the best

conditions, quality control is tough for herbal supplements because

they start from plants containing many chemical compounds, and

constituent concentrations vary from batch to batch. And unlike

regulated pharmaceuticals, the active ingredients for botanical

medicines and dietary supplements are not well-characterized or in

some cases even known.

 

Consumer concerns about quality cropped up in the late 1990s, as many

companies rushed to bring herbal products to mainstream markets.

Consumers grew confused by the flood of new brands. Widespread

newspaper reports of deaths and other serious adverse reactions,

scandals over product labels that misrepresented ingredient content,

the discovery of contaminants such as heavy metals, and mixed results

in efficacy trials further dampened public enthusiasm. Supplement

sales have plateaued since. " Consumers seem to be more skeptical than

they were in 1998, " says Floyd Leaders, CEO of Botanical Enterprises,

a company that develops natural products.

 

Nevertheless, botanical supplements were still popular in February

2003, when a pitcher for the Baltimore Orioles major league baseball

team died as a result of taking a supplement containing ephedra. Until

then, ephedra (also known as ma huang) was one of the most popular

products for losing weight and enhancing athletic performance,

although for years reports of adverse reactions had signaled potential

health risks.

 

Weeks after the baseball player's death, the FDA proposed a set of

mandatory " good manufacturing practices " (GMPs) for dietary

supplements to ensure more reliable quality. These resembled practices

enacted for over-the-counter drugs, including guidelines for

regulating temperature, sanitation, and equipment maintenance. By law,

the supplement GMPs followed requirements for food GMPs rather than

those for drugs. The proposed GMPs were enacted early this year, with

phased-in requirement depending on the size of the manufacturer (large

manufacturers must comply within one year, medium-sized manufacturers

within two years, and small manufacturers within three years).

 

Articles in the 26 March and 17 September 2003 issues of JAMA raised

concerns about ephedra's safety, drug interactions caused by other

supplements, and the rise in unscrupulous advertisements for

supplements on the Internet, keeping up the call for regulatory

action. At the end of 2003, the FDA finally announced a ban of dietary

supplements containing ephedra, which took effect in April 2004.

Manufacturers were warned that other risky supplements could be next.

 

Shortly thereafter, to improve oversight specifically of botanicals

used in prescription drugs, the FDA issued a new guidance document, a

move that industry watchers found encouraging. The guidance gives

incentives for companies to take products through the clinical trials

that can lead to stronger claims: if a botanical product is legally

marketed in the United States with no known toxic effects, the

manufacturer can delay certain preclinical trials on toxicity and move

more quickly into the clinical trials phase to determine efficacy.

Without gaining premarket approval to sell the product as a drug, a

supplement maker can make claims about the product's effect on the

body (so-called structure-function claims, such as " calcium builds

strong bones " ), but they cannot claim to treat disease (for instance,

" calcium reduces the risk of osteoporosis " ).

 

Leaders welcomes the new FDA guidance, which he says puts the agency

" two or three years ahead of the industry " in terms of understanding

that public perception of an industry's reliability is critical to

product acceptance. What many in the industry don't yet fully

comprehend, says Leaders, is that the new guidance streamlines the

process by which manufacturers can gain exclusive claims of benefit.

It also gives the FDA a better basis for determining a product's safety.

 

The FDA's pursuit of ephedra brought a shift in the government's

approach to making its case for regulatory action, according to Ilene

Ringel Heller, senior staff attorney for the Center for Science in the

Public Interest (CSPI), a consumer advocacy group based in Washington,

D.C. " What took FDA so long in the case of ephedra is that FDA has the

burden of proving that a supplement poses a significant or

unreasonable risk before it can take action [to restrict its use], "

she says--an extremely difficult case to make in the absence of

adverse event reports. " Eventually, FDA decided . . . to do a

risk-benefit analysis and decide whether it poses an unreasonable

risk. And that's how ephedra got banned. But it's not certain that

this will be upheld in court. " Furthermore, points out George Lucier,

an advisor to the National Toxicology Program (NTP), good risk-benefit

analysis is simply not possible without good data on both efficacy and

toxicity.

 

A New Crop of Research

 

The framework for federal research on botanical products has evolved

to help produce those sorely needed data. The NIH Office of Dietary

Supplements (ODS), created by DSHEA, has grown from a $5 million

budget in 1999 to one more than five times that size in 2004. Yet

according to ODS director Paul Coates, the office's new five-year

strategic plan does not mark a dramatic shift in direction. The new

plan has major strategic goals very similar to the ones in the first

plan. The difference, says Coates, is one of emphasis: the ODS will

continue to support research to improve analytical methods and enhance

understanding of the mechanisms by which popular herbal supplements

act, and plans to assess the role of dietary supplements in reducing

the risk of chronic disease.

 

In its work, the ODS collaborates with most of the NIH institutes and

centers, including the National Center for Complementary and

Alternative Medicine (NCCAM), the NIEHS, and the John E. Fogarty

International Center for Advanced Studies in the Health Sciences.

Referring to NCCAM, Coates says, " We have areas of natural

complementarity, given that a great many dietary supplements have been

used in traditional healing environments. "

 

NCCAM's history parallels that of the ODS: established by Congress in

1998, the center quickly developed a program of research trials that

included studies of herbal products used in traditional medical

systems such as Indian Ayurvedic medicine and Chinese herbal medicine.

NCCAM also established an Office of Clinical and Regulatory Affairs.

 

Jonathan Berman, director of that office, says the center studies

dietary supplements according to a drug model to see if they are safe

and effective, and to determine dosage. Throughout its existence,

while exploring various alternative therapies, NCCAM has approached

dietary supplements with the aim of steering as many as possible

toward the FDA's drug approval process and its benefits of premarket

approval and more accountable manufacturing. Berman says NCCAM leaders

believe the new FDA guidelines for botanicals used in prescription

drugs will lead to safer products all around.

 

Research on botanical dietary supplements is also being conducted by

other branches of the NIH. In recent years, the ODS, NCCAM, and the

NIEHS joined forces to create six new research centers devoted to such

studies. These university-based centers meet annually to share

progress and compare notes, according to Diane Birt, director of the

Center for Research on Dietary Botanical Supplements at Iowa State

University. Other centers are located at the University of California,

Los Angeles (Center for Dietary Supplements Research: Botanicals), the

University of Illinois at Chicago (Center for Botanical Dietary

Supplement Research in Women's Health), the University of

Missouri-Columbia (Center for Phytonutrient and Phytochemical

Studies), Purdue University and the University of Alabama at

Birmingham (Botanicals Research Center for Age Related Diseases), and

the University of Arizona (Center for Phytomedicine Research).

 

Researchers at the NIEHS and the NTP also are conducting studies on

the safety of compounds found in dietary supplements. Since 1998, the

NTP has performed literature reviews for 41 candidate substances, with

studies actually conducted on about 20. Among the substances studied

were the alkaloids in comfrey (Symphytum officinale), an herb used by

the ancient Greeks to stop bleeding and heal wounds. Comfrey, however,

contains pyrrolizidine alkaloids, which are known to cause liver

cancer (in 1993 the FDA cited these effects in its report

Unsubstantiated Claims and Documented Health Hazards in the Dietary

Supplement Marketplace). The NTP quantified the alkaloid content of

comfrey samples and relayed the results to the FDA, and in July 2001

the FDA advised manufacturers to take comfrey products off the market.

" Although the FDA cannot require toxicological data for herbal

products, they can take regulatory action if data indicative of risk

become available. So studies like the NTP studies are important for

addressing public health concerns, " says Lucier.

 

Besides preclinical studies, the ODS supports efforts to standardize

methods for assessing supplements, as Congress mandated in 2002. This

mandate answered a need voiced by the industry itself, according to

Michael McGuffin, president of the American Herbal Products

Association (AHPA), a trade association based in Silver Spring,

Maryland. The industry welcomes standardized methods, McGuffin says,

so that the same analytical methods are used by producers, the media,

and the FDA alike. This can avert conflicting safety and efficacy

reports that leave consumers baffled.

 

Some experts maintain that even the big NCCAM-supported clinical

trials are not as definitive as they should be. One such major study,

focusing on St. John's wort (Hypericum perforatum) and published 10

April 2002 in JAMA, found the herb to be " no better than placebo for

the treatment of major mental depression, " says Berman. Observers

inside and outside the industry were dismayed perhaps less by the

findings than by how they were reported. " There appeared to be bias in

the reporting, " Leaders says--what the medical journal didn't note was

the authors' finding that the currently accepted treatment for

depression likewise performed no better than placebo, thus casting

doubt on the entire experiment.

 

Adds Mark Blumenthal, who directs the nonprofit American Botanical

Council of Austin, Texas, " Just as there have been problems with

quality control in some aspects of the herbal industry, there are also

some serious problems of quality control in the way that the media and

the medical journals themselves have reported on the herbals. "

Coates acknowledges the need for clearer public information. " The

people who commented on our strategic planning process more than once

said that we have to pay more attention to the development of

appropriate communications and information tools, " he says, " and we're

planning to do that. "

 

Growth Under DSHEA

 

In recent years, the FDA has reorganized itself to better reckon with

the challenges posed by DSHEA. In February 2003, the Office of

Nutritional Products, Labeling, and Dietary Supplements created a

separate Division of Dietary Supplement Programs. Susan Walker, who

heads that division, says it continues to explore relationships with

the NIH and its research institutes, including the NTP, and to

coordinate with other parts of the FDA, notably the National Center

for Toxicological Research.

 

The FDA and other agencies have become more vigilant in enforcing laws

pertaining to supplements. In late 2003 and early this year, the FDA

sent 119 warning letters to distributors of supplements and refused

entry of over 1,100 imported products, according to a 19 April 2004

agency press release. Enforcement by other agencies has been stepped

up too. The Federal Trade Commission, the FDA's partner in

enforcement, cracked down on unscrupulous advertisers of dietary

supplements in 2003 as part of an ongoing effort known as Operation

Cure-All. The result was 83 warning letters demanding that companies

cease making illegal claims on their websites and in their literature.

 

Manufacturers, too, are finding ways to live with the new policies. In

the past, companies complained that there was no incentive for drug

research on herbs because they couldn't patent a natural product. But

there are ways around that obstacle, for example by patenting the

process for extraction. " The process defines the product, " says

Leaders. He gives the example of brewing coffee: Starting from the

same coffee beans, you can either brew very strong Turkish coffee or a

drink as weak, he says, " as my mother used to make. "

 

Leaders says one of the two main weaknesses of the 1994 law was that

it did not require manufacturers to report adverse reactions to the

FDA. The latter point was echoed recently by a review panel of the

Institute of Medicine in its April 2004 report Dietary Supplements: A

Framework for Evaluating Safety, and by consumer groups. " FDA needs

authority to require mandatory adverse event reporting, " says Heller.

" It's a major shortcoming that FDA doesn't have it. "

 

The FDA does have a voluntary system in place for reporting adverse

events--the Center for Food Safety and Applied Nutrition Adverse Event

Reporting System is a computerized database of records submitted by

consumers, health care providers, and industry. Yet despite some

revamping of the system, Heller says the fact remains that reporting

to this system is, by virtue of being voluntary, largely ineffective.

Indeed, the April 2001 Department of Health and Human Services report

Adverse Event Reporting for Dietary Supplements: An Inadequate Safety

Valve cites an unnamed FDA-commissioned report as finding that the FDA

receives reports of less than 1% of all adverse events associated with

dietary supplements.

 

Other nations, too, are looking at issues related to botanical

supplement safety. Both the European Union and Canada have added a new

" traditional medicine " category for products that have a history of

use in the literature without adverse reactions. Like the United

States, Europe is reviewing how to assess the risks and benefits of

botanical dietary supplements. An expert group of the European branch

of the International Life Sciences Institute (ILSI Europe), a

Brussels-based nonprofit foundation that is funded primarily by

industry members, published a paper in the December 2003 issue of Food

and Chemical Toxicology offering new guidance on how to assess the

safety of botanicals. The authors stated that " ultimate safety in use

depends on the establishment of an adequate safety margin. " This

margin is the ratio between the dose demonstrated to be safe from

research and the dose actually consumed, explains Nico van Belzen,

executive director of ILSI Europe.

 

Defining what size margin is adequate, however, is a thorny

proposition and requires a case-by-case determination, admits van

Belzen. ILSI Europe suggests a decision tree approach to the

evaluation process, and has created a model for risk-benefit analysis

of micronutrients that can provide a tool to help officials weigh the

risk of deficiency (making the dosage too low for users to experience

a product's benefit) against the risk of toxicity (exceeding the

tolerable upper limit). That model will be published in an upcoming

issue of Food and Chemical Toxicology.

 

In the shadow of the ephedra mêlée, the system for balancing the

potential risks and benefits of botanical dietary supplements clearly

is still taking shape. With better understanding of herbal compounds

and improved regulation of the claims made on their behalf, however,

manufacturers and the public alike could reap a rich harvest.

 

 

 

--

 

 

The individual is supreme and finds its way through intuition.

Sepp (Josef) Hasslberger

 

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Search the net! There are literally thousands of alternative sources

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