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Jill Wechsler is Pharmaceutical Technology Europe's Washington Editor, firstname.lastname@example.org.
As the US Food and Drug Administration (FDA) strives to streamline its regulatory process for bringing new drugs to market (see sidebar "Manufacturing data key to spurring drug development"), efforts to ensure the quality, safety and efficacy of dietary supplements and herbal medicines are gaining more attention.
As the US Food and Drug Administration (FDA) strives to streamline its regulatory process for bringing new drugs to market (see sidebar "Manufacturing data key to spurring drug development"), efforts to ensure the quality, safety and efficacy of dietary supplements and herbal medicines are gaining more attention. FDA is working with the Federal Trade Commission (FTC) to crack down on unsubstantiated health claims by supplement makers; reports of serious adverse events involving weight-loss supplements containing ephedra, a medicinal herb, have led to product seizures and FDA legal action against manufacturers. Researchers are also investigating whether herbal products with kava, another medicinal herb, cause liver toxicity. Manufacturers and regulators hope that new good manufacturing practice standards (GMPs) will help ensure the safety and quality of supplements on the market and overcome demands to regulate these products more like drugs.
Manufacturing data key to spurring drug development
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), dietary supplement makers do not have to prove efficacy or even safety to go on the market, as is required for drugs. Manufacturers merely have to assure FDA that a product is "reasonably expected to be safe," shifting the burden to FDA to demonstrate that a product poses a significant or unreasonable risk to consumers before enforcement action can be taken. DSHEA permits manufacturers to make "structure/function" claims for supplements (such as "relieves stress" or "supports joint function") but not "health claims" (such as "reduces risk of cardiovascular disease"), a fuzzy distinction that has generated fierce legal battles.
However, the proliferation of questionable dietary product health claims - and the growth of the supplement market from $3.3 billion in 1990 to approximately $18 billion today - is prompting government regulators and enforcement officials to call for stronger oversight. Some members of Congress want to revise DSHEA to clarify government authority to remove unsafe products from the market and to require supplement manufacturers to file adverse event reports (AERs) with FDA.
In response, FDA's Center for Food Safety and Nutrition (CFSAN) is establishing a new AER data system for dietary supplements, food additives and cosmetics to detect more safety "signals" from the relatively few AERs filed for these products. FDA commissioner Mark McClellan has also launched a programme to clarify what health claims can be made for conventional foods, as well as supplements and other medical products, and what scientific evidence is needed to support such claims. However, a more liberal policy on health claims includes plans for stepped-up enforcement action against manufacturers that make false or misleading statements.
All parties agree that supplement regulation would be greatly improved by FDA's adoption of manufacturing standards. DSHEA has authorized FDA to do this, but the GMP development process has been excruciatingly slow. Manufacturers found an initial FDA GMP proposal too similar to standards for drugs. FDA tried to move the process forward by publishing a set of standards proposed by manufacturers in 1997, but then was slow to come up with its own version. A proposed rule that was headed for final publication in late 2000 was pulled by the Bush administration for further review.
Last October (2002), the Department of Health and Human Services (HHS) finally sent a revised proposed rule to the Office of Management and Budget (OMB) for clearance and announced in January (2003) that the proposal was coming "very soon."
Officials at CFSAN's Office of Nutritional Products, Labeling and Dietary Supplements (ONPLDS) plan to hold public meetings to encourage broad dialogue on this long-awaited policy, but a final rule remains months, if not years, away. The debate is expected to focus on requirements for the validation of manufacturing processes and analytical methods, plus the need for expiration dating on products versus "use before" recommendations. Small supplement makers oppose strict validation policies as too costly and unnecessary, and don't want to do the extensive stability testing needed to set expiration dates. Once FDA adopts final GMPs, the agency plans to establish an inspection programme to ensure industry compliance.
One possibility is that FDA will modify inspection requirements for manufacturers that participate in voluntary quality audit programmes established by private organizations and laboratories. The National Nutritional Foods Association (NNFA) has a partnership with NSF International to audit and certify the quality of dietary supplements. NNFA requires members to comply with its own GMPs voluntarily. These call for firms to establish procedures and maintain records on plant maintenance, facility sanitation, equipment design, quality control operations, process controls, personnel training and distribution procedures.
NNFA members who want to certify GMP compliance may sign up for a third-party audit programme, a step taken by approximately 40 companies, with 60 more in the pipeline. The association has also launched a "true label" programme that conducts random tests on the ingredients in certain supplement product categories to see if what is in the product matches the label. Compliance with GMPs, explained NNFA executive director, David Seckman, at a conference on dietary supplements sponsored by the Food and Drug Law Institute (FDLI) in January, requires companies to understand, analyse and control their manufacturing and distribution processes and to demonstrate to third-party auditors that they keep required records and meet set standards.
NSF International has its own programme for certifying that individual supplement products meet quality standards recognized by ANSI, which involves demonstrating compliance with GMPs. Manufacturers submit products for testing and undergo an audit of production facilities. Under its agreement with NNFA, NSF will accept NNFA GMP certification and vice versa. NSF also offers GMP registration, which is particularly attractive to contract manufacturers that don't want to certify the quality of specific products.
The US Pharmacopeia (USP) has also established a dietary supplement verification programme (DSVP) that is open to all supplement firms. Manufacturers may display the DSVP seal on products that USP tests to ensure ingredients meet labelling strengths, have acceptable contaminant levels and meet USP manufacturing standards. USP conducts lab tests on products to evaluate composition, strength, contaminants and dissolution; reviews manufacturer quality control documentation, test methods and stability data; and inspects manufacturer facilities to ensure compliance with GMPs.
USP recently announced that it would award its seal to a number of products in Pharmavite's "Nature Made" line and to Kirkland products sold in Costco stores. Weider Nutrition International and Inverness Medical Innovations have products undergoing USP's testing process, and other supplement makers are signing up, according to USP vice president Srini Srinivasan. He believes that the USP audit programme complements FDA compliance efforts and that manufacturers that qualify for the USP seal will meet FDA GMP requirements.
Although GMPs and certification are important for ensuring that manufacturers operate high-quality production systems, they do not guarantee product purity, consistency or safety. GMPs will help bring all industry players up to a higher level of quality, observed Annette Dickinson, acting president for the Council for Responsible Nutrition (CRN) at the FDLI conference, but added that GMPs can be oversold as a guarantor of quality. Also needed are analytical methods and standards to ensure product purity and safety; her organization, for example, has issued a voluntary quality monograph on omega-3 fatty acids and is updating a publication on safe intake limit ranges of vitamins and minerals.
FDA, USP, National Institutes of Health (NIH) and others have launched a number of initiatives to analyse and set quality standards for supplements and botanicals, which are listed below:
Analysis. FDA is conducting a systematic pharmacological analysis of ephedra products on the market to fully assess if they contain synthetic ephedrine alkaloids and thus would qualify as drugs and be subject to drug regulations. So far, such analysis has found that certain supplements marketed as "natural" actually contained the pharmaceutical-grade chemicals, ephedrine hydrochloride and caffeine anhydrous, which make them illegal and subject to prosecution.
Monographs. USP is updating and expanding ingredient monographs for botanicals and dietary supplements, building on its original charge in 1820 to set standards on natural medicinal products such as chamomile, valerian and ginger. USP has published 28 monographs on botanicals and more than 100 on other supplement products based on more sophisticated analytical techniques, and dozens more are in the works. The organization has also issued reference standards for amino acids, botanicals, vitamins and minerals, and other products which can be used as standards to ensure product quality, purity and potency around the world.
Supplements. FDA and NIH's Office of Dietary Supplements (ODS) have awarded a contract to AOAC International (Gaithersburg, Maryland, USA) to provide accurate, validated analytical methods for 20 supplements during the next 5 years. An AOAC dietary supplement task group has drafted a priority list for evaluating ingredients based on product market share, FDA safety concerns and the availability of test methods. Expert review panels will identify best analytical methods for validating product quality and identity, starting with existing laboratory test methods for substances such as mcarotene, black cohosh, ginkgo, kava, ginseng and saw palmetto. The programme aims to train laboratory scientists to use accepted analytical methods and will disseminate official methods through an online electronic compilation of analytical methods. Recommended methods may be included in USP monographs and other standards.
Research. ODS at NIH supports a broad research programme to develop more information on safety and health claims for certain common supplements (for example, chromium's impact on diabetes and alternative therapies for treating benign prostate symptoms). One initiative is to create a database of research on supplement ingredients. ODS has also established several botanical research centres to identify and characterize botanicals, assess bioavailability and bioactivity, identify active ingredients and explore mechanisms of action.
Information. The American Botanical Council (ABC) seeks to document the value of herbal preparations by publishing more information on these products. In 1996, it issued a translation of German monographs on more than 300 herbs and combinations. ABC subsequently published a more in-depth guide to 107 popular US herbs. This year it will issue a clinical guide to 29 commonly used herbal medicines that provides information for practitioners on preparation, dosage, adverse events and herb-drug interactions.
Safety. A joint committee formed by the Institute of Medicine's Food and Nutrition Board and the National Research Council has established a framework for evaluating the safety of dietary supplement ingredients. The panel recently issued prototype monographs and solicited public comment on six common ingredients - chaparral, shark cartilage, glucosamine, melatonin, saw palmetto and chromium picolinate. The monographs focus on ingredient safety issues, as opposed to health claims and effects, and aim to help FDA detect unsafe substances in supplements.
Manufacturers generally support public-private initiatives to document product quality and curtail illegal claims to promote consumer confidence in supplements and herbal remedies, as well as head off more stringent government regulation. "Industry needs to step up to the plate and take responsibility for products," commented Dickinson of CRN. She considers third-party validation programmes sponsored by USP and other independent laboratories a good way to help companies demonstrate their commitment to quality.
At the same time, ongoing legal and regulatory battles concerning products such as ephedra have undermined public confidence in supplements overall and has prompted closer scrutiny of supplement marketing by FDA, FTC and state officials. "It's bad for industry, bad for FDA and bad for consumers for an issue like this to go on for years," Dickinson commented. Supplements may offer health benefits, but manufacturers need to be proactive about compiling evidence on product safety and benefits to retain public confidence.