FDA ensures equivalence of generic drugs - Food and Drug Administration - includes related articles on bioequivalency and filling prescriptions

When Stuart Addison goes to the pharmacy in Margate, Fld., he has the pharmacist fill his prescriptions with generic drugs. Addison. a retired federal government auditor, is one of many Americans who are choosing genetics when they buy drugs.

"My motivation is to keep the prices down," said Addison, noting that his insurance plan pays for his prescriptions. "My pocketbook is not directly affected, but in the long run, I'm helping to keep down insurance premiums."

Although not all approved drugs are available

in a generic version, those that are can offer substantial savings to consumers. For millions of Americans, the less-expensive drugs could mean the difference between getting necessary therapies and not being able to afford proper medical treatment.

Insurance companies' recommendations to policy holders that they choose genetics over brand-name drugs whenever possible, coupled with the promotional efforts of large drag chains, have helped heighten consumer awareness of the availability of generics. The result has been that genetic sales have been booming most of the years since 1984, when Congress passed the Drug Price Competition and Patent Term Restoration Act. This act expanded the number of drugs eligible to be manufactured as genetics. The new rules eliminated the need for duplicate safety and efficacy testing for genetics, saving industry time and money. The Food and Drug Administration also developed and issued explicit guidelines for a genetic product's bioequivalency (see accompanying article) and stability, ensuring that products retain potency. In addition, products must meet specifications set by the U.S. Pharmacopeial Convention, a private scientific organization that sets standards for drugs and drug products in the United States. Almost 80 percent of U.S. generic drug production is done by brand-name firms in modem manufacturing plants.

In 1991, consumers spent about $5.5 billion for generics and are expected to spend more than $15 billion in 1995, according to a report issued earlier this year by Frost & Sullivan International, a health information research organization. The report found that expiring patents on pioneer (brand-name) drugs, coupled with increased attention to containing health-care costs, will play important roles in the growth of the generics industry in the next decade.

Since 1984, there has been a succession of top-selling chugs that have lost their market exclusivity and been challenged for market share by genetic brands. An average of about 15 pioneer drugs lose patent protection annually, and FDA has prepared for an expected explosion of new generic drug applications through the end of 1995. Among the top-selling brandname drugs scheduled to lose protection are Eli Lilly's anti-infective Ceclor, Marion Merrell Dow's calcium channel-blocker Cardizem SR, and the firm's nonsedating antihistamine Seldane. Also scheduled to lose their exclusive market niche are the anti-inflammatories Anaprox by Syntex and Voltaren by Geigy, hypoglycemics Glucotrol by Roerig and Micronase by Upjohn, and Squibb's antihypertensive Capoten.

Scandal Rocks Industry

Popularity of the copycat products grew significantly after 1984, when the approval process was widened. But that popularity took a downturn in 1989, when scandal rocked the industry. Federal investigators uncovered such problems as illegal gratuities, fraud, obstruction of justice, and noncompliance with various manufacturing procedures by some industry officials.

The investigations revealed that several FDA employees had accepted money or other compensation in exchange for information and assistance that gave certain firms an advantage in the approval procedure. Investigators also uncovered submissions of fraudulent data by several manufacturers. In one case, a company submitted the pioneer drug disguised as a genetic version with its bioequivalence studies.

Subsequently, FDA investigators rushed to reevaluate data presented in hundreds of generic drug applications. More than 2,550 samples of the top 30 prescribed genetic drugs---or about 30 percent of all genetic drugs on the market--were collected and laboratory-tested. The agency conducted intensive inspections of 36 of the largest generic drug firms and 12 contract laboratories.

Agency Steps Up Testing

In early 1990, more than 300 scientists at 17 FDA labs tested samples from genetic drug companies. The agency determined that only 27 samples, or approximately 1 percent of those tested, did not comply with standards of potency, dissolution, content uniformity, product identification, moisture determination, or purity.

FDA also tested 429 samples representing at least three different batches of all 24 then-currently-marketed, narrow-therapeutic-range drugs (those in which the difference between a therapeutic dose and a toxic dose is small) made by 73 brandname and generic drug manufacturers. The 24 drugs were selected because of their nigh potential for adverse reactions or therapeutic failure if they lacked bioequivalency. Only five of the samples--all aminophylline tablets, a bronchodilator--failed to meet USP standards. None of the defects in the generic drugs posed a public health hazard.

Based on these restfits and the fact that brand-name products experience similar failures at a similar rate, the agency recommended that doctors continue to consider prescribing genetic drugs when appropriate, to offer lower-cost products to consumers.

FDA investigators continued to scrutinize operations at dozens of plants, and, in response to government findings, a number of firms made voluntary drug recalls due to manufacturing deficiencies. FDA's Office of Generic Drugs, directed by Roger L. Williams, M.D., is charged with conducting reviews and is responsible for the subsequent approval of the imitator products. The office interacts with a national network of FDA field offices to monitor the production methods of genetic makers. Williams said, "the office's increased emphasis on quality, integrity and performance in the development, manufacture and review of genetic drugs has led to a strong industry, a better review process, and better generic products for the consumer."

Pre-Approval Inspectors

In 1990, the agency instituted product-specific, pre-approval inspections of manufacturing sites listed in a sponsor's application. During inspections, FDA reviews the step-by-step manufacturing process and monitors how much and what kind of active ingredients, excipients (material added to make products a suitable consistency), flavorings, and other substances will be used. Sponsors must even identify the type of machinery that will be used in each step of the manufacturing process. Just as it does with brand-name drugs, the agency closely regulates generic makers' production sites and blocks the marketing of any drugs produced in substandard facilities. FDA conducts more than 5,000 inspections at drug plants annually.

Agency inspectors also review on-site production records, examine exhibit hatches, and determine whether the plant is capable of producing the drug properly before giving a satisfactory recommendation for the drug's approval. Plant managers must be able to show that the operation has sterile production facilities where required, acceptable assembly-line procedures, and that labeling procedures are designed to prevent mix-ups. The company must also prove that finished products are kept in a temperature-controlled storage area and that products can be easily identified to prevent drug mix-ups.

Richard Davis, director of FDA's division of field investigation, said new policies and procedures help prevent fraudulent activities and help ensure the availability of safe and effective generic products.

"We believe we have ferreted out virtually all of the fraud that was involved in the scandal," Davis said. "There shouldn't be any reason to be concerned about the equivalency, safety and effectiveness of generic drugs. We now have a very vigorous pre-approval inspection program."

Other Safeguards

Other safeguards have also been established. In May, President Bush signed into law an act that calls for the mandatory debarment of any individual convicted of a federal felony related to the development or approval of any drug application. The violator will be permanently prohibited from working in any capacity for any individual, partnership, corporation, or association that produces an approved drug and will be fined up to $250,000. A company convicted of a federal felony related to the development or approval of a genetic drug application will be prohibited from submitting applications for 1 to 10 years and fined up to $1 million.

Todd Dankmyer of the National Association of Retail Druggists credited FDA's swift actions, comprehensive compliance plan, and the subsequent survey after the generics scandal for restoring the faith of the medical community and consumers in generics.