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CDER Report to the Nation: 1999

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Drug Review (continued)

Generic Drug Review

We received 196 submissions and approved 186 generic products in 1999, including 43 that represent the first time a generic drug was available for the brand name product. The median approval time for generic drugs stabilized last year at 18.6 months, about half a month longer than required in 1998.

Initiatives to streamline the generic drug review process have paid off in an overall downward trend in approval times since 1994. The 18.6-month median approval time last year compares to 18.0 in 1998 and 19.3 in 1997.

We have also seen a drop in the number of review cycles needed to approve abbreviated applications for generic drugs. In 1999, the average application required 2.5 cycles to reach approval compared to 2.6 cycles in 1998. These were down from 2.9 in 1997 and 3.6 in 1996.

1999 generic drug statistics

• 186 generic drug approvals
• Median approval time: 18.6 months

Notable 1999 generic drug approvals

Examples of first time approvals include:

• Nicotine gum, for use as a smoking deterrent.
• Propofol injectable emulsion, used as a sedative for maintenance of anesthesia during surgery.

We also issued 56 tentative approvals last year compared to 40 in 1998. The only difference between a full approval and a tentative approval is that the final approval of these applications is delayed due to existing patent or exclusivity on the innovator's drug product. Examples of tentative approvals include:

• Lovastatin tablets, a cholesterol lowering agent.
• Fluoxetine hydrochloride capsules used for depression.

The approval of generic versions of these products and other generic approvals in 1999 could save the American people and the federal government hundreds of millions of dollars.

Quicker approvals without user fees

We don't receive user fees to review applications for marketing generic equivalents of prescription or over-the-counter drugs.

New Counting System

Note: Drug approval data in this report are based on a new counting system that allows certain variations in a drug product to be included in a single application. This year's report reflects our final conversion to the new system, and numbers in this report cannot be directly compared to those in previous reports.

How we approve generic drugs

The abbreviated mechanism for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, known as the Hatch-Waxman Act.

Generics are not required to repeat the extensive clinical trials used in the development of the original, brand-name drug. Instead, they must show they are bioequivalent to the pioneer drug and fall into acceptable parameters for bioavailability, or the extent and rate at which the body absorbs the drug.

Scientists measure the time it takes a generic drug to reach the bloodstream. This gives them the rate of absorption or bioavailability of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream and in the same time as the pioneer drug. Brand-name drugs are subject to the same bioequivalency tests as generics when their manufacturers reformulate them.

"In 1994, purchasers saved a total of $8 billion to $10 billion on prescriptions at retail pharmacies by substituting generic drugs for their brand-name counterparts."

-How Increased Competition from Generic Drugs Has Affected Prices and Returns in the Pharmaceutical Industry,
Congressional Budget Office,July 1998

Generic drug electronic submission initiative

Last year, for original submissions, we received 44 electronic submissions for bioequivalence data and 55 electronic submissions for chemistry, manufacturing and controls data. For comparison, we received 32 bioequivalence electronic submissions and 44 CMC in 1998 and ten bioequivalence and none with CMC data prior to 1998. In continued support of the electronic submissions initiative, we:

• Enhanced our information technology infrastructure to support the electronic review process.
• Promoted electronic submissions directly to industry and trade groups.
• Held training sessions for industry.
• Published a Guidance for Industry: Preparing Data for Electronic Submissions in ANDAs.

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Manufacturing Supplement Review

We review many types of changes in the manufacturing of drugs and their packaging, including location, machinery, processes and suppliers of raw materials. We do this so that American consumers can trust in the high quality of FDA-approved medicines. Manufacturers notify us in advance of certain manufacturing changes. These are known as "manufacturing supplements" to new drug or generic drug applications. In many cases, they represent the industry's efforts to modernize plants and equipment or to make manufacturing more efficient.

Manufacturing Supplements to New Drug Applications

In 1999, we took action on 1,747 manufacturing supplements, of which 1,419 were approvals.

We began tracking manufacturing supplements to new drug applications and their review times as part of the performance goals agreed to for the original Prescription Drug User Fee Act.

NDA manufacturing supplement statistics

• 1,419 approvals
• Median total review time: 5.2 months

Manufacturing Supplements to Generic Drug Applications

In 1999, we approved 2,293 manufacturing supplements to generic drug applications. We received 2,499 manufacturing supplements during the year. In 1997, we began counting generic drug manufacturing supplements separately from all supplements to generic drug applications.

Note: Each product's supplement is tracked individually. A "global supplement" requires only one review but can apply to multiple products.

Generic drug manufacturing supplement statistics

• 2,293 approvals
• 3,036 receipts

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User Fee Review Performance

The quick and consistent level of drug reviews in recent years reflects the importance of our managerial reforms and the additional resources provided us under the Prescription Drug User Fee Act. The law was first enacted in 1992 and renewed for an additional five years in the 1997 FDA Modernization Act. Under the law, the drug industry pays user fees for new drug applications, efficacy supplements and some other activities. User fees helped us hire additional scientists to perform reviews.

In 1992, we agreed to specific performance goals for the prompt review of four categories of submissions:

• Original new drug applications.
• Resubmissions of original NDAs.
• Efficacy supplements to already approved marketing applications.
• Manufacturing supplements to already approved new drug marketing applications.

We exceeded the progressively more stringent user fee performance goals for each successive fiscal year except for one goal in fiscal year 1998.

In 1997, Congress, with the industry's and our support, enhanced the user fee program and extended it for five years as part of the FDA Modernization Act. We have committed to goals that will help speed the time it takes for drugs to be appropriately tested and developed before submitting those results for FDA review.

These new goals include those related to meeting management, clinical holds, resolving major disputes and reaching agreement on certain protocols. There are added expectations regarding electronic applications and submissions, simplification of action letters and expedited notification of deficiencies in applications.

Fiscal year cohorts

When comparing the fiscal year user fee performance charts with the calendar year performance charts, remember that work on one year's submission cohort is often performed in the following year.

Original NDAs

Improved performance goals were a key element of the reauthorization of user fees:

• Standard drugs began a phase-in to 10-month reviews in fiscal year 1999.
• Priority drugs have a performance goal of 90 percent reviewed and acted upon within six months.
• New molecular entities have the same review performance goals as standard and priority drugs.

Resubmissions of original NDAs

Beginning in 1998, resubmissions were divided into two classes:

• Class I, involving minor changes, are targeting 90 percent two-month reviews by fiscal year 2001.
• Class II, involving changes not specifically identified in the user fee goals document, retain a six-month review.

Efficacy supplements

• Standard efficacy supplements began a phase-in to 10-month reviews in fiscal year 1999.
• Priority efficacy supplements began a six-month performance goal in fiscal year 1998.

Manufacturing supplements

• Manufacturing supplements to NDAs that require our prior approval before implementation have a phase-in to a four-month review.
• The goal for those that don't require our prior approval-changes being effected-remains at 90 percent reviewed and acted on within six months.

Refusal to file an application

As a result of the user fee program, the quality of applications submitted by industry has improved. In addition we have exercised increased consistency in applying our authority to refuse to file an application. We refuse to file an application only when we determine there is a significant omission of needed information.

Before 1993, we were refusing to file approximately 25 percent to 30 percent of submitted original new drug applications. The percentage of refused-to-file applications has dropped steadily to approximately 4 percent in recent years.

Clinical Holds

By working with sponsors more closely, the percentage of commercial investigational new drug applications put on clinical hold has decreased dramatically. A clinical hold temporarily halts the testing of a drug in humans because of concerns about safety. We have developed and published procedures that outline specific responsibilities and timelines for handling clinical holds imposed on investigational new drugs.

Drug Review Team

We use project teams to perform drug reviews. Team members apply their individual special technical expertise to review applications:

• Chemists focus on how the drug is manufactured. They make sure the manufacturing controls, quality control testing and packaging are adequate to preserve the drug product's identity, strength, potency, purity and stability.
• Pharmacologists and toxicologists evaluate the effects of the drug on laboratory animals in short-term and long-term studies, including the potential based on animal studies for drugs to induce birth defects or cancer in humans.
• Physicians evaluate the results of the clinical trials, including the drug's adverse and therapeutic effects, and determine if the product's benefits outweigh its known risks at the doses proposed.
• Project managers orchestrate and coordinate the drug review team's interactions, efforts and reviews. They also serve as the review team's primary contact for the drug industry.
• Statisticians evaluate the designs and results for each important clinical study.
• Microbiologists evaluate the effects of anti-infective drugs on germs. These medicines-antibiotics, antivirals and antifungals-differ from others because they are intended to affect the germs instead of patients. Another group of microbiologists evaluates the manufacturing processes and tests for sterile products, such as those used intravenously.
• Biopharmaceutists evaluate the rate and extent to which a drug's active ingredient is made available to the body and the way it is distributed, metabolized and eliminated. They also check for interactions with other drugs.
• Clinical pharmacologists evaluate factors that influence the relationship between the body's response and the drug dose. They assist physician members of the team in assessing the clinical significance of changes in the body's response to drugs through the use of exposure-response relationships.

Consumers benefit from user fee reforms

Two studies released last year document the benefits of FDA's review and approvals and indicate that Americans have an increasingly fast access to new medications of worldwide origin.

• One of the studies (Tufts Center for Study of Drug Development, July 1999) showed that since the passage of the Prescription Drug User Fee Act of 1992, total development time for new drugs in the U.S. has dropped by 18 percent.
• Another study (Ashton CMRI International News, Spring 1999, Vol. 17, No. 1) found that, in 1998, about 75 percent of worldwide new molecular entities were first launched in the United States.

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