About CDER - Report

CDER Report to the Nation: 2000

Table of Contents

Drug Review (continued)

Generic Drug Review

Manufacturing Supplement Review

Assessing Data Quality and Other Activities

User Fee Review Performance

Generic Drug Review

We received 365 submissions and approved 244 generic products in 2000, including 34 separate molecules in 52 products that represent the first time a generic drug was available for the brand-name product. The median approval time for generic drugs was 18.2 months.

Initiatives to streamline the generic drug review process have resulted in an overall downward trend in approval times since 1994. We have also seen a drop in the number of review cycles needed to approve abbreviated applications for generic drugs. In 2000, the average application required 2.8 cycles to reach approval.

We also issued 61 tentative approvals last year. 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.

Our approval of generic drugs last year could save the American people and the federal government hundreds of millions of dollars.

2000 generic drug statistics

• 244 generic drug approvals
• Median approval
  time: 18.2 months

Notable 2000 generic drug approvals

• Examples of first-time approvals include:
• Doxazosin mesylate tablets, used in treating benign prostatic hyperplasia and hypertension.
• Paclitaxel injection, used in treating various ovarian and breast cancers.
• Nifedipine extended release tablets, used in treating angina and hypertension.

Generic drug submissions

• 2000: 365
• 1999: 296
• 1998: 345
• 1997: 330
• 1996: 307
• 1995: 283
• 1994: 199
• 1993: 215

Generic drug electronic submission initiative

Last year, for original submissions, we received 85 electronic submissions for bioequivalence data and 79 electronic submissions for chemistry, manufacturing and controls data. 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.

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.

How we approve generic drugs

Generics are not required to repeat the extensive clinical trials used in the development of the original, brand-name drug. Instead, they must show bioequivalence to the brand-name reference listed drug.

Scientists measure the amount of the generic drug that reaches the bloodstream and how long it takes to get there. This rate and extent of absorption is called bioavailability. The bioavailability of the generic drug is then compared to that of the brand-name reference listed drug.

The generic version must deliver the same amount of active ingredients into a patient's bloodstream and in the same time as the brand-name reference listed drug. Brand-name drugs are subject to the same bioequivalency tests as generics when their manufacturers reformulate them.

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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 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.

New drug manufacturing supplement statistics

• 1,345 approvals
• Median FDA review time: 4.0 months

Manufacturing supplements to generic drug applications

In 2000, we approved 2,314 manufacturing supplements to generic drug applications. We received 2,522 manufacturing supplements during the year.

Generic drug manufacturing supplement statistics for 2000

• 2,314 approvals
• 2,522 receipts

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Assessing Data Quality, Research Risks

To protect the rights and welfare of volunteers and verify the quality and integrity of data submitted for our review, we perform on-site inspections of clinical trial study sites, institutional review boards, sponsors, study monitors and contract research organizations. Our programs to protect volunteers are challenged by increases in the number of clinical trials; the types and complexity of products undergoing testing; and the increased number of trials performed in countries with less experience and limited or no standards for conducting clinical research.

When obtaining data about the safety and effectiveness of drugs, sponsors rely on human volunteers to take part in clinical studies. Protecting volunteers from research risks is a critical responsibility for us and all involved in clinical trials, including manufacturers, institutional review boards, study sponsors, clinical investigators and their staffs, monitors, contract research organizations, hospitals and other institutions.

Sponsors and clinical investigators protect volunteers by ensuring that:

• Clinical trials are appropriately designed and conducted according to good clinical practices.
• Research is reviewed and approved by an institutional review board.
• Informed consent is obtained from participants.
• Ongoing clinical trials are actively monitored.

Special attention is given to protecting vulnerable populations, such as children, the mentally impaired or prisoners.

We require sponsors to disclose financial interests of clinical investigators who conduct studies for them. This helps identify potential sources of bias in the design, conduct, reporting and analysis of clinical studies.

Inspections of clinical research in 2000

We conducted a total of 528 inspections last year.

• 296 U.S. clinical investigators
• 49 foreign clinical investigators
• 155 institutional review boards
• 28 sponsors, monitors or contract research organizations
• Top 5 deficiency categories for clinical investigator inspections
• Failure to follow the protocol
• Failure to keep adequate and accurate records
• Failure to report adverse events
• Failure to account for the disposition of study drugs
• Problems with the informed consent form

International inspections

We have conducted 422 inspections in 45 countries from 1980 to 2000.

We participate in international efforts to strengthen protections for human volunteers worldwide and encourage clinical investigators to conduct studies according to the highest ethical principles.

These efforts include our work with the International Conference on Harmonization and the Declaration of Helsinki.

Pediatric Exclusivity

The 1997 FDA Modernization Act authorized us to grant six months of marketing exclusivity to manufacturers who conduct and file pediatric studies in response to our written requests. Pediatric exclusivity has helped us uncover important new information that will help pediatricians and other prescribers use drugs to treat children more safely and confidently.

As of April 1, 2001, we had received 218 proposed pediatric study requests and had issued 188 written requests. These studies could potentially involve more than 20,000 children. In less than three years, more than 58 pediatric studies have already been conducted. Reports from these studies have been submitted, and exclusivity granted to 28 drugs.

Drugs that have or soon will have pediatric use information in their labeling are used to treat conditions such as:

• Diabetes mellitus.
• Gastroesophageal reflux disease.
• Hypertension.
• Juvenile rheumatoid arthritis.
• Obsessive compulsive disorder.
• Pain.
• Depression.
• HIV infection.
• Seizures.
• Anesthesia and sedation.

A full report on our experiences with pediatric exclusivity is at http://www.fda.gov/cder/pediatric/reportcong01.pdf. Our pediatric medicine page is at http://www.fda.gov/cder/pediatric/index.htm.

Pediatric exclusivity statistics

• 218 proposed pediatric study requests received
• 188 written requests issued

Pregnancy labeling

We have reviewed the current system of labeling drugs for use by pregnant women and are developing an improved, more comprehensive and clinically meaningful approach.

We are consulting with multiple government agencies, medical experts, consumer groups and the pharmaceutical industry to develop this new labeling format.

Antimicrobial Resistance

The emergence of drug-resistant bacteria is considered to be a major threat to the public health.

We play an active role in the federal government's efforts to address this growing problem and its effects on drug development and regulation.

We are developing approaches to provide education and information on the appropriate use of antibiotics to health care professionals and consumers.

Details of our efforts and other resources are at http://www.fda.gov/cder/drug/antimicrobial/default.htm.

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.

Scientific training for reviewers

Our systematic training program for reviewers in science, policy and job-related skills is based on core competencies, learning pathways and individual development plans.

The program grew from seven courses offered in 1997 to more than 20 currently offered. Existing courses were also revised.

Reviewer participants increased six-fold, from about 250 in 1997 to 1,500 currently.

Reviewer training hours quadrupled from 4,000 hours a year in 1997 to 16,000 hours currently.

Training costs were reduced through partnerships with pharmaceutical firms, associations, academic institutions and foreign governments.

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User Fee Review Performance

The timely performance of high-quality 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, first enacted in 1992, was 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 and manufacturing supplements to already approved new drug marketing applications. We have continued to meet or exceed nearly all the progressively more stringent user fee performance goals.

With the reauthorization of user fees in 1997, we committed to goals that will help speed the time it takes for drugs to be appropriately tested and developed before submitting those results for our review. These goals include those related to meeting management, clinical holds, resolving major disputes and reaching agreement on certain protocols. There are expectations regarding electronic applications and submissions, simplification of action letters and expedited notification of deficiencies in applications.

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.
• 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

Resubmissions are divided into two classes:

• Class I, involving minor changes, are phasing in two-month reviews.
• 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.
• Priority efficacy supplements have a six-month review goal.

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.

Notes:

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 or years.

The first four charts in this section show a cumulative total and a subset. For example, the performance chart for NDAs shows performance on 12-month reviews and the subset of those that are 10-month reviews.

This report tracks all applications, including those exempt from user fees, according to user fee goals. These numbers may differ slightly from numbers found in FDA's official reports on applications that pay user fees.

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 refuse-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.

User fee reforms benefit consumers

As we continue to meet and exceed our application review performance commitments, more quality products are reaching American practitioners and consumers faster.

The Prescription Drug User Fee Act has resulted in increasing numbers of applications filed, higher quality applications and quicker approvals for products with the requisite data. Our goals become more challenging each year. Nonetheless, application filings and quality remain high by historic standards and approval times continue to drop.

Increasingly, American patients are receiving the benefits of important new drugs before they are available to citizens of other countries:

• Of the new molecular entities approved in the United States from 1991 to 1995, primarily pre-PDUFA submissions, 43 percent received their approvals within a year of their first introduction on the world market.
• That percentage almost doubled to 80 percent for NMEs approved in the United States from 1996 to 1998, primarily years of user-fee submissions.

Source: Tufts University Center for the Study of Drug Development data in FDA's fiscal year 2000 user fee performance report at http://www.fda.gov/ope/pdufa/report2000/.

User Fee Performance: 1993-1997