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ACTIVITIES OF FDA’S MEDICAL PRODUCT CENTERS IN 2001

In the year 2001, the three centers of the Food and Drug Administration that regulate human medical products continued their usual high-level performance in reviewing marketing applications and monitoring the safety and effectiveness of drugs, biological medications and medical devices.

The Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH) assured the availability to patients of a total of 136 innovative health care products. Some of the most important FDA approvals included a breakthrough drug for cancer, the first biological treatment for the most serious type of sepsis, and an advanced device for monitoring sugar in blood.

The agency significantly enhanced the protections for thousands of patients, including those who participate in clinical trials, by acting to reduce or better manage risks involved in testing and using new therapies. And in one of its major achievements last year, the FDA once again met all of the demanding application review goals of the Prescription Drug User Fee Act (PDUFA), despite the program’s severe resource constraints.

But however effective, routine operations are not the sole hallmark of a year that witnessed the terrorist attacks on and after September 11. The brutal assaults challenged the FDA to rise to the defense of the Nation’s consumers, and the agency—in close cooperation with other federal, state and local authorities—has responded with its traditional vigor, initiative and scientific expertise.

FDA developed strategies to strengthen the protection of all regulated products against willful contamination, and to improve the availability of medical products for the prevention or treatment of injuries caused by biological, chemical or nuclear agents.

For example, CDER took the initiative to clarify that the antibiotics doxycycline and penicillin G procaine are effective and approved for use in treating all forms of anthrax infections. This notice included explicit dosing based on FDA’s review of scientific literature and data from the same rhesus monkey study that had been used to support the August 2000 approval of ciprofloxacin for anthrax. The assurance that the three drugs are effective against all forms of anthrax infection eased the public’s concerns about a potential shortage of medication for the victims of the mailed anthrax powder.

CDER also stepped up its work on measures to encourage the development of new drugs to counter the toxic effects of chemical, biological, radiological and nuclear weapons. CBER worked closely with industry and other government agencies in an effort to assure adequate supply of products for immunization against anthrax, botulinum, smallpox and other substances that might be used by terrorists, and to evaluate adverse experiences reported after administration of anthrax vaccine in order to optimize the safe use of this vaccine.

CDRH has contributed to the development of methodology for the detection of biological agents with bioterrorism potential, and cooperated with CDER and the National Institutes of Health in developing a guidance on the use of potassium iodide to reduce the risk of thyroid cancer in radiation emergencies.

In addition to doing its part in protecting the Nation’s public health against terrorism, FDA last year evaluated many new pharmaceutical products and medical devices that advanced the frontier of modern medicine.

In 2001, CDER approved 66 new drugs, 24 of which were new molecular entities (NMEs) with ingredients never before marketed in the U.S. Ten of the 66 new drugs (7 of the NMEs) received priority status and were reviewed and approved in the median time of 6 months. The other 56 approvals were reviewed under a standard status. Their median review time was 12 months (15.7 months for the 17 standard NMEs), and their median total approval time was 14 months (19 months for the NMEs).

CBER reviewed a total of 16 complex biological license applications (BLAs) in the median time of 13.8 months and approved them in the median time of 20.3 months. Two of the BLAs, which were classified as priority products, were reviewed in the median time of 11.5 months and approved in the median approval of 13.2 months. Approvals of 10 of the BLAs, 6 BLA supplements for new or expanded uses, and 3 premarket approval applications (PMAs) were considered major actions. Most of the products approved by CBER were designed to detect or treat infectious diseases.

CDRH approved 54 premarket approvals (PMAs), of which 24 were for devices with novel technologies or new uses. The median total approval time for the 54 products was 11.3 months.

Some examples of FDA’s major product approvals last year for the benefit of various groups of patients follow:

Cancer patients: One of FDA’s most important approvals last year was for Gleevec (imatinib mesylate or STI-571), a new oral treatment for patients with chronic myeloid leukemia, a rare life-threatening form of cancer. FDA reviewed the drug in two- and-a-half months and approved it under a special procedure that permits the marketing of important therapies on the basis of their effect on surrogate markers. The sponsor is committed to carry out additional studies demonstrating Gleevec’s long-term safety and effectiveness.

Gleevec was developed for use in a U.S. patient population below 200,000, and was therefore designated by FDA as an “orphan drug.” Sponsors of such products receive inducements that include seven-year marketing exclusivity, tax credit for the product-associated clinical research, research design assistance by FDA, and grants of up to $200,000 per year.

In addition to two cancer drugs for women which are described below, FDA approved Campath (alemtuzumab), a new biological product for the treatment of patients with B-cell chronic lymphocytic leukemia who have been treated with alkylating agents and have failed fludarabine therapy.

FDA also cleared a new device that can facilitate early detection of cancer of the small intestine. The Given Diagnostic Imaging System is a swallowable capsule containing a tiny camera that snaps pictures twice a second as it is moved by natural muscular waves of the digestive track trough the small intestine. The device enables the physician to see areas that are not reachable by endoscope.

Women and children: FDA approved two cancer products for women. One of them, a combination of Xeloda (capecitabine) and Taxotere (docetaxel), was approved for the treatment of metastatic breast cancer that has not responded to an anthracycline-containing cancer therapy.

The other approval was a new indication for Femara (letrozole) as a first-line treatment for advanced or metastatic breast cancer in postmenopausal women with hormone receptor positive or unknown disease. Femara had been approved for treatment of breast cancer in women whose cancer had not responded to antiestrogen drugs.

FDA also approved two contraceptive devices that deliver continuous doses of progestin and estrogen hormones to prevent pregnancy.

One of the devices, Ortho Evra, is the first skin patch approved for birth control. The patch, which has to be changed each week, releases the hormones through the skin into the blood stream. The other device, NuvaRing, delivers the hormones through a flexible, transparent polymer ring that is inserted in the vagina. Both the patch and the ring have to be removed one week each month when the woman menstruates.

FDA also approved one important device for children. AED is the first automatic external defibrillator system for use on infants and young children who experience cardiac arrest. The device is designed to restore normal heart rhythm by using conductive adhesive pads to administer an electric shock through the chest wall.

Heart patients: In addition to the above-described (AED) system for use on infants and young children, FDA approved four highly advanced medical devices for heart patients:

One of them is Biotronik Home Monitoring System, the first implanted pacemaker that includes a tiny transmitter capable of automatic, remote data transmission. The device can be programmed to collect data on the patient’s heart condition and at certain intervals automatically send them to the patient’s physician.

Another first-of-a-kind product is the WCD System, a vest- like device that is worn under clothing to monitor and treat abnormal heart rhythms in people at risk of dying from sudden cardiac arrest. The device, which is suitable for patients who cannot have or do not want an implanted defibrillator, senses heart malfunction and automatically delivers an electrical shock when needed to restore normal heart rhythm.

InSync Biventricular Cardiac Pacing System, which was also cleared for marketing in 2001, is a new type of pacemaker that sends specially timed electrical impulses to the heart’s lower chambers to treat the symptoms of moderate to severe congestive heart failure. The impulses are generated by an implanted pulse generator and delivered to the heart by three wires.

FDA also approved PercuSurge, a device consisting of balloon and aspiration catheters. The device is used to collect and remove blood clots and other debris created by angioplasty and stenting of a blocked bypass vein graft.

One important new drug approved last year for cardiac patients is Natrecor (nesiritide) injection for the treatment of acute congestive heart failure. The medication, which was developed with the use of recombinant DNA technology, is a synthetic version of a human hormone that dilates veins and arteries.

Infectious diseases: FDA approved Xigris, the first biologic treatment for the most serious forms of life-threatening sepsis, which claims 225,000 lives in the U.S. each year. The new treatment is a genetically engineered version of a naturally occurring human protein, Activated Protein C, which interferes with some of the body’s harmful responses to severe infection.

PEG-Intron (peginteferon alfa 2b) injection was approved for the treatment of patients with chronic hepatitis C, an infectious disease responsible for as many as 10,000 deaths per year in the U.S. PEG-Intron is a longer acting form of interferon than Intron A (an earlier approved form of interferon), and requires only one injection per week for one year compared to three per week for Intron A. FDA also approved a supplemental application for the use of PEG-Intron with Rebetol (ribavirin) capsules, which was shown to be somewhat more effective than Intron A with Rebetol.

FDA approved a new combination vaccine that protects adults against diseases caused by the hepatitis A virus (HAV) and the hepatitis B virus (HBV). The vaccine, called Twinrix, combines two already approved vaccines, Havrix (Hepatitis A Vaccine, Inactivated) and Engerix-B [Hepatitis B Vaccine (Recombinant)] so that people at high risk for exposure to both viruses can be immunized against both at the same time. Twinrix is recommended for travelers who are at high risk for HBV, and who are visiting countries where there is a substantial incidence of both HAV and HBV disease.

The agency’s approvals also included Cancidas (caspofungin acetate) intravenous infusion, a new anti-fungal medication for patients not responsive to or unable to tolerate standard therapies for the invasive form of aspergillosis. This is the first approval in a new class of drugs called echinocandins, which are believed to work by disrupting the formation of fungal cell walls.

Another novel product approved last year is Viread (tenofovir disoproxil fumarate), a new anti-viral drug for the treatment of HIV-1 infection in combination with other antiretroviral medicines. Viread is the first nucleotide analog approved for HIV-1 treatment.

Other important approvals: Lumigan (bimatoprost ophthalmic solution) and Travatan (travoprost ophthalmic solution) are new medications to treat elevated intraocular pressure often associated with glaucoma. The solutions are indicated for use in patients who are intolerant of other intraocular pressure- lowering medications.

Novel devices approved in 2001 included GlucoWatch Biographer, a wristwatch-like device that provides adult diabetics with more information for managing their disease. The gadget extracts the wearer’s fluid every 20 minutes by sending out tiny electric currents, and sounds an alarm if the glucose level reaches dangerous levels.

Another advanced device approved last year is the Lap-Band Adjustable Gastric Banding System, an inflatable device that is surgically placed around the upper stomach to limit food consumption and create an earlier feeling of fullness. It is intended for people at least 100 lbs overweight who have failed to reduce weight by dieting and other methods, and who are at greater risk for serious diseases such as hypertension, gall bladder disease and diabetes.

Aranesp (darbepoetin), another new biologic, was approved for treatment of anemia associated with chronic renal failure, including both patients on dialysis and not on dialysis.

The agency approved the first HIV drug resistance test for use as an aid in monitoring and treating HIV infected patients. The test detects mutations in HIV that confer resistance to - drugs used to treat HIV infections.

An important focus of FDA’s activities in 2001 was the strengthening of patient protections through programs and measures designed to enhance the ethical standards of clinical trials and the safety and effectiveness of approved health care products.

For example, FDA last year issued an interim rule to provide additional safeguards for children participating in clinical studies. The new rule provides specific criteria, such as an assurance of informed consent by the children and their parents, that have to be maintained by the Institutional Review Boards that supervise the trials.

FDA also proposed a rule that would make publicly available information on all new or ongoing clinical trials involving gene therapy or xenotransplantation. Access to most of the trial designs and safety data should contribute to the assurance of their ethical conduct as well as the public’s confidence in advanced product studies. The rule would continue safeguarding commercial information and the identity of the study participants.

In addition, FDA proposed and a regulation covering the methods, facilities and controls used to manufacture human cellular and tissue-based products. This was the last of three FDA proposals of a comprehensive risk-based regulatory framework to help ensure the safety and quality of new technologies and products. The first of the proposed rules, requiring establishments that manufacture human cells, tissues and cellular and tissue-based products to register with FDA and list their products, was finalized.

Another new measure, which is of particular significance for people with AIDS, is an agreement between FDA and the Veterans’ Administration (VA) to improve clinical knowledge of adverse effects of drugs used to treat HIV infections. Under the agreement, FDA and VA are jointly conducting an epidemiological study to determine whether avascular necrosis—the destruction of bone cells due to deficient blood supply that affects people with AIDS—is linked to the use of certain drugs to treat HIV.

Cancer patients will benefit from a new joint research program announced in July by FDA and the National Cancer Institute (NCI). The three-year, $1.1 million-a-year Clinical Proteomics Program utilizes new technologies that generate protein fingerprints that may provide early warnings of drug side effects. The pioneering research combines the study of proteins in living cells with clinical care for patients.

Recipients of blood products will be better protected thanks to FDA’s licensing of the first nucleic acid test systems intended for screening of plasma donors. These systems are expected to further ensure the safety of plasma-derived products by permitting earlier detection of HIV and HCV infections in donors.

The safety of hospital patients has been improved by two new measures. One of them is FDA’s requirement of evidence that all but the lowest-risk reprocessed single-use devices—such instruments as laparoscopy scissors and balloon angioplasty catheters—are as safe and effective as the original products. The other new measure is an FDA guidance for the safe use of bed rails, which have been involved in nearly 400 reported accidents in hospitals, nursing homes and home use.

In 2001, FDA and the Department of Health and Human Services’ Office of Women’s Health awarded two contracts to study labetalol and atenolol, medications that are used by pregnant women to treat high blood pressure despite scant clinical data on the use of these products in this patient population. The studies are to determine appropriate dosages of greatest benefit and least risk for pregnant women and their babies.

FDA proposed guidance on the establishment and operation of clinical trial data monitoring committees, which play a critical role in safeguarding patients’ interests and contribute to their protection.

In addition, FDA awarded several contracts to enable it to access commercial databases on the actual use of marketed prescription drugs in adults and children. The information, which does not reveal the identity of patients, helps FDA to determine the public health significance of reports it receives through its Adverse Event Reporting System.

Finally, the FDA last year announced the creation of a new Drug Safety and Risk Management Subcommittee to the Advisory Committee for Pharmaceutical Science. The new subcommittee, which consists of nationally-recognized experts in areas related to risk perception and management, pharmacology and other related disciplines, will advise FDA on general and product- specific safety issues.

FDA’s human drug program once again met all of the demanding review goals of the Prescription Drug User Fee Act (PDUFA) as reauthorized in 1997. For applications submitted In fiscal year (FY) 2000, the latest year for which meaningful review statistics can be reported, CDER and CBER reviewed 33 priority applications and 101 standard applications. The projected median approval times for FY 2000 submissions are 6 months for priority applications and 12.5 months for standard applications.

Notwithstanding these successes, the agency has encountered challenges in trying to meet the PDUFA II goals. The fees the FDA has collected have been significantly less than expected due to a reduced number of new drug applications and an increased proportion of submission whose fees were waived. At the same time, the number of goal-driven tasks for which FDA collects no fees has increased substantially under PDUFA II. Although so far the FDA has been able to meet most of its performance goals, the agency does not foresee increasing or even maintaining performance levels until resources are available to meet the increased workload.

The agency's efforts to meet the PDUFA II goals may have had an unintended impact on approval times of standard new drug and biologics applications. These approval times have begun to increase because more applications require multiple review cycles to reach approval. This may be due to the fact that reviewers, pressed to meet the new PDUFA II goals for drug development (e.g., meetings, special protocol assessments, and responses to clinical holds), have had less time for resolving last minute problems with these standard applications before the action goal date. Such applications must undergo an additional review cycle with its attendant timeframes and goals. Statistics on this trend are preliminary and the agency is watching it closely. However, if the user fee program is to continue, it must be on a sound financial footing and based on reliable estimates of workload and resources.

The Agency will continue to work with the industry, the Congress, and all other stakeholders on a reauthorization of the PDUFA program that will continue to bring benefits to American consumers by bringing important new therapies to market quickly without compromising scientific review standards.

FDA is also concerned about the safety of new drugs and biologics following approval and marketing. In recent years fully 50% of all new drugs world-wide have been launched in the U.S., and American patients have had access to 78% of the world's new drugs within the first year of their introduction. More rigorous safety monitoring of newly approved drugs in the first few years after a product is on the market could help to detect unanticipated problems earlier. The current system for detecting adverse drug and biologics events does not provide sufficient data on the actual incidence of problems.

To protect American patients, FDA urgently needs to strengthen its ability to carry out post-market drug surveillance and other non-user fee functions it carries out in conjunction with PDUFA.

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