The fast track to market

If your product is indicated for treatment of a serious disease, it may be eligible for expedited regulatory review

Continuing our discussion of the Food and Drug Modernization Act of 1997 (FDAMA), this month's column addresses Section 112 ("Expediting Study and Approval of Fast Track Drugs"), which is included here in the "Section 112" box for easy reference. To support implementation of that section of the act, the Fast Track Working Group, comprising both CDER and CBER staff, published a guidance document (1). This column illustrates key features of the fast track procedure detailed in those two documents.

Fast track status enables FDA to assist in the development and to expedite the review of a drug intended to treat a serious or lifethreatening condition, demonstrating the potential to address unmet medical needs for that condition. Serious conditions are considered to include those that are life threatening. With regard to eligibility for fast track designation, no distinction need be made between serious and life-threatening conditions.

Fast track designation does not apply to a product alone. Fast track classification applies to the combination of a product and its specific indication. The indication must include both the condition for which the product is intended and the anticipated or established clinical benefits of using the product. Thus, a development program for a specific drug intended for a specific indication can receive fast track designation.

Regulatory Evolution

Expedited development, evaluation, and marketing of new therapies intended to treat life-threatening and severely debilitating illnesses, especially when there is no satisfactory alternative therapy, were available informally for years before they were added to Subpart E of the investigational new drug (IND) regulations in 1988 (2). Treatment IND and expanded access provisions of the drug regulations also were promulgated in the late 1980s (3). In 1992, FDA's Accelerated Approval Rule for the first time allowed the marketing of products developed using surrogate endpoints that were reasonably likely to predict clinical benefit (4). Surrogate endpoints have been defined as laboratory or physical signs used in therapeutic trials to substitute for clinically meaningful endpoints that directly measure how patients feel, function, or survive. Surrogate endpoints are expected to predict a therapy's effects.

The decade before regulations appeared was marked by the onset of the AIDS crisis and the emergence of patient-activists. Th3 1980s also saw an increasing systematization of FDA's Office of Orphan Products and expanded influence of patient-- advocate groups such as the National Organization for Rare Diseases (New Fairfield, CT, www.pcnet.com/ -orphan).

Experience with Subpart E and Accelerated Approval regulations revealed the difficulty of convincing desperately ill patients to enroll in controlled trials -- those in which the treatment being received was not divulged until the study was closed. Given the alternative of compassionate use or expanded access programs, such patients frequently chose to obtain known experimental therapies instead.

As with much of FDAMA, the U.S. Congress built upon and codified that regulatory experience. In Section 112, the language of the law changed somewhat ("serious and life-threatening" replaced "life-threatening and severely debilitating"). Congress defined and codified the term "fast track product." A formal request procedure for fast track status was established, requiring FDA to respond to such requests within 60 days. By confirming the acceptability of surrogate endpoints and requiring sponsors to conduct postapproval studies, the fast track provisions codified the Accelerated Approval Rule and made new therapies available to patients by enabling sponsors to market their products faster than before. Of course, FDA retained the responsibility to review all promotional material before distribution.

Whereas the expanded access programs were intended to allow access to investigational drugs before their approval, FDAMA's Fast Track programs are intended to speed up review, approval, and marketing of eligible products.

Fast Track Application

Sponsors may apply for fast track designation at the time of their initial IND submission or at any time before approval of an NDA or a BLA. A fast track designation confers eligibility for several FDA programs, including regular contact with the appropriate FDA reviewing division; regular written correspondence regarding meeting minutes, proposed protocols, and modifications in the development plan; priority review of a BLA or an NDA; and early review of portions of a marketing application.

Demonstrating unmet medical need is easy when no available therapy for an indication exists. When another therapy is already available, a new product would address an unmet medical need if it provided improved effects on serious outcomes, if it brought about serious outcomes not known with alternative treatments, or if it provided benefits to patients who are unable to tolerate or are unresponsive to the alternative agents. Additionally, a new product addresses unmet medical needs if it avoids a common serious toxicity that causes discontinuation of treatment or if it provides benefits by improving on some factor, such as compliance or convenience, which may lead to improved effects on serious outcomes.

Demonstrating the potential of a new product would depend on its stage of clinical development. Before human studies are initiated, a drug's potential is mainly theoretical. As clinical development progresses, FDA will use the evolving data to consider the potential of the product to address unmet clinical needs. At later stages of development, the agency is likely to determine whether continued fast track status is warranted based on clinical comparison of the product with existing therapies.

Both CBER and CDER have wellestablished priority review procedures. Fast track products are ordinarily eligible for priority review; but priority review products are not necessarily fast track products. The sponsor of an NDA or a BLA need not seek fast track designation to be eligible for priority review. Similarly, all programs -- except early review - that are available to fast track products are also available to products that are not in fast track development programs.

Early review of portions of an application is the only program exclusively available to Fast Track products. Historically, sponsors could submit chemistry, manufacturing, and controls (CMC) sections 90120 days before the anticipated submission of the balance of an NDA (5). The early review provisions of the Fast Track program allow FDA to review portions of an NDA or a BLA before the complete marketing application has been submitted. Under that provision, the applicant provides a schedule for submission of complete sections of information for FDA acceptance and pays applicable user fees. The agency must agree to that schedule. Although review of pivotal trial data or other critical information may begin early, FDA's review clock does not begin until the complete BLA or NDA has been submitted.

Under the new law, FDA has the authority to withdraw quickly any approved fast track product that fails to demonstrate the clinical benefits predicted by the early surrogate endpoint(s). Also, if postmarketing experience demonstrates that a product is not safe or effective when used as labeled, FDA may withdraw it quickly from the market. The expedited withdrawal provision of the fast track rule also authorizes FDA to remove products from the market if their sponsors fail to conduct required postapproval studies or if they disseminate false or misleading information.

The "First Fast-Trackers" box describes some of the companies that have taken advantage of the fast track program.

Will It Last?

With expedited review and approval inevitably will come market withdrawals. Some of those will happen when surrogate endpoints are not borne out in clinical benefits. Other products will be withdrawn because of adverse effects. The Public Citizen Health Research Group (Washington, DC, www.citizen.org/hrg) asserts that withdrawal from market for safety concerns presents a conflict of interest because it is in the hands of the same reviewers who approved the drug in the first place (6). Yet there are some who would disband drug regulation altogether (see the "Politics of Drug Development" box). Personal injury lawyers will surely use withdrawals from market to indict both FDA and the drug sponsor.

In an era of patient-activists who insist on the availability of new therapies, a Congress determined to streamline FDA procedures for marketing approval, and an FDA rising to the challenge of reinventing itself, it seems likely that the forces that led to the codification of the Fast Track program will continue to encourage rapid development and approval of drugs to fulfill unmet medical needs. Indeed, a return to "the drug lag" of the 1980s would serve no one well.

AN AWARD WINNER

BioPharm is owned by Advanstar Communications, an international business information company that publishes 105 magazines and directories and produces 110 exhibitions and conferences worldwide. The magazines compete in a quarterly program, the Advanstar Quality Editorial (AQE) awards, judged by faculty of distinguished journalism schools throughout the United States, to acknowledge exceptional content and design. Please join us in congratulating Nancy Chew on the third-quarter AQE gold "Best Column" award for her September 1998 BioPharm column titled "Xenotransplantation: Science, Regulation, and Ethics." The entries were judged by journalism professors at Stanford University (Stanford, CA) who called it "a thoughtful, balanced, and well-informed discussion of an issue of considerable consequence to readers."

[Sidebar]

SECTION 112 OF THE FOOD AND DRUG MODERNIZATION ACT OF 1997

SEC. 112. EXPEDITING STUDY AND APPROVAL OF FAST TRACK DRUGS.

(a) IN GENERAL- Chapter V (21 U.S.C. 351 et seq.), as amended by section 125, is amended by inserting before section 508 the following:

SEC. 506. FAST TRACK PRODUCTS. (a) DESIGNATION OF DRUG AS A FAST TRACK PRODUCT

IN GENERAL- The Secretary shall, at the request of the sponsor of a new drug, facilitate the development and expedite the review of such drug if it is intended for the treatment of a serious or life-threatening condition and it demonstrates the potential to address unmet medical needs for such a condition. (In this section, such a drug is referred to as a `fast track product'.)

(2) REQUEST FOR DESIGNATION- The sponsor of a new drug may request the Secretary to designate the drug as a Fast Track product. A request for the designation may be made concurrently with, or at any time after, submission of an application for the investigation of the drug under section 505(i) or section 351 (a)(3) of the Public Health Service Act.

(3) DESIGNATION- Within 60 calendar days after the receipt of a request under paragraph (2), the Secretary shall determine whether the drug that is the subject of the request meets the criteria described in paragraph (1). If the Secretary finds that the drug meets the criteria, the Secretary shall designate the drug as a Fast Track product and shall take such actions as are appropriate to expedite the development and review of the application for approval of such product.

(b) APPROVAL OF APPLICATION FOR A FAST TRACK PRODUCT

(1) IN GENERAL-The Secretary may approve an application for approval of a Fast Track product under section 505(c) or section 351 of the Public Health Service Act upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit.

(2) LIMITATION- Approval of a Fast Track product under this subsection may be subject to the requirements

(A) that the sponsor conduct appropriate postapproval studies to validate the surrogate endpoint or otherwise confirm the effect on the clinical endpoint; and

(B) that the sponsor submit copies of all promotional materials related to the Fast Track product during the preapproval review period and, following approval and for such period thereafter as the Secretary determines to be appropriate, at least 30 days prior to dissemination of the materials.

(3) EXPEDITED WITHDRAWAL OF APPROVAL- The Secretary may withdraw approval of a Fast Track product using expedited procedures (as prescribed by the Secretary in regulations which shall include an opportunity for an informal hearing) if

(A) the sponsor fails to conduct any required postapproval study of the Fast Track drug with due diligence;

(B) a postapproval study of the Fast Track product fails to verify clinical benefit of the product;

(C) other evidence demonstrates that the Fast Track product is not safe or effective under the conditions of use; or

(D) the sponsor disseminates false or misleading promotional materials with respect to the product.

(c) REVIEW OF INCOMPLETE APPLICATIONS FOR APPROVAL OF A FAST TRACK PRODUCT

(1) IN GENERAL- If the Secretary determines, after preliminary evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective, the Secretary shall evaluate for filing, and may commence review of portions of, an application for the approval of the product before the sponsor submits a complete application. The Secretary shall commence such review only if the applicant

(A) provides a schedule for submission of information necessary to make the application complete; and

(B) pays any fee that may be required under section 736.

(2) EXCEPTION- Any time period for review of human drug applications that has been agreed to by the Secretary and that has been set forth in goals identified in letters of the Secretary (relating to the use of fees collected under section 736 to expedite the drug development process and the review of human drug applications) shall not apply to an application submitted under paragraph (1 ) until the date on which the application is complete.

(d) AWARENESS EFFORTS-The Secretary shall

(1 ) develop and disseminate to physicians, patient organizations, pharmaceutical and biotechnology companies, and other appropriate persons a description of the provisions of this section applicable to Fast Track products; and

(2) establish a program to encourage the development of surrogate endpoints that are reasonably likely to predict clinical benefit for serious or life-threatening conditions for which there exist significant unmet medical needs.

(b) GUIDANCE- Within 1 year after the date of enactment of this Act, the Secretary of Health and Human Services shall issue guidance for Fast Track products (as defined in section 506(a)(1) of the Federal Food, Drug and Cosmetic Act) that describes the policies and procedures that pertain to section 506 of such Act.

Source FDAMA Public Law No. 105-115, Section 112, www.fda.gov/cder/guidance/ index.htm, Appendix 1, Reference 1.

[Sidebar]

FIRST FAST-TRACKERS

During the first year of its availability, the FDA Fast Track program was met with interest and enthusiasm by the pharmaceutical industry. Fast track status was sought and successfully used to gain approval for at least two products that had been developed through other FDA expedited review programs. These brief descriptions serve to illustrate the kinds of innovations that characterize some of the early entrants on the fast track.

Sustiva (efavirenz) from DuPont Pharmaceuticals Company (Wilmington, DE) was granted fast track status for the treatment of HIV-1 infection (in combination with other drugs) in May 1998. An NDA was submitted in June and approved 17 September 1998. The once-a-day therapy was approved to treat HIV and AIDS in both children and adults. Early approval granted to Sustiva was based on surrogate endpoints rather than on clinical endpoints such as delay in death or reduction in opportunistic infections. FDA approved Sustiva after 24-week studies showed it effectively suppressed the human immunodeficiency virus. The drug's effect on HIV beyond that period had not been demonstrated. If postmarketing studies fail to verify Sustiva's clinical benefits, FDA may withdraw approval.

On 25 September 1998, Genentech, Inc. (South San Francisco, CA) received approval to market its fast track drug, Herceptin (trastuzumab). The completed Herceptin BLA had been submitted to FDA early in May of 1998. A targeted approach to the treatment of metastatic breast cancer, Herceptin received unanimous approval by FDA's Oncologic Drugs Advisory Committee on 2 September 1998 and was granted marketing approval 25 September 1998. Before being approved for marketing, Herceptin was available through an expanded access program undertaken by the National Cancer Institute working in cooperation with Genentech and FDA. The intravenous treatment for metastatic breast cancer is approved for use in patients whose tumors overexpress the human epidermal growth factor receptor 2 (HER2) protein. It is used in combination with paclitaxil in first-line therapy and as a single agent in second- and third-line therapy.

During the last quarter of 1998, Discovery Laboratories (Doylestown, PA) received two fast track designations for Surfaxin, a synthetic peptide that mimics surfactant peptide B. The company has completed a Phase II trial of the product for meconium aspiration syndrome and a Phase II-III trial for acute respiratory distress syndrome. Orphan status had previously been granted for each of these Surfaxin indications. For the meconium aspiration syndrome indication, Discovery was awarded an Orphan Products Development Grant from FDA in October 1998.

AltaRex Corporation (Edmonton, Alberta, Canada) received fast track designation in December 1998 for the OvaRex monoclonal antibody treating patients with advanced ovarian cancer. OvaRex received orphan drug status in November 1996. The antiidiotype antibody is intended for patients whose tumors express CA 125 antigen.

[Sidebar]

THE POLITICS OF DRUG DEVELOPMENT

Consider FDA's mandate to protect the public health. Consider the "stakeholders" whom Congress consulted during enactment of FDAMA: patients, physicians, pharmaceutical manufacturers, and their own constituents. Consider the passion with which plaintiffs' lawyers argue irresponsibility on the part of both FDA and pharmaceutical companies. As a further example of the emotion engendered by government drug regulation policies, consider this excerpted Libertarian Party news release of 20 March 1998:

"Why is the government forcing terminal cancer patient Teresa Pelzer to play the lottery to prolong her own life? That's the question Libertarians were asking as Pelzer, a 36-year-old mother of three in Detroit, tried desperately to obtain Herceptin. The drug had been wildly successful in clinical trials, but FDA hadn't yet approved it, and Pelzer's only hope was to be selected by a computerized lottery.

"'FDA, get out of the way!' said Steve Dasbach, national chairman of the Libertarian Party. `Politicians and bureaucrats have no business dictating what kind of medicine Americans can take whether experimental or not. By restricting access to this drug, the FDA has in effect sentenced Teresa Pelzer to death by regulation.'

"Pelzer's days were numbered, but Herceptin could have extended her life by as much as 18 months. But FDA allowed only limited supplies to be dispensed through its `compassionate use' program, which selects winners by computerized lottery. So far, just 469 of the estimated 60,000 women afflicted with the disease have received that medication.

"`So much for government compassion,' Dasbach said. `By keeping this medication off the market, these power-hungry bureaucrats are turning the lives of suffering cancer victims into a lottery game. In a freemarket economy, pharmaceutical companies would immediately start producing a sufficient supply of this drug, making money and saving lives in the process. Of course, that would satisfy everyone except government workers, who would be deprived of their jobs, and their power over our lives and our health.'

"Libertarian Party, 2600 Virginia Avenue, N.W., Suite 100, Washington, DC 20037. For additional information, contact George Getz, press secretary, (202) 333-0008 extension 222, email 76214.3676@ compuserve.com."

[Reference]

References

(I) Fast Track Working Group, "Guidance for Industry: Fast Track Drug Development Programs -- Designation, Development, and Application Review" (U.S. Food and Drug Administration, Rockville, MD, September 1998), www.fda.gov/cder/guidance/index.htm and www.fda.gov/cber/guidelines.htm.

(2) Code of Federal Regulations, Food and Drugs, Title 21, Parts 312.80-312.88 (U.S. Government Printing Office, Washington, DC).

(3) Code of Federal Regulations, Food and Drugs, Title 21, Part 312.34 (U.S. Government Printing Office, Washington, DC).

(4) Federal Register 57, 58942 (11 December 1992).

(5) Code of Federal Regulations, Food and Drugs, Title 21, Part 314.50 (d)(1)(iv) (U.S. Government Printing Office, Washington, DC).

(6) N. Chew, "1998: That Was the Year That Was," BioPharm 12 (1), 20-25 (1999). See sidebar on page 22, "FDAMA Free-for-All: Everyone Join In!" It

[Author Affiliation]

Contributing editor Ntl sy J. Chew is president of Regulatory Affairs North America LLC, P.O. Box 72375, Durham, NC 27722-2375, (919)4799956, fax (919) 479-9954, email nchew@ranallc.com.