BY MARK S. LESNEY

This federal agency regulates, guides, and ultimately evaluates the process of clinical trials in ways often confusing to the uninitiated.

Anyone setting up clinical trials or moving new drug candidates along is well aware of the role of the FDA in the process. But unless you are part of the system, it is often difficult for someone to fully appreciate the complexities of the FDA’s role from beginning to end—much less the effort and time involved in producing the mass of paperwork and data required to fulfill the (sometimes onerous-seeming) demands of the FDA.

This column will attempt to provide a thumbnail sketch of the FDA’s role in clinical trials. It is not meant to offer procedural or legal information for those already in the know; rather, it is an introductory outline for the general researcher or manager to help provide initial grounding in the complex regulatory process in clinical trials initiation, progress, and completion.

The first step
IND (Investigational New Drug) applications are the entrèe to the world of clinical trials and to the halls of FDA regulation. INDs provide all the material needed for the agency to evaluate whether a drug can be tested in human subjects. The application is submitted by a “sponsor”—the organization that is proposing to conduct the actual clinical trials. Sponsors may or may not be the company producing the drug. In the new world of contract research organizations (CROs), phase trials are often performed for the original drug producer by outside clinical specialists. According to the FDA Center for

clinicaltrialsweb

Tracking FDA clinical trials information (a Web guide to CDER) FDA Center for Drug Evaluation and Research (CDER) Home Page. www.fda.gov/cder. Electronic Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, current through May 2000. www.fda.gov/cder/ob. The CDER Handbook. www.fda.gov/cder/handbook/index.htm. FDA Center for Drug Evaluation and Research, Fact Book 1997 (PDF format). www.fda.gov/cder/reports/cderfact.pdf. FDA Consumer; magazine index and archives (articles about CDER). www.fda.gov/fdac/fdacindex.html. Guidance for Industry on Content and Format of INDs (PDF format). www.fda.gov/cder/guidance/clin2.pdf.

Drug Evaluation and Research Fact Book 1997, the average length of time for a promising drug candidate to be synthesized, purified, and subjected to animal testing before IND submission is 18 months. Under normal circumstances, the IND must be evaluated within 30 days of submission.

INDs must include information on drug purity and manufacturing details, available pharmacological data, and a general investigational plan. This plan can help the FDA “anticipate sponsor needs”, especially in cases in which the first human studies are performed merely to determine early pharmacokinetic or pharmacodynamic properties of a new compound.

As part of the material presented, INDs must include a copy of the protocol for the conduct of each proposed clinical trial. Phase I study protocols may be less detailed and more flexible than Phase II and III studies. The primary details that must be specified are those “critical to subject safety, such as necessary monitoring of vital signs and blood chemistries and toxicity-based stopping or dose adjustment rules.” Toxicology data based on animal and in vitro studies are presented both as an integrated summary and in full tabulations of individual studies, including reactions and fates of the individual animals included in the research.

Guidance in dealing with IND regulations can be obtained online from the source (see “ClinicalTrialsWeb”) in a joint publication by the FDA Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research entitled Guidance for Industry: Content and Format of Investigational Drug Applications (INDs) for Phase I Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products.

Arising in part from increasing demand for rapid availability of new AIDS drugs, several CDER programs have been designed to speed access of promising new therapies to patients with life-threatening conditions. These initiatives include the Treatment IND, Parallel Track, and Accelerated Approval programs.

Institutional review boards
Growing out of a history of U.S. scandals and reactions to Nazi medical war crimes, the U.S. government ultimately developed strict guidelines and safeguards to protect participants in clinical trials (see “The Time Line”, Modern Drug Discovery, May 2000, p 91). Every clinical trial in the United States must be approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are as low as possible and are worth any potential benefits.

An IRB is an independent committee of physicians, statisticians, community advocates, and others that ensures that a clinical trial is ethical and that the rights of study participants are protected. All institutions that conduct or support biomedical research involving humans must, by federal regulation, have an IRB that initially approves and periodically reviews the research. At least five people compose an IRB, and at least one member must come from a nonscientific discipline such as the law or the clergy.

The IRB typically has the right to stop the trial or to request changes in procedures. According to Richard Thompson in an article in the January 1995 FDA Consumer Special Issue, “periodically, the FDA inspects IRB records and operations to certify that approvals, human subject safeguards (including informed consent), membership, and conduct of business are what they should be. Sometimes, these inspections yield evidence of problems, such as in 1993, when the FDA imposed penalties on a large California university for infractions that included a failure to report deaths.”

FDA participation in clinical trials
At any time in the clinical trials process, the FDA is allowed to issue a “clinical hold” if it is deemed necessary. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed investigation or to suspend an ongoing investigation entirely. When a clinical hold is issued, no new subjects are allowed to enter the program, and patients already in the study must be taken off the drug unless discontinuing the treatment could interfere with patient safety. Within seven days from issuance of a clinical hold, the FDA is required to send a letter to the sponsor outlining the perceived deficiency in the trial. The FDA must respond to the sponsor’s response to its letter within 30 days. Unless an unfavorable response from the FDA is given, after 30 days, the trial is allowed to continue.

Grounds for Phase I clinical holds include unreasonable risk to human subjects, unqualified clinical investigators, and misleading or insufficiently supplied information. Phase II and III holds can be called for any of the above, as well as for a determination that the protocols are deficient in design for achieving their stated objectives.

New drug applications
The company seeking to market a new drug is responsible for testing it and providing whatever evidence the FDA determines is necessary to prove its safety and effectiveness. Once Phase I–III clinical trials and appropriate long-term animal testing are successfully completed (at least in the company’s opinion) for a particular drug, the company must submit its accumulated results to CDER as an NDA (New Drug Application) or, in some cases, an abbreviated NDA. A typical NDA can be 100,000 pages long.

Because a “new molecular entity” (a drug distinctly different in chemical structure from those already on the market) cannot be marketed until the NDA is favorably reviewed, efforts to streamline the process are ongoing. The Prescription Drug User Fee Act of 1992 requires drug companies to pay fees when submitting NDAs to provide the financial backing for the FDA to expedite the review process. In special instances, funds are required for the FDA to hire more reviewers.

Regulation of the materials used

CDER’s Office of Compliance oversees the production of all drugs and biologicals given to patients during clinical trials and in subsequent sales to the general public. Companies must comply with “Good Manufacturing Practices” regulations established by the FDA. Companies must also comply with “Good Laboratory Practices” during animal toxicological studies.

To evaluate submitted NDAs, CDER has 13 reviewing divisions grouped into five Offices of Drug Evaluation. Each office oversees drugs based on the medical condition involved. Office I is responsible for cardiorenal, neuropharmacological, and oncologic drug products; Office II for pulmonary, metabolic, and endrocrine, anesthetic, and addiction drug products; Office III for gastrointestinal, coagulation, reproductive, urological, medical imaging, and radiopharma- ceutical products; and Office IV for antiviral, anti-infective, special pathogen, and immunologic drug products. Over-the-counter compounds are the province of Office V. According to Tamar Nordenberg, staff writer for FDA Consumer, the various divisions also “work side by side with reviewers in the Office of New Drug Chemistry, the Office of Clinical Pharmacology and Biopharma-ecuetics, and the Office of Epidemiology and Biostatistics to evaluate a drug’s safety and effectiveness.” The FDA also consults advisory committees of outside experts when it is determined necessary.

According to Bertram A. Spiker, senior vice president for scientific and regulatory affairs at PhRMA, although the FDA is allowed, by law, six months to review an NDA, the typical review time for the approval of new molecular entities in 1997 was 16.2 months. According to the 1997 FDA-CDER Fact Book, the average time between the IND approval and NDA submission was five years, with NDA evaluation and approval averaging 15 months.

Postmarketing demands
The FDA also has the right to demand further clinical trials after marketing in the form of Phase IV trials (see “Phase IV: When and why”, Modern Drug Discovery, June 2000, p 28). Similarly, it is the responsibility of the company to provide the FDA with periodic information regarding adverse reactions to products marketed to the general public that in rare cases, can be sufficiently damaging as to lead to product recall, change of labels, or outright revocation of marketing approval. The FDA also has a system called MedWatch (www.fda.gov/medwatch), by which consumers and health professionals can report adverse drug reactions directly to the agency.

 © 2000 American Chemical Society.  

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