General Regulatory Background In The United States

In the United States, new drugs are approved under authority of section 505 of the Federal Food, Drug, and Cosmetic Act (United States Code, Title 21, Chapter 9; Guidance for Industry, 1998). Section 505 of the Act (21 U.S.C. §355) describes the legal framework for the evaluation, review, and approval of new drugs for introduction into interstate commerce. Under section 505(a), 'no person shall introduce or deliver into interstate commerce any new drug, unless an approval of an application filed ... is effective with respect to such drug'. Following passage of the Food, Drug, and Cosmetic Act in 1938, drug manufacturers were required to show only that a candidate drug was safe. In 1962, partly in response to the thalidomide tragedy, the United States Congress amended the Federal Food, Drug, and Cosmetic Act to require that in addition to safety, effectiveness had to be demonstrated in order to support approval to market drug and biologic products in the United States. These amendments included provisions that required manufacturers of drug products to provide 'substantial evidence' of a drug's effectiveness. 'Substantial evidence' is defined in section 505(d) of the Act as 'evidence

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consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof'.

Since 1962, there have been many discussions about the meaning of the term 'substantial evidence' and the quantity and quality of the evidence needed to demonstrate effectiveness. It had been FDA's position that Congress intended to require at least two adequate and well-controlled studies, each convincing in its own right, to establish effectiveness. In section 115(a) of the 1997 Food and Drug Administration Modernization Act (FDAMA) (the Modernization Act) for human drug and biological products (Public Law 105-115), Congress amended section 505(d) of the Act to clarify that the Agency may consider 'data from one adequate and well-controlled clinical investigation and confirmatory evidence' to constitute substantial evidence if FDA determines that the data and evidence are sufficient to establish effectiveness (Guidance for Industry, 1998).

Biological products are approved under authority of section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. §262). The requirements for licensure include a showing that the products are 'safe, pure, and potent'. 21 CFR 600.3(s) states, 'The word potency is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.' Starting in 1972, FDA began a process for reviewing the safety and effectiveness of all previously licensed bio-logics and stated that in this review process, proof of effectiveness would consist of controlled clinical investigations as defined in the provision for 'adequate and well-controlled clinical studies' for new drugs (21 CFR 314.126) unless waived as not applicable to the biological product or essential to the validity of the study and that an alternative method is adequate to substantiate effectiveness (21 CFR 601.25(d)(2)). Serological response data have been identified as examples of adequate alternatives 'provided that a previously accepted correlation with clinical effectiveness existed' (Guidance for Industry, 1998).

In 1998, the United States Food and Drug Administration (FDA) published Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.The document was intended 'to provide guidance to applicants planning to file new drug applications (NDAs), biologics license applications (BLAs), or applications for supplemental indications on the evidence to be provided to demonstrate effectiveness'. In addition, the document was intended to meet certain other requirements of FDAMA. Although the evidentiary standard for biological products was not changed by the 1997 amendment to the law, Congress directed the agency to take measures to 'minimize differences in the review and approval' of products required to have approved Biologics License Applications (BLAs) under section 351 of the PHS Act and products required to have approved NDAs under section 505(b)(1) of the FDC Act.This guidance document, which may be found on the FDA website at cber/guidelines.htm, discusses in detail the scientific reasoning underlying the legal standard for demonstration of substantial evidence of clinical effectiveness and describes the rationale for both the quantity and quality of evidence needed to support effectiveness.

In order to meet regulatory requirements in the United States, any clinical trial in support of an NDA designed to meet the standard of demonstrating 'substantial evidence of effectiveness' must also meet the requirements for being 'adequate and well controlled' as defined in the Code of Federal Regulations at 21 CFR 314.126. In order for clinical trial results to meet the regulatory requirements, there should, among other things, be a clear statement of the objectives of the investigation, a summary of the actual methods of analysis in the study protocol and in the report of the results of the study. Claims being sought should be defined prospectively, i.e., before the study begins, and they should be amenable to evaluation using outcomes that are direct measures of clinical benefit. The design should permit valid comparison with a control so that a quantitative assessment of the treatment effect can be made.

On occasion, an applicant can use a surrogate marker of efficacy (surrogate-endpoint), as for example under the provisions for accelerated approval (21 CFR 601.41 or 21 CFR 314.510) which state that 'FDA may grant marketing approval for a new drug on the basis of adequate and well controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit ' One definition in the literature states that a surrogate marker is a laboratory measurement or physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives (Meinert, 1986; Temple, 1995). Generally, an effect on a valid surrogate marker would correlate with a meaningful clinical outcome (Temple, 1995; Friedman et al., 1996). If the pathophysiology of a disease and/or the mechanism of action of a therapeutic intervention are well understood, it may be possible to link specific effects on the surrogate marker to anticipated effects on a clinical endpoint of interest. A valid surrogate marker has biological plausibility; the effects of an intervention on the surrogate should predict the effects of the intervention on a clinical outcome. It is important to note that a surrogate endpoint might be valid for one clinical effect but may have no relationship to another. It is also important to keep in mind that the relationship between a surrogate marker and the clinical event of interest may not be causal; the relationship may be coincidental or the surrogate and the clinical event of interest may both be independently related to some third factor (Temple, 1995; Friedman et al., 1996).

For safety purposes, clinical trials capture information about new and/or novel adverse events, as well as quantitative and/or qualitative increases in expected adverse events above their underlying background rate/intensity. Studies may also be designed to capture interactions of study product with a wide variety of co-morbid conditions. As noted above, for any indication, a drug or biologic must have a favorable benefit to risk profile.

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