US FDA issues guidance for clinical trial endpoints for approval of cancer drugs and biologics


The US FDA has issued the final guidance on clinical trial endpoints for the approval of cancer drugs and biologics. This according to the industry is a major benefit for the companies that export products to both the developing and developed world. The guidance provides recommendations on endpoints for cancer clinical trials submitted to the US FDA to support effectiveness claims in new drug applications (NDAs), biologics license applications (BLAs), or supplemental applications. It also provides background information and discusses general regulatory principles. The endpoints discussed in this guidance are for drugs to treat patients with an existing cancer. However, the norms do not address endpoints for drugs to prevent or decrease the incidence of cancer. This guidance is a revision of the final guidance of the same title that published in May 2007, said the regulatory authority. Clinical trial endpoints serve different purposes. In conventional oncology drug development, early phase clinical trials evaluate safety and identify evidence of biological drug activity, such as tumour shrinkage. Endpoints for later phase efficacy studies commonly evaluate whether a drug provides a clinical benefit such as prolongation of survival or an improvement in symptoms. It discusses the general regulatory requirements for efficacy and how they have influenced endpoint selection for the approval of cancer drugs.

It also describe the endpoints in more detail whether they might serve as measures of disease activity or clinical benefit in various clinical settings. For traditional approval, applicants show direct evidence of clinical benefit. In oncology, survival improvement is considered an appropriate measure of clinical benefit. In addition, sponsors have used other endpoints for cancer drug approval. In many cancer types, radiographic tumour assessments directly measure components of the disease, and tumor measures commonly trigger treatment decisions in clinical practice. Therefore, tumour measure-based endpoints are considered more clinically relevant than other biomarkers. Tumour assessment endpoint selection should include two judgments. First, a determination of whether the endpoint may support either accelerated approval or traditional approval should be ascertained. Second, the endpoint should be evaluated for the potential of bias or uncertainty. Drug applications using studies that rely on tumour assessment endpoints as sole evidence of efficacy may need confirmatory evidence from a second trial. Accuracy in measuring tumours can differ among tumour settings. For the Clinical Trial Design and Analysis Considerations studies must allow a valid comparison to a control and must provide a quantitative assessment of the drug’s effect. The most reliable method for demonstrating efficacy is to show a statistically significant improvement in a clinically meaningful endpoint in randomized controlled trials. For the randomized studies designed to demonstrate non-inferiority, it should demonstrate the new drug’s effectiveness by showing that the new drug is not less effective than a standard regimen This non-inferiority margin should be a clinically acceptable loss that is not larger than the effect of the active control drug. The standard regimen should have a well-characterized clinical benefit. If the new drug is inferior to the active control by more than the non-inferiority margin, it will be presumed to be ineffective. Although the general principles outlined in this guidance should help applicants select endpoints for marketing applications, we recommend that applicants meet with the regulatory officials before submitting protocols intended to support NDA or BLA marketing applications. The FDA will ensure that these meetings include a multidisciplinary team of oncologists, statisticians, clinical pharmacologists, and external expert consultants as needed.

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