Scientific Advances Require Innovative Clinical Research Models


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-07-01-2018
Volume 27
Issue 7

FDA is testing various strategies to streamline research and regulatory oversight by looking to novel clinical trial designs to advance new treatments.

FDA is testing a number of strategies to streamline research and regulatory oversight of new cancer treatments,

Jill Wechsler

cell and gene therapies and more targeted medicines, with an eye to advancing innovative methods for developing protocols and evaluating research data in multiple drug categories. FDA Commissioner Scott Gottlieb told the American Society of Clinical Oncology (ASCO) in June that new steps to accelerate cancer R&D will “make the entire continuum of drug development more efficient,” lowering costs and promoting innovation, (see

With more than 500 cell and gene therapies in early development, and nearly 20 designated as Regenerative Medicine Advanced Therapy (RMAT), FDA is looking to novel clinical trial designs to advance new treatments. The agency issued six draft guidances in July that provide scientific advice on developing novel treatments for hemophilia, retinal disorders, and rare diseases, plus long-term follow-up and manufacturing (see Because these products target devastating diseases, FDA expects to approve promising therapies based on surrogate measures, with required post-market studies that use registries and real-world patient evidence to document continued benefit or detect safety issues.

Early advice

To speed the development of cancer therapies, FDA’s Oncology Center of Excellence (OCE) is testing new strategies for improving the evaluation of clinical data in applications. One pilot establishes a “real-time oncology review” (RTOR) process. The program allows sponsors to share with FDA bottom-line data from a clinical trial soon after locking the study database. Applicants gain early feedback on data quality and how best to analyze results to answer important questions, and FDA staff is able to pre-review the data and address regulatory questions before formal review. When the sponsor files its new drug application, an agency review team familiar with the product will be able to conduct “a more efficient, timelier and thorough review,” Gottlieb explained. He estimated that this approach should free 10% to 30% of reviewers’ time, leaving more opportunity for staffers to engage with product developers. In July, FDA used the RTOR process in approving an expanded indication in less than one month followingreceipt of the application for Novartis’ Kisquali (ribociclib) for advanced breast cancer.

Another pilot is testing the use of a new template for assessing submissions for supplemental applications. This review tool enables FDA reviewers and sponsors to note areas of agreement and disagreement and additional findings directly on the review document, instead of creating separate reports that repeat the same data. This “more agile platform” for reviewing data should reduce the administrative burden on FDA reviewers and help them focus on critical results and analyses. The end result should be a single, annotated application ready for advisory committee review. If successful, Gottlieb envisions expanding this approach to original drugs and biologics in other treatment areas.

Patient perspectives

Initiatives to advance precision oncology treatments were further discussed at a June workshop on clinical outcomes assessments in cancer clinical trials, co-sponsored by FDA and ASCO. OCE leaders and research experts examined new approaches for assessing patient-reported outcomes (PROs) in cancer trails, different systems for developing PRO strategies, and FDA policies for using PRO data in regulatory review.

At the same time, FDA published the first of several guidances designed to further utilize patients’ perspectives in drug development. An initial draft advisory recommends methods for collecting patient data in clinical trials (see, and additional guidances will provide more detail on using interviews and survey information, on identifying issues most important to patients, and in selecting patient-focused study endpoints. The overall goal is to map out sound methodology for collecting patient input, so it provides data that can inform regulatory decisions.

A related goal is to encourage more patient enrollment in all clinical studies, and FDA plans to roll out guidances with strategies for including more under-represented patients in trials. Efforts to promote broader inclusion criteria are seen in a recent guidance that supports studying adolescent patients in adult oncology trials, based on evidence of similar disease occurrence and toxicity in both adults and adolescent age groups (see FDA wants trials to examine more elderly subjects and patients with poor performance status and comorbidities and to address geographic and financial barriers that prevent participation, possibly by advising sponsors to conduct studies in the communities where patients live.

The larger goal for FDA, Gottlieb says, is to create a regulatory system that approves new cancer drugs and other breakthrough therapies without large, prospective, randomized clinical studies to prove overall survival. More targeted therapies can demonstrate high benefits in studies on smaller cohorts of carefully selected patients using relevant surrogate endpoints, and more pragmatic clinical trials at the point of care will be able to harness the vast amount of data generated by routine patient interactions.


Jill Wechsler is the Washington Correspondent for Applied Clinical Trials.


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