Q: How are biomarkers assessed by the OCE in the context of totality of evidence? 

A: Some cancer clinical trials use biomarkers to select the patient population, particularly in situations where the investigational product is a targeted therapy. In other trials, biomarkers are collected for secondary/exploratory endpoints. The OCE considers oncology biomarkers in the context of cancer clinical trials, based on an understanding of the science. When patients who benefit from treatment are identified by a biomarker, companion diagnostics are reviewed by the Center for Devices and Radiological Health (CDRH), and CDRH will work closely with the OCE as part of a multidisciplinary team to review information submitted. In certain situations, the FDA may accept biomarkers that are used and accepted in the community as signals of response. Information on a companion diagnostic with FDA marketing authorization can be found in the product labeling.

Q: What is the difference between a head-to-head trial versus add-on trial?

A: An add-on trial shows the additional incremental efficacy benefit compared to the background treatment and can help isolate the effect of the investigational product. A head-to-head trial will look at the investigational product compared to another treatment (typically a product administered as standard-of-care treatment). Head-to-head comparisons are viewed differently than add-on trials when considering the magnitude of effect, as the alternative treatment may offer an improved toxicity profile or ease of administration.

Q: Suppose there is an ongoing or recently completed clinical trial. If during this time the treatment landscape has changed with a changed standard of care, how will the data from the clinical trial be considered during regulatory decisions?

A: The treatment landscape at the time FDA makes a decision on an application is taken into consideration, providing part of the context for FDA’s structured benefit-risk analysis of the investigational product. For example, if a drug is approved for an indication, this may be relevant when FDA evaluates the magnitude of benefit of the investigational product, as well as trial design and endpoints used in the trials; if there is an approved oncology product with overall survival benefit, then FDA may need to consider whether a study that evaluates treatment benefit for the same indication based on progression-free survival as the primary, earlier endpoint is appropriate. The magnitude of benefit is considered differently for an add-on trial design (example: A vs. A+B) versus a head-to-head comparison (example: A vs. B). In either case, however, the sponsor must provide substantial evidence of effectiveness, which may be achieved in different ways depending on the circumstances, such as by comparing the investigational drug to an active control standard of care and showing that is it better and/or not inferior. The FDA encourages sponsors to contact the appropriate review division to discuss specific questions related to their oncology product development and studies.

Q: Are patient reported outcomes (PROs) part of regulatory decision making? 

A: PROs are considered during the regulatory review if they are rigorous and sound in science. When appropriate, PROs are included in section 14 of product labeling. The OCE has a dedicated Patient-Focused Drug Development program to foster collaboration between the COE and external stakeholders involved in patient outcomes research in patients with cancer.

Q: How does OCE determine a meaningful progression-free survival versus overall survival? 

A: There are advantages and challenges with PFS and OS as endpoints. Overall survival is a meaningful to patients and healthcare providers, can be determined objectively, accounts for the efficacy and safety of an oncology product, is a direct measure of a patient’s survival, and is unbiased. However, it can take a long time to reach the OS endpoint, OS can be confounded by the future treatments, including cross-over, can require intense resources, including a large number of patients, etc. Generally, any significant OS benefit may be considered meaningful, as OS reflects both efficacy and safety. OS may not be required in all trials, but the FDA will look at OS and if a detriment is seen, this may impact the approvability of a drug.

Progression-free survival accounts for a stable tumor, more readily allows for trials that are not affected by future treatments a patient may receive and that will not be affected by cross-over, can be objective if assessed centrally or by blinded review, requires a smaller number of patients, and has a shorter duration of follow-up compared to OS. However, PFS can be hard to measure in certain situation (i.e. bones, fluid collections), can be affected by the frequency of assessments (since it cannot be measured on a daily basis and missing assessments will impact results), and cannot be interpreted without a control arm. The magnitude of treatment effect on PFS plays an important role in decision-making. Additionally, PFS can be impacted by site of lesion for assessment, biases, and can be assessor dependent.

Q: Does FDA consider price when it is making decisions?

A: No, the FDA does not take the price of drugs into consideration when making approval decisions – pricing is out of the FDA’s regulatory purview.

Q: Since FDA does not consider pricing, how should “me-too” drugs be considered? 

A: Many factors should be considered, including safety, efficacy, endpoint selection, comparator arm, and overall clinical trial design. While the regulations do not require comparative efficacy, the FDA strongly considers if the treatment received by patients on the comparator arm is reflective of the current standard of care in the U.S.