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.

Q: What is OCE's role in relation to the FDA?

A:  The Oncology Center of Excellence (OCE) was authorized by the 21st Century Cures Act of 2016 and established on January 19, 2017. The Center unites experts across the FDA to conduct expedited review of medical products for oncologic and hematologic malignancies. The OCE also leads a variety of research and educational outreach projects and programs to advance the development and regulation of medical products for patients with cancer.

Q: How does the OCE consider available therapies when granting accelerated approval?

A: The FDA does not review drugs in isolation, and considers the available therapies as part of its review for safety and effectiveness. Medication dosing, administration, efficacy, safety, and improvement(s) over available therapies can be important considerations when approving any medical product. Accelerated approval does present some special aspects, because it allows patients access to innovative therapies earlier than traditional approval, based on a demonstrated effect on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Due to greater uncertainty about whether clinical benefit will be verified and the possibility of undiscovered risks, accelerated approval is reserved for drugs intended to treat a serious condition and that appear to provide a meaningful advantage over available therapy.  Additionally, the FDA may require a confirmatory trial(s), and ideally, these should be ongoing and well-underway at the time of the accelerated approval. The Applicant should also have a comprehensive clinical development plan in place at the time of accelerated approval. OCE’s Project Confirm provides transparency around the accelerated approval process, including what the planned confirmatory trial is, expected completion dates, milestones, withdrawals and more. 

Additional information on accelerated approval can be found here:

• Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics
• Accelerated Approval informational website

Q: What is the process for withdrawing an approved indication?

A: If the FDA finds data showing that the drug is unsafe, or that new evidence is available showing the drug lacks substantial evidence from adequate and well-controlled investigations for the approved indications, the FDA will generally notify the Applicant of an opportunity for a hearing on a proposal to withdraw approval of an indication or application. In addition, FDA will generally withdraw approval of an application or indication if the Applicant requests its withdrawal and will consider a written request for a withdrawal and a waiver of an opportunity for a public hearing.

Q: Are there educational resources for patients and advocates?

A: We encourage everyone interested in learning more about the OCE to visit our website. 

Additionally, we have resources that may be of interest to patients and advocates, including a patient-friendly glossary of terms commonly used in clinical trials, and Project Livin' Label, a moderated informal conversation discussing the backstory of an oncology product's development and approval.

Q: What is Project Optimus? 

A: Project Optimus is an initiative to shift the dose optimization and dose selection paradigm away from ”maximum tolerated dose” in oncology drug development. This is a relatively new initiative; we are working with sponsors to integrate this into earlier stages of development. 

Additional information can be found on the Project Optimus webpage, and in this ASCO Post article.