Four Key Trends for Identifying Regulator and Payer Evidence Needs in Oncology Drug Development

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How to leverage novel trial designs and real-world data to support a cancer drug submission with an evidence strategy that is both approvable and reimbursable.


Over the past decade, oncology drug development has been at the forefront of regulatory, scientific, and clinical advances, from expedited mechanisms to biomarkers to adaptive trials. The COVID-19 pandemic has only accelerated the adoption of regulator and payer acceptance of innovations in the oncology space, such as decentralized clinical trials (DCTs) and real-world data (RWD). There will be no going back to a pre-COVID world. To succeed in this evolving landscape, developers need to create oncology therapies that are both approvable and reimbursable. This requires a solid, integrated evidence strategy that accommodates the necessary data to support regulators’ safety, quality, and efficacy requirements. Ultimately, sponsors must decisively demonstrate how any new therapy is relevant to patients’ real lives.

To discuss recent advancements in evidence needed to support oncology drug development, experts from Parexel shared insights from both the regulatory as well as the payer perspective on key topics.

  • Benefits of early advice in oncology strategy development
  • Acceptance of novel trial designs versus traditional evidentiary standards
  • Evidence considerations for accelerated approvals
  • Options for filling evidence gaps by utilizing RWD when relying on single-arm studies to support applications.

The Impact of the COVID-19 Pandemic on Oncology Drug Development
The impact of the COVID-19 pandemic on regulatory bodies in the oncology space has been relatively limited. In 2021, the US Food and Drug Administration (FDA) oncology program was on par with pre-pandemic activity. They approved 16 New Molecular Entity (NME) applications, 50 Pre-Market Approval (PMA) supplements for new indications, 25 Breakthrough Therapy designations, 58 Fast Track designations, and 70 Priority Review designations. Not only did the level of Investigational New Drug (IND) submissions continue to increase historically between 2019 and 2021, but oncology also represented a greater proportion of the INDs (Figure 1).

From a payer perspective, the COVID-19 pandemic produced several persistent changes in market dynamics. First, clinical trials have been delayed, creating a chokepoint in the drug development pipeline. Second, patients have been restricted from accessing services, resulting in delayed diagnoses and potential disruptions to therapy. Third, there has been a new emphasis on accelerating the movement of treatment into the community setting. Fourth, health technology assessments/ appraisals (HTAs) have been delayed due to the prioritization of COVID-19 and the pandemics’ impact on the workforce and practices. The overall economic forecast, and the forecast for drug budgets, have also been subdued due to the pandemic.

1. Benefits of Early Advice in Oncology Strategy Development

Sponsors can be highly strategic in the current landscape by seeking regulatory and payer advice early in the drug development process. In the past two years, the FDA Oncology Center of Excellence has announced a number of programs that affect oncology drug development. One example is Project Optimus. This aims to improve collaboration among stakeholders to optimize the dose and regimen of novel agents prior to starting a pivotal trial. It represents a policy shift in oncology to be more in line with other therapeutic areas. Examining more than one dose in a randomized setting is required to reduce the need for post-marketing dose optimization requirements. Another example is an initiative to promote the transparency of outcomes related to accelerated approvals, particularly when confirmatory studies have not confirmed clinical benefit but for which marketing authorization continues—so-called “dangling” accelerated approvals.

Two other examples of programs that outline policy shifts are concerned with issues of diversity, equity, and inclusion. First is the 2017 amendment to the Pediatric Research Equity Act. Historically, companies could get a waiver from the FDA for submitting a pediatric oncology development plan, particularly if there was an orphan designation or the targeted type of cancer did not normally appear in pediatric patients. Currently, any original New Drug Application (NDA) or Biologics License Application (BLA) submitted on or after August 18, 2020 for a new active ingredient must contain a molecularly targeted pediatric cancer investigation if the drug is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of the pediatric cancer. Of note, this requirement applies even if the adult cancer indication does not occur in the pediatric population and even if the drug has an orphan designation. This is a big change from what had been practiced previously in the United States.

Although guidance is still emerging, Project Equity represents a second program in diversity, equity, and inclusion. The goals include:

  • Developing and promoting policies to ensure adequate enrollment of historically underrepresented and vulnerable subgroups in oncology clinical trials
  • Collaborating with stakeholders on research, policy, and educational initiatives to promote access to and advance equity in clinical trials
  • Conducting and presenting data analyses in ways that facilitate the evaluation of outcomes across diverse subgroups

Given all these recent policy shifts, regulatory advice is best sought early and often. Prospective changes to clinical development plans or studies are better received than ad-hoc adjustments. From the payer perspective, “go early and go often” remains very good advice. It can be useful to access advice simultaneously from the regulatory and payer sides, particularly when the product is highly innovative, first-in-class, targets an ultra-orphan condition, has an immature data package, and/or requires an in-depth health economics discussion (Figure 2). Informal advice from multidisciplinary advisory boards and interviews is helpful. More formally, various health technology assessment bodies provide non-binding advice; however, go forward with a mindset that any proffered advice will be acted upon.

2. Acceptance of Novel Clinical Trial Designs

The field of oncology continues to lead in terms of novel clinical trial designs, including basket studies, platform studies, seamless phase 2/3 studies, and sample size re-estimation. All of these have been used to support pivotal studies. In 2020, the FDA launched Project Significant, a collaboration with the American Statistical Association, which promotes international collaboration among stakeholders to improve clinical trial designs and analyses in the oncology space. There have been seven publications released to date from this collaboration, with more guidance forthcoming.

While novel trial designs are becoming more acceptable to regulatory agencies, they can remain a struggle for payers. Cancers with small populations have unique challenges, leading to uncertainties that erode value. First, for many rare cancers, epidemiology and burden of illness data are lacking. Additionally, there are usually limited treatment guidelines and an unclear standard of care. There are often no branded comparators and no prior clinical trials in the disease space. Recruitment can be difficult, making randomized controlled trials impossible. Novel trial designs that use small study populations are often used instead, such as the single-arm trial.

A single-arm trial can provide data sufficient to accelerate development and approval from a regulatory perspective. From a payer perspective, the lack of a control arm means that it is impossible to separate study effects from treatment outcomes. This is problematic when the key question is whether or not the drug offers value over the current standard of care. Adding to the complexity from the payer perspective is the use of surrogate endpoints. Regulators are very comfortable with surrogate endpoints, like overall response rate (ORR) and progression-free survival (PFS), standing in for overall survival (OS). Payers would like to run cost-effectiveness assessments, and the extent to which treatment extends life is a major driver of those assessments. Unfortunately, PFS and ORR do not always correlate to improved OS in oncology indications. Payers may be assessing a single-arm trial with a small population using a surrogate endpoint. Those levels of uncertainty are cumulative, and cumulative uncertainty erodes the value of the product.

3. Evidence Considerations in Oncology Development

Recently, there has been heightened scrutiny toward the FDA around accelerated approvals in the oncology space.
Project Confirm was introduced in 2021 and has resulted in a searchable product database that is available to the public. Listings for products include which indications have been studied and when. They also indicate if any clinical benefit has been verified, pending verification through ongoing studies, or has not been verified, and the product has been withdrawn. The FDA has emphasized assessing dangling accelerated approvals, which are products for which clinical benefit has not been confirmed but for which marketing authorization continues. A number of recent Oncologic Drug Advisory Committee (ODAC) meetings have resulted in withdrawals of accelerated approval where confirmation of clinical benefit was not forthcoming or where confirmatory studies were not successful. The FDA will accept single-arm studies using surrogate endpoints as evidence for an accelerated approval; however, the agency is now requiring confirmatory data more quickly thereafter.

On the payer side, there are significant challenges in demonstrating the economic value of new oncology therapies, particularly in rare diseases. Demonstrating value is especially challenging when a novel therapy is indicated for use in a combination regimen. It is then necessary to demonstrate value for an expensive novel therapeutic added to an already expensive combination regimen. There are many innovative reimbursement approaches that can be taken to mitigate these challenges for payers, as seen in Figure 3. While these come in a variety of forms, all reduce the risk by reducing or eliminating a large, up-front payment. Unfortunately, none of these options is a magic bullet because each has a level of complexity and cost attached to it.

4. Filling the Evidence Gaps in Oncology Drug Development

Two current trends in filling evidence gaps in oncology drug development are dose optimization and RWD. Dose optimization is an important issue because the FDA has indicated it will put pivotal studies on hold if a sponsor does not have an appropriately justified dose and regimen, and the agency has become unsupportive of post-marketing requirements for dose optimization. It is thus critical to justify the dose and regimen as early as possible in the phase 1/2 stage.

RWD has historically been used in rare disease settings to fill data gaps in regulatory submissions by furnishing comparator evidence. However, one rare disease example of a case in which RWD furnished primary evidence was with a breast cancer product. The product was initially approved as part of a combination regimen for women only, and RWD was successfully used to support an extension to men as well. There are other rare disease examples of RWD used as primary evidence for efficacy and safety in cases of the contribution of components to a combination regimen. Note that even when RWD has been used as primary evidence, the analyses are rarely included in labeling.

While guidance about RWD is available from many regulatory agencies, it typically focuses on technical aspects of data acquisition, auditing, and handling and has been much less detailed on how to support submissions. In terms of HTA evaluations, RWD are used to reduce uncertainty and, therefore, risk. Most international agencies have frameworks in place to support the use of RWD (Figure 4). It is critical to plan for its use in advance and to work with payers to establish what will be accepted and what will not. As more RWD comes into play, more provisional approvals may be granted in the next few years.

Case Study: Comparing an Existing Treatment Arm with an External Control Arm

Parexel was brought on board to assist a sponsor with preparing for a regulatory submission in a rare disease space based upon a single-arm, open-label phase 2 study that required a historical comparator cohort. There was little precedent from which to draw guidance for a successful submission because there were few examples of RWD used successfully to support a marketing application at the time of this study. There were also quite ambitious timelines to meet. Parexel’s approach included collaborative support from our clinical operations, regulatory, and RWD teams to develop and implement a unique study design that leveraged US electronic medical record data and US and European Union (EU) site-generated data for the external control arm. The project plan was optimized to include validation, interim analysis, and full reporting. Partner technologies were harnessed for data aggregation and de-duplication for US patients across data sources. Multidisciplinary experience across teams was used to inform best practices for risk identification and mitigation. This was a very successful case, and applications for this product were supported for regulatory approval in both the US and EU.


It is clear that the COVID-19 pandemic has produced and accelerated persistent changes in market dynamics in the oncology space. To be successful, oncology drug development strategies should include seeking regulatory and payer advice early in the process and acting upon any guidance received. Seeking informal advice from multidisciplinary advisory boards and interviews is also recommended. This is particularly true when relying upon novel trial designs, such as single-arm trials, basket studies, or RWD, all of which have gained acceptance by regulatory agencies but can face challenges with payers. The use of surrogate endpoints can add complexity and uncertainty, which can erode value if sponsors are not aware of mitigation strategies. Many oncology drugs are approved under an accelerated approval process, which is facing increasing regulatory scrutiny at this time. Sponsors must work with regulatory agencies and payers to establish what types of evidentiary support will be accepted and what will not. Consider that the data package at launch will need to evolve relatively quickly post-launch to verify clinical benefit and ensure continued approval. Partnering with a multidisciplinary, experienced team to inform best practices for risk identification and mitigation throughout the process can make the difference between product approval or withdrawal.