Non-binding Guidance: Recent Developments in Oncology Drug Development

This installment of Ropes & Gray’s podcast series Non-binding Guidance explores recent regulatory developments related to the development and approval of oncology drugs in the U.S.—previously summarized in a recent client alert—and Europe. On this episode, hear from Ropes & Gray FDA regulatory partner Josh Oyster and head of the European life sciences practice Lincoln Tsang as they compare approaches from FDA and E.U. legislation, and discuss what that means for companies researching and developing new oncology products for a global market.

Transcript:

Josh Oyster: Hi, I'm Josh Oyster, a partner in the life sciences regulatory and compliance practice group at Ropes & Gray. Welcome to Non-binding Guidance, a podcast series focused on current trends in life sciences regulatory law, as well as other important developments affecting the life sciences industry. Joining me today is my partner Lincoln Tsang from our London office. Lincoln is the head of our European life sciences practice. Delighted to have you here, Lincoln, with me, because today's topic has a global appeal, focusing on recent regulatory developments related to the development and approval of oncology drugs. We're going to compare and contrast approaches in the U.S. and Europe, and discuss what that means for companies trying to bring new oncology products to market.

Lincoln Tsang: Thank you, Josh. Timely and equitable patient access to innovation has always been a recurring theme of the E.U. regulatory system, which continues to evolve. It is timely today to have this conversation because a few days ago on the 26th of April, the European Commission published potential major reform of the E.U. pharmaceutical legislation. The evolving regulatory system seeks to strike the right balance of regulatory control of innovation on one hand, based on robust evidence, and the timely patient access to transformative innovation on the other hand. This has been a continuing debate amongst the regulatory authorities, the legislature, payors, health care professionals, and most importantly, the patients.

Josh Oyster: To kick us off, I'll briefly recap a few recent FDA developments that tee up some of the key issues. In late March, FDA published a draft guidance describing clinical trial considerations to support accelerated approval of oncology drugs. FDA's accelerated approval program, as most know, allows for the earlier approval of drugs that treat serious or life-threatening conditions, that provide a meaningful advantage over available therapies, and that have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. For those drugs that receive accelerated approval, FDA generally requires a sponsor to conduct a confirmatory study to verify and describe that clinical benefit as a condition of continued approval. Our team at Ropes & Gray analyzed this March draft guidance in a client alert in more detail, but in a nutshell, the guidance describes FDA's current thinking on a few key issues.

• First, FDA reiterated its preference for randomized control trials, as opposed to single-arm trials, to support the accelerated approval of oncology drugs in the U.S. FDA has long recognized that randomized control trials are the most reliable method for demonstrating efficacy, but FDA appears to be upping the ante now, and more directly suggesting that single-arm trials to support accelerated approval will only be accepted in limited circumstances.
• Second, FDA also discussed one-trial versus two-trial approaches for the approval of oncology drugs. In a one-trial approach, a surrogate endpoint, like objective response rate, would be evaluated to support accelerated approval, and then, a different endpoint, like overall survival, would be used to verify clinical benefit after a longer follow-up period, and then support traditional FDA approval. The one-trial approach has the potential to increase efficiency and reduce enrollment issues that can come with separate confirmatory trials in the two-trial approach, but the one-trial approach also has the potential to introduce bias.
• And the last thing I'll mention up front is that FDA's recommendations also suggest that the agency is interested in having sponsors evaluate oncology drugs in earlier lines of therapy, earlier in the development process.

Now, Lincoln, let's switch gears and bring you into the conversation. How has the E.U. been addressing these sorts of issues? And perhaps you might start by explaining how the E.U.'s conditional authorization process is a little bit different from the accelerated approval process we have here in the U.S.

Lincoln Tsang: Thank you, Josh. Turning to your specific question, the equivalent of the U.S. accelerated approval process is the conditional approval process. The conditional authorization framework was created in 2004, as part of the overhaul of the E.U. regulatory framework. This allows for early approval on the basis of less complete clinical data than normally required, because the benefit of the earlier patient access outweighs the potential risks of limited data, conditional authorizations through specific obligations to incrementally generate complete data sets on the medicines after the authorization. The conditional approval is granted to meet unmet medical needs of patients for treating seriously debilitating or life-threatening diseases, but approval is still predicated upon the need to demonstrate a positive benefit-risk evaluation. In 2021, there were 13 medicines approved on a conditional basis.

Josh Oyster: Thanks, Lincoln. So, how does the regulatory standard for approval work in this context? Does the conditional marketing authorization process lower the bar compared with a standard approval?

Lincoln Tsang: That's a very interesting question. The E.U. legislation does not set out a substantial evidence standard like in America, nor does it state that an approval must be based on two pivotal clinical trials either. Rather, the law specifies that, if possible, randomized control clinical trials are expected to evaluate the effect of the test drug against a placebo and an active comparator of proven therapeutic value. But the applicant can use other trial designs, provided that it is justified to do so. The test for granting approval is centered around the evaluation of whether the clinical benefits outweigh the risks. The same evidentiary standard applies to full-marketing authorization, as much as conditional-marketing authorizations. Put simply, whilst there is no formal requirement to include two or more pivotal studies, in most cases, a program with several studies is the most, and perhaps only, feasible way to demonstrate an internal consistency (i.e., lack of bias). The positive treatment effect must be pharmacologically and biologically plausible.

Josh Oyster: So, how does this standard apply with cancer drugs, in particular? And how do factors, like study design and a selection of endpoints, factor into the review and approval process?

Lincoln Tsang: That's an important question to ask. The evidentiary standard for approving cancer drugs, including drugs intended to treat rare cancer types, is exactly the same as drugs for other therapeutic areas.

Turning to the endpoint selection, which seems to be the key question you want me to address, the starting point seems to be that the primary endpoint should be the validated and reliable variable, capable of providing the most clinically relevant and convincing evidence, directly related to the primary objective of the trial, to provide strong, scientific evidence in relation to efficacy. The primary variable should be the one used when estimating the sample size. Now, in relation to the cancer development arena, overall survival has long been considered by global regulatory authorities, such as the U.S. FDA and the European Medicines Agency, as the gold standard for the evaluation of new oncology therapies. Overall survival is an unambiguous endpoint measure because it is evaluated on a continuous time scale, which gives precise accuracy for the time of the event. However, the use of overall survival can be extremely challenging. Take for example: If the survival is only incrementally improved by a new treatment, the demonstration of increased overall survival may require large patient populations several years of accrual and follow-up, and higher costs. Now, this is especially true if the natural history of the disease course is lengthy.

In the increasingly challenging drug-pricing environment, costs and efficiency of completing clinical development are becoming more relevant than before. Now, over the last 10 years, there has been increasing interest in using other outcome measures than overall survival to study new anti-cancer drugs, including what you have alluded to, and also the debate on use of progression-free survival. The interest in progression-free survival as an endpoint stems in part from the challenges associated with overall survival as an endpoint, but it also has been stimulated by the fact that many new cancer drugs are targeted towards molecular mechanisms of action that are cytostatic (i.e., you stop the disease progression—cytostatic, rather than cytotoxic—to kill the cancer cells). Those drugs are not expected to provide the same objective response rates of earlier drugs, and instead, act to prevent progression rather than cause tumors to regress, and thereby, impact mortality.

Now, interest in PFS has also been stimulated by increasingly common use of treatment paradigms that allow for multiple rounds of treatment—first-, second-, third-, or even fourth-stage therapies—each producing incremental changes that are difficult to capture in the context of a single study using overall survival as the primary endpoint. In contrast, PFS can be studied in short-term context for its treatment without the confounding influence of the next. The question here is whether or not PFS could be considered as a surrogate for overall survival, which is the gold standard. It is now recognized that the correlation between PFS and OS is both variable and unpredictable, and depends on a tumor type and tumor stage, as well as the particular drug being investigated. PFS not always a reliable surrogate for overall survival is not surprising as a proposition, given that tumor pathways affected by new drugs, the nature of drug and tumor interaction, as well as drug toxicity, are often incompletely understood.

In relation to your question, Josh, of the use of PFS, the E.U. position is that an effect on prolonging PFS of sufficient magnitude can be considered as clinically relevant, provided that it does not cause detriment on the other important endpoints. The reason is that documented progression of disease is generally assumed to be associated with subsequent onset or worsening of symptoms, worsening of quality of life, and a need for subsequent treatments, usually associated with lower efficacy and worse toxicity. If the assumption does not hold, then the PFS effect would not be considered as clinically relevant. If PFS is used as a primary endpoint, then the overall survival in Europe should be included as a secondary endpoint.

Josh Oyster: Thanks, Lincoln, for all that helpful insight. On the topic of endpoints, and the topic of PFS, another interesting development in the U.S. was a recent research article published in March from a group of FDA officials—including several from FDA's Oncology Center of Excellence—that highlighted these concerns you were mentioning, with the ability of endpoints, like PFS and objective responses rate, to serve as surrogate endpoints for overall survival. The article discusses instances where there has been discordance between ORR and OS, or PFS and OS, and the FDA authors concluded “the divorce between the efficacy findings of early endpoints, like ORR and PFS, and their complicated relationship to OS, highlights possible irreconcilable differences.” In 2023, the FDA's Oncology Center of Excellence is planning a series of workshops to examine the role of early endpoints, their relationship to overall survival, and considerations around obtaining the information necessary to make informed decisions on the risks and benefits of a novel cancer therapy. I think on the FDA side, we're still exploring a lot of the issues that you mentioned, Lincoln, in figuring out how exactly PFS and OS are related, and how reliable they are, but it's something that we'll have to watch and see.

Lincoln Tsang: Absolutely, Josh—I think that's a very important observation you have made.

Josh Oyster: Then, turning back to another point I mentioned earlier on the FDA side, talking about the FDA's perspective on single-arm studies—in the E.U., is there still acceptance of single-arm studies, particularly for oncology drugs, or is the E.U.'s position on that evolving along the lines of the FDA's?

Lincoln Tsang: Again, this is a very important and interesting question you have raised, and also very timely, because the European Medicines Agency just published a reflection paper on this particular topic for public consultation. The paper was the combination of the initial discussion in 2016 between the European Medicines Agency and its advisory committee and the ESMO, which is the European Society for Medical Oncology, on single-arm trials in oncology. The genesis of the debate lies on the observations that single-arm trials have led to regulatory approval of oncology drugs in Europe, in cases of dramatic activity in well-defined patient populations with higher medical needs. When randomized-control trials are not possible, single-arm trials, augmented with appropriate statistical approaches, could be become the standard basis of evidence of efficacy for new applications. Now, this really illustrates the willingness of the regulators on this side of the pond to exercise a measured degree of regulatory latitude, to determine the evidentiary standard for establishing clinical efficacy and safety.

The agency's proposal also challenges the statutory standard for a three-arm clinical trial, designed to establish clinical efficacy, as we have discussed earlier, and it also challenges the general dogma that a comparative trial must ideally include an internal control group, whether it is a placebo or an active comparator. In order to obtain an unbiased estimate of the true treatment effect, the need for an internal control applies even for an evaluation of the clinical efficacy of a drug intended to treat a very small patient population, such as an anti-cancer drug for treating a rare cancer type. Even though internal controls are a preferred option for comparative trials, the agency as well as its advisory committee, have accepted, under exceptional circumstances, that external controls may be used (for example, historical controls).

Now, the EMA's advisory committee has indicated in the past that the absence of any control data is only likely to be acceptable if the natural cause of disease is very well known. In this context, a patient registry—another topical regulatory consideration—may provide important information on a natural cause of disease and may help in assessing efficacy and safety. And also, a validated registry could be used as a source for historical controls to inform efficacy assessment. Now, one thing is very clear from the draft reflection paper: It highlights the need to identify, manage, and mitigate sources of bias in a single-armed study, to establish the true treatment effect of a new oncology drug.

Josh Oyster: Thanks so much, Lincoln—really appreciate the insight there. We've talked a lot about the U.S. and Europe so far today. With the time we have left, I'm curious, do you expect the U.K., after Brexit, to take a different position on any of these issues we've been discussing? I realize that's probably an incredibly complicated question, but I'd be curious to have your thoughts.

Lincoln Tsang: Thank you very much, Josh, for raising this important topic. I really don't think that there will be a substantial difference between the U.K. and the European approach, in terms of evaluating clinical efficacy and safety of oncology drugs. The current E.U. oncology guideline was initially authored by the U.K. agency, and the underlying principles remain, as far as I can see, valid. Post-Brexit, the U.K. government's policy, as well as the U.K. MHRA public statement, is that it wants to be positioned as an international agency by working more closely with its international coalition partners, such as U.S. FDA and other overseas agencies. In fact, for cancer drug approvals, the U.K. agency is already part of the international collaboration efforts, initiated by U.S. FDA’s Project Orbis program, which was initiated in May 2019 to provide a framework for concurrent submission and the review of oncology drugs amongst various international agencies. This is in recognition of the fact that the pivotal clinical trials in oncology are usually conducted internationally and globally, and those global trials are increasingly important for investigating the safety and effectiveness of cancer drugs for approval in the U.S. and beyond. Now, future drug development may benefit by establishing a greater uniformity of new global standards, which we have been talking about today, leading to really optimal design of these important clinical trials to benefit patients.

Josh Oyster: Great—thank you, Lincoln. I think that's unfortunately all the time we have for today. I really appreciate you joining as part of this important conversation. I'm sure we'll be back together again soon on another podcast. We want to thank all of our listeners for tuning in, as well. For more information about our life sciences regulatory and compliance practice, please visit our practice pages at www.ropesgray.com. You can listen to Non-binding Guidance and other RopesTalk podcasts through our podcast newsroom on our website, or you can subscribe wherever you listen to podcasts, including on Apple and Spotify. Thank you, again, for listening—we'll see you next time.