The FDA Oncologic Drugs Advisory Committee expressed decisive support for the agency’s view that data from trials of checkpoint inhibitors performed in mainland China aren’t applicable to the U.S. population.
At a meeting Feb. 10, ODAC voted 14:1 in support of the agency’s position that additional clinical trials demonstrating applicability to U.S. patients and U.S. medical care should be required prior to a final regulatory decision for the first such drug to be presented to the agency.
The committee’s vote in effect tosses the application back to the sponsors.
The agent in question is sintilimab, sponsored by Innovent Biologics (Suzhou) Co., Ltd. in collaboration with Eli Lilly & Co. Agency officials said they are aware of 25 such applications for approval in the U.S.
FDA is precluded from considering drug pricing or competition in its regulatory decision making. Nonetheless, in an eleventh-hour move, the day before the ODAC meeting, Lilly released sintilimab’s price, which would fall 40% below the prices of comparable agents approved in the U.S.
In discussion of a non-voting question, ODAC members came out in support of the agency’s view that the results of the applicants’ clinical trial are not generalizable to the U.S. population and inconsistent with U.S. medical practice. Also prompted by FDA, the committee focused on the range of clinical trials that could make such data generalizable–from small pharmacokinetic studies to large non-inferiority trials.
“I want people to have an understanding that if we move in the direction of accepting data from one geographic area, this is a step backwards in all of our conversations about ethnic and racial diversity,” Richard Pazdur, director of the FDA Oncology Center of Excellence, said at the meeting. “We have several programs at the FDA, including Project Equity, trying to address this issue. We just had a meeting yesterday with external groups to celebrate Black History Month, and the primary thing that many people said was, ‘We want people that look like us on this trial.’”
The sintilimab application had some obvious vulnerabilities.
Prominent among the application’s weaknesses is the absence of a preplanned survival analysis in an indication where approved therapies confer a survival of over a year. The sponsors’ trial was powered for progression-free survival, without prespecified statistical testing for overall survival. Now, with sintilimab as the precedent-setting example, the agency may not feel compelled to bring other developed-in-China “me-too” drugs to ODAC.
Innovent and Lilly sought approval for sintilimab as the first-line treatment of adult patients with stage IIIB, IIIC, or stage IV non-squamous non-small cell lung cancer with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations. Sintilimab is a monoclonal IgG4 antibody targeting the programmed cell death protein-1.
The agency has been vocal in expressing its concern about “me-too” checkpoint inhibitors coming from China. The leaders of the agency’s oncology office recently published papers in The New England Journal of Medicine and The Lancer Oncology. Last week, FDA officials sat down for an interview with The Cancer Letter (The Cancer Letter, Feb. 4, 2022).
Like many of the 25 drugs cited by FDA, sintilimab was developed exclusively in China. There was no IND, and the FDA was not consulted about the initial development plan. The application was based on Study CIBI308C302 (ORIENT-11), an ongoing, randomized, double-blind trial conducted exclusively in China.
The study was conducted in order to secure approval in China, but was submitted to FDA after the sponsors came to believe that the agency would be inclined to accept single-country data, the sponsors said at the committee meeting.
In the ORIENT-11 study, a total of 397 patients were randomized 2:1 to receive four cycles of sintilimab (n=266) or placebo (n=131) in combination with pemetrexed and investigator’s choice of platinum-based chemotherapy followed by sintilimab or placebo in combination with maintenance pemetrexed until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Patients on the placebo arm with confirmed disease progression are permitted to cross over to receive sintilimab monotherapy for up to 24 months at the discretion of the investigator.
According to briefing documents, applications based solely on foreign data can be approved if they meet these three criteria:
- The foreign data are applicable to the U.S. population and U.S. medical practice;
- The studies are performed by investigators of recognized competence; and
- There is FDA validation of trial data through on-site inspections or other appropriate means.
Failure to meet any of these criteria will result in an application not being approvable based on the foreign data alone. FDA will apply this policy in a flexible manner according to the nature of the drug and the data being considered.
While many of the drugs being developed in China are “me-too” checkpoint inhibitors, some are innovative, and several are focused on indications that are more common in Asia, including, for example, nasopharyngeal cancers, FDA’s Richard Pazdur said to The Cancer Letter last week.
Such situations “may warrant a greater degree of regulatory flexibility, but nevertheless require confidence in the generalizability of the data to the U.S. and data integrity,” Pazdur said in the interview. “This may be accomplished with more restrictive indications or request for additional trials conducted in the U.S.”
Accelerated approval—a pathway where indications hit the market based on intermediate endpoints and receive a full approval after demonstrating patient benefit—will not apply in this setting, FDA officials indicated.
“Many of the applications we’re seeing that rely on clinical data from China are similar to previously conducted multiregional clinical trials that led to U.S. approval,” Harpreet Singh, director of FDA Division of Oncology 2, said to The Cancer Letter. “So, they don’t fulfill an unmet need in the U.S.”
The agency’s summary of topics for discussion at the ODAC meeting follows:
Multiregional clinical trials represent the preferred approach to global drug development as described in ICH E17. Importantly, MRCTs allow for a structured exploration of consistency of treatment effect across regions and subpopulations.
The results from ORIENT-11 are not applicable to U.S. patients or U.S. medical practice based on 21 CFR 314.106. The trial was conducted without FDA consultation or oversight, with a comparator arm and endpoint (PFS) that do not meet U.S. regulatory standards or align with U.S. medical practice. Comparison of sintilimab to an approved drug would ensure that there is no loss in OS advantage.
ORIENT-11 is not reflective of a diverse U.S. population, and does not account for both known and unknown differences amongst populations.
The FDA may apply policies on applicability of foreign data in a flexible manner according to the nature of drug and data being considered. ORIENT-11 closely resembles existing MRCTs, yet was powered for a less clinically meaningful endpoint.
The trial results do not fulfill an unmet need, thus do not warrant regulatory flexibility when considering applicability to a U.S. population.
Should additional data be required to demonstrate applicability to the U.S. population, given ORIENT-11 was conducted in a single foreign country?
What Pazdur said at 2019 AACR
Some insiders, including the sponsors of sintilimab, came to believe that FDA tacitly supports the entry of “me-too” drugs from China into the U.S. market.
This belief appears to have been based on an interpretation of comments Pazdur made three years ago at the annual meeting of the American Association for Cancer Research, at a session titled “East meets West: Chinese pharma explores Western markets.”
During the question-and-answer period, Pazdur, who was not on the panel, twice stepped up to the microphone and made statements about FDA approval standards as they relate to drugs developed exclusively in China.
An edited transcript of his statements from the 2019 AACR appears below:
When I was [in China], I was asked two questions, and it gave me pause to think about what is the strategy of the pharmaceutical companies, the domestic Chinese pharmaceutical companies, of cracking into the Western market.
Obviously, one is innovation, and that is a laudable goal. However, much of the resources are being done with PD-1 drugs. We really shouldn’t criticize the Chinese pharmaceutical companies, because we have six [PD-1] drugs now approved in the United States, with many more being done. So, this is not a Chinese issue whatsoever. It is a global issue. And, as everybody knows, in the pharmaceutical companies, the idea is risk reduction.
The two questions that I was asked [are]: Question Number One: Will the U.S. FDA accept only Chinese data? And the answer is Yes, if the data is good quality. The second question is, will the U.S. FDA consider price? That is obviously No, but it does give you an idea of where they’re going, potentially.
Now, with the six [PD-1] drugs that we have approved, there have been no differences in price. Let’s face it, this is not a free market situation where the number of drugs equals a reduction in price.
Do you see the Chinese coming into the U.S. market, looking at price and undercutting price? Here again, I could see a very easy development strategy. In lung cancer, for example, you could simply do the studies that the major pharmaceutical companies have already done.
In fact, you actually know the effect size to aim at. So, these are very, very low-risk studies to be done, and could lead to full approval of these drugs. And, obviously, they could have very similar results, so we would have very little to say in the approval of these drugs in question.
Do you see that as a strategy of breaking into this market?
As you know, the whole principle, especially when you’re starting out, is risk reduction. And yes, innovation is a laudable goal, but you’ve got to have a company, and it’s got to be successful before you go into a very risky venture. But the genesis of my question is, do you see competition of price? That could potentially be a great thing for everyone, because we haven’t seen the major Western pharmaceutical companies moving on price.
Later during the same 2019 Q&A session, Pazdur returns to the mic and elaborated on his earlier statement:
There is no comparative efficacy standard. You don’t have to be better than another drug, but you have to demonstrate safety and efficacy.
So, if a new PD-1 drug was being developed, and this is the point that I was trying to make, if I was developing a PD-1 drug in China and I wanted to go after the first line lung indication that Pfizer had, I would just simply do that study in China and duplicate it.
You don’t have to do a non-inferiority study, you already know the effect size. There’s very little risk here. I could write the statistical plan for you. You don’t even have to be a statistician to do it.
To put these statements in perspective, that year’s AACR included a broad overview of the pharmaceutical industry’s efforts to develop PD-1/PD-L1 drugs (The Cancer Letter, Oct. 7, 2016).
The annual meeting also featured a session titled “PD-1 pandemonium” that focused on a broad range of issues, including the use of accelerated approvals in getting checkpoint inhibitors on the market. This resulted in a series of ODAC meetings aimed at controlling the problem of what Pazdur dubbed the “dangling indications” of PD-1 and PD-L1 drugs (The Cancer Letter, April 30, 2021; June 25, 2021; Oct. 15, 2021; Dec. 3, 2021).
Has the world changed over the past three years?
At the Feb. 10 ODAC meeting, after his 2019 remarks were noted by the sponsors and mentioned in the press, Pazdur noted three important scientific and societal changes that have occurred over the past three years.
The sponsors would have received valuable guidance had they brought their data to the agency during the development process, Pazdur said at the ODAC meeting.
Pazdur’s comments at this week’s ODAC follow:
Since that time, there have been at least seven approvals [of PD-1 drugs] for non-small cell lung cancer. All of them are based on overall survival. In addition to that, the survival data on pembrolizumab has been updated, which now shows an over-one-year improvement in overall survival.
We strongly believe in the FDA that we should not lose this year of overall survival. That’s why we have brought this forward, to make sure that people understand that the world has changed.
Comments that were made at an AACR meeting should not be viewed as regulatory policy. Conversations should be held within the FDA–especially with regards to the submission of an application.
Nevertheless, we believe that the landscape has significantly changed since those comments, especially with the demonstration of the overall survival and the maturation of that over time. So, the landscape has changed here, folks.
Number two, over the past two to three years, especially since the pandemic, this country has experienced significant social change, and there has been a tremendous outcry for diversity in clinical trials and representation. We, as a public agency, the FDA, have to adhere to what patients want in the United States.
As I stated before, we’ve heard clearly from all patient groups that they want faces like theirs represented in their clinical trials. So, we have a huge commitment to diversity.
Single-country submissions is a step backward in achieving the racial diversity that we need in the United States.
I just want people to understand that this is going to be a major goal of not only oncology submissions, but also submissions throughout the FDA.
Single-country submissions is a step backward in achieving the racial diversity that we need in the United States.
Richard Pazdur
The third point I want to address with regards to change in our perception of what we want from international trials, is this issue of multiregional trials. We want to bring China into the multiregional arena.
We feel that we would all benefit by having China participate fully in multiregional trials with the U.S., with Europe, with South America, Central America, and, hopefully, Africa. The world will be a better place with having all countries participate in these multiregional trials.
These single-country trials are a step backward in that regard. We don’t want to pit one country against the world. We want to have everyone participate together.
Singh: ODAC asked to address generalizability
In her opening remarks, FDA’s Singh said ODAC is being asked to address the broad questions about generalizability of data from trials conducted exclusively in China.
Today’s ODAC will not follow the traditional paradigm of assessing the benefit-risk profile of a single drug.
Rather, the concept of generalizability and applicability of single-country foreign data to a U.S. population is the central issue for which we referred this application to the committee.
I will provide a high-level overview of ORIENT-11, a study conducted exclusively in China, followed by regulations and guidances with which to consider foreign data in support of a U.S. marketing application. We will then move to key issues with ORIENT-11, ending with our voting question for the committee.
I will note that, while FDA recognizes the societal implications of cost of drugs, pricing and competition may not be considered as part of FDA regulatory decisionmaking, and should not be included in our discussions today.
ORIENT-11 randomized patients in a 2:1 ratio to either chemotherapy plus sintilimab, an anti PD-1 monoclonal antibody, or chemotherapy alone as initial treatment for metastatic non-small cell lung cancer.
The primary endpoint was progression-free survival by an independent review committee, with crossover permitted at time of progression.
ORIENT-11 met its primary endpoint demonstrating PFS by blinded independent central review with a HR of 0.48. Overall survival and overall response rate were descriptive endpoints, not formally tested.
Conducted exclusively in China, the trial design, enrollment criteria, and statistical assumptions of ORIENT-11 closely resemble landmark trials which established immune checkpoint inhibitors as part of initial treatment for NSCLC.
Rather than an isolated case, this application reflects an increasing number of oncology development programs based solely on, or predominantly on, clinical trial data from China.
This strategy is in contrast to multiregional clinical trials, which have been promoted by the global regulatory community as the preferred development strategy.
FDA regulations are established by Title 21 of the Code of Federal Regulations, which contains specific criteria on acceptability of foreign data.
Guidances from the International Council of Harmonization also stand as FDA guidance, and represent our current thinking on a particular topic.
A marketing application based solely on foreign clinical data may be approved if:
- Foreign data are applicable to the U.S. population and U.S. medical practice;
- Studies are performed by investigators of recognized competence; and
- There is FDA validation of trial data through on-site inspection or other appropriate means.
Failure to meet any of these criteria will result in an application not being approvable based on the foreign data alone. Notably, the FDA does have flexibility in applying this policy according to the nature of the drug and data being considered.
International consensus guidelines on global drug development have evolved from the late 1990’s with ICH E5 to more current thinking in ICH E17.
E5 describes strategies to extrapolate foreign data through bridging studies from one, often heterogenous region to a typically homogenous population.
The goal was to fulfill an unmet need and broaden global access to novel therapies. However, bridging studies are inherently limited in their ability to demonstrate applicability to a new population. They were conducted sequentially after completion of MRCT, which actually delayed access to important drugs.
With this in mind, the ICH reconvened with additional global partners, including China, and in 2017 issued guidance calling for concurrent global registration strategies. This guidance reflected an emerging consensus that trials requiring international collaboration were preferred over single country trial
In keeping with the shift from a local to global mindset, the historical underrepresentation of Asian countries in MRCTs and subsequent reliance on bridging trials has led many Asian countries to increase their participation in MRCTs over the past decade.
An FDA analysis of the relative patient contribution for registrational studies submitted to oncology by geographic region, shows that China has had limited participation in MRCTs, relative to other Asian countries.
The true value of MRCTs are emphasized in the ICH E17 framework. These trials have typically formed the basis for new drug registration. By drawing from diverse geographic areas and ethnic populations, MRCTs allow for evaluation of regional consistency of treatment effect, avoid duplicative efforts and the need for bridging studies, and ultimately promote international harmonization of best medical practices.
ORIENT-11 was initiated in China in 2018 after this international guidance was issued, despite China’s regulatory authority joining the ICH in 2017.
Per the CFR and applicability standards outlined in ICH E5, ORIENT-11 is not applicable to a U.S. population.
The Keynote-189 trial forms the basis for U.S. standard of care at the time ORIENT-11 was initiated. The 2017 accelerated approval, followed by the 2018 regular approval of pembrolizumab with chemotherapy based on a formally tested, statistically significant improvement in overall survival, shifted the treatment paradigm, moving immune checkpoint inhibitors to a front line setting, and rendering chemotherapy alone an inappropriate initial regimen.
Four-year followup from this landmark trial shows a median OS of 22 months vs. 10.6 months, approximately one year of OS improvement, for patients treated with pembrolizumab,
ORIENT-11 could not have been conducted in the U.S., as it was no longer applicable to U.S. medical practice. Investigators would not have enrolled patients to a chemotherapy control arm, given available FDA approved therapies conferring substantial survival benefit..
Had FDA been consulted regarding ORIENT-11, a formal head to head comparison of sintilimab to an FDA approved checkpoint inhibitor would have been recommended as an initial registration strategy. This type of trial could help address the need for clarity in a crowded field by comparing regimens directly.
Instead, ORIENT-11 only contributes to the lack of coordination and redundancy in the checkpoint inhibitor space.
ORIENT-11 was powered for progression-free survival, without statistical testing for overall survival. Overall survival is generally the preferred endpoint in oncology clinical trials when it can be reasonably assessed. To date, all FDA approvals of first-line immunotherapy-based regimens for metastatic NSCLC have been based on a statistically significant improvement in OS.
Given this precedent, single-country foreign data powered for a less meaningful endpoint, PFS, provides no therapeutic advantage to patients, rather only offers uncertainty, given lack of formal testing for OS.
ORIENT-11 shows a lack of diversity by design, and does not reflect the ethnic and racial makeup of a U.S. population, notably with regards to groups traditionally underrepresented in clinical trials.
There are both known and unknown factors which may impact study interpretation and generalizability.
Acceptance of single-country data would be incongruent with calls to address the underrepresentation of racial and ethnic minorities in drug development.
The CFR requires that data be validated through on-site inspection or other appropriate means.
However, only a handful of sites are clinically inspected, which does not account for heterogeneity in trial conduct and data quality.
The FDA’s Office of Scientific Investigation inspected two of the 48 clinical sites for ORIENT-11. They found that the investigators underreported both adverse events and concomitant medications. Corrective actions were taken, including training on good documentation practices.
For both investigators, this was their first FDA inspection.
These findings underscore the need for MRCTs with investigators who have gained experience in regulatory submissions to the FDA, which may mitigate concerns regarding data integrity.
The applicant claims to fulfill the CFR on foreign data based on similar clinical practice standards to the U.S. However, SOC was not similar at the time of trial initiation, resulting in an inapplicable comparator arm. While the applicant claims similar pharmacokinetic and pharmacodynamics of sintilimab between Chinese and U.S. patients, there is insufficient data provided to make this conclusion given the vast diversity of a U.S. population.
Finally, the applicant cites an exploratory FDA analysis to show similar efficacy of checkpoint inhibitors between Chinese and U.S. patients. However, multiple retrospective FDA analyses have shown mixed results, and this would be best evaluated in a prospective MRCT.
ORIENT-11 fails to meet criteria outlined in the Code of Federal Regulations, As discussed, the trial endpoint and comparator arm are not applicable to U.S. regulatory standards. The population is not reflective of the diversity with the U.S. and there are concerns regarding compliance with GCP, as well data integrity. Lung cancer is not a rare disease, or endemic to China; thus, MRCT trials can easily be performed.
To address FDA concerns regarding applicability to a U.S. population, the applicant proposed a randomized, non-comparative study including 150 patients from the U.S., E.U., and China, comparing two doses of sintilimab.
The FDA does not consider this dose finding study adequate to address issues of generalizability.
A possible strategy would be a formal comparison of sintilimab to an approved immune checkpoint inhibitor in a MRCT with an OS endpoint, which could be conducted prior to FDA registration.
The current landscape of “me-too” drugs was not envisioned in ICH E5 when considering bridging studies as a means of extrapolating foreign data. In an already crowded space of approved checkpoint inhibitors, sintilimab offers uncertain benefit. What is best for drug development is to bring China into the fold, as a key player in MRCTs.
Neither company involved in the development of sintilimab engaged the FDA through formal mechanisms. It is critical to maintain the survival advantage for U.S. patients demonstrated with multiple approved therapies. The applicant utilizes post hoc cross trial comparisons to address the uncertain benefit sintilimab provides.
If ORIENT-11 had been designed as a well-conducted MRCT, there would have been early communication with international regulatory authorities and FDA would have provided appropriate advice on selection of comparator arm and study endpoint.
An MRCT would have permitted direct evaluation of safety and efficacy across geographic regions and would have addressed concerns regarding applicability to a U.S. population.
MRCT trials can be strengthened by adding participants such as China, Africa, and Latin American countries.
This greater diversity may help the U.S. in answering the calls to address underrepresentation of racial and ethnic minorities in drug development.
Increased participation in these trials provides a framework to establish experience in submitting data to multiple regulatory agencies around the world.
This patient centered approach will expedite global access to therapeutic advances in oncology and should be widely adopted.
Approval of this application would not signify progress in drug development; rather, it takes a step backwards on issues of applicability and diversity, offering uncertain clinical benefit relative to available therapies.
The committee will be asked to discuss the generalizability of ORIENT-11 to a U.S. population and U.S. medical practice, as well as what potential trials, if any, may address issues of applicability.
After the discussion, we will ask the committee to vote on the following question: Should additional clinical trials demonstrating applicability to U.S. patients and U.S. medical care be required prior to a final regulatory decision?
FDA: To get guidance, schedule a formal meeting
FDA’s Singh said the sponsors of sintilimab would likely have benefited from seeking FDA guidance on trial design instead of showing up with data after the trial’s completion.
The exchange between the agency and the sponsors follows:
Singh: I found the sponsors’ depiction of this to be a bit misleading. Let me take this moment to clarify: the FDA had no knowledge that this trial was ongoing until the primary efficacy results became available. The trial had completed accrual. They came to us with their progression-free survival results.
Let me take this moment to clarify: the FDA had no knowledge that this trial was ongoing until the primary efficacy results became available.
Harpreet Singh
We told them at that time that there were concerns regarding applicability and generalizability to a U.S. population. We did discuss the possibility of asking for additional data. We did not elicit exactly what type of data that would look like—this is a topic that has evolved over time within the agency; it has involved multiple high-level discussions, but we certainly did express our concerns with the data, with the fact that the study population did not adequately represent the U.S. population.
We invoked the Code of Federal Regulations, as you heard today. I do want to take this moment to clarify, because I do believe that the applicant presented this in a way that was somewhat misleading. I’d like to ask Dr. Julia Beaver to follow up on this topic as well.
Julia Beaver, chief of medical oncology at OCE, acting deputy director of the FDA Office of Oncologic Diseases: Along these points, it’s really well known across industry that in order to receive formal regulatory advice or potential agreement on a drug development plan, discussion with FDA is critical in a formal setting.
This is the way most programs are developed; it allows for that mutual understanding of appropriateness of a trial design and formal discussion regarding FDA opinions compared to, for example, interpreting informal discussions at a public meeting.
Therefore, I’d actually like to ask the applicant a follow-up question, because we’re still, I think, confused, and would like the applicant to comment on why you did not come to FDA for discussion of this trial either prior to initiation or perhaps earlier on in development, and instead came only after the trial results were obtained.
Ben Anderson, global product leader at Eli Lilly:Thank you for the question related to the timing of our interaction and sponsors’ interaction with FDA.
As we’ve stated in our presentation, this was an application initially intended for approval in China. After seeing the data and recognizing guidance provided a pathway for use of that data in filings in the U.S., the sponsor sought a meeting with the FDA per the Code of Federal Regulations guiding sponsors to have meetings to discuss potential applications prior to submission. That was the sequence of events.
If we mischaracterized that in our presentation, we apologize, as well as with respect to the feedback that was received at that meeting as well. If we might take the opportunity to share feedback that was received at the meeting, at least from our perspective, just to ensure that we’re not mischaracterizing that.
The feedback that we’ve been acting on is highlighted here in the slide from the meeting minutes, that address the comments that we have been actively discussing with FDA on the potential for post-marketing data in a population representative of the U.S. population.
Singh: I find this incredibly misleading. I can show you the word-for-word comments from our meeting package from April 2020, in which we used much stronger language invoking the Code of Federal Regulations. We are happy to break out the public record and show all of our correspondence, and we can do that.
Voting question
The voting question read:
“Should additional clinical trial(s) demonstrating applicability to U.S. patients and U.S. medical care be required prior to a final regulatory decision?”
This is not standard phrasing for an approval question, which would be something along the lines of “Should Drug X be approved?”
With this unusual phrasing, the “No” vote constituted a vote to clear a regulatory path toward approval of sintilimab and other similar drugs.
The only committee member to vote “No” was Jorge J. Nieva, MD, associate professor of clinical medicine, section head for Solid Tumors at University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine of USC.
Nieva explained his vote:
This drug works, adding value over chemotherapy alone in the first line therapy of advanced lung cancer patients. We have no evidence that the data presented is unreliable, synthetic, or otherwise fraudulent. We have adequate FDA inspections that were not hampered. If more inspections were needed, it is expected that the FDA would’ve performed them.
The PFS endpoint is appropriate with a crossover design. OS findings appear clear, with no identified issues in randomization or blinding that would’ve raised questions about this. I don’t believe we have an excess number of drugs for lung cancer. If we did, we would’ve seen downward pricing pressure by now, and there has not been, nor is our job to decide how many drugs is too many. Rather, it’s our job to determine if drugs are safe and effective.
Regarding the need for resolving health equity issues in the U.S., health equity, I think, will improve when there are fewer cost barriers to care. Having more drugs competing for those same patients will have, I think, greater impact on equity than the need for diversity in clinical trial enrollment, which I believe is important.
Multiregional clinical trials are ideal, but I do not believe they should be a fixed requirement for approval. Performing these trials requires a global infrastructure, and it creates unnecessary barriers to entry for new drugs, small firms, and eliminates middle income countries from developing their own pharma drugs developed in nations that don’t have access to new drugs. This study is an example of that effect.
I think “me-too” drugs are good things. They bring down drug prices and increase access to care for all patients. It seems the chief sin that the applicant has committed is not doing things the way the FDA would like it to have been done. They failed to show a proper process. Not that they failed scientifically.
I think the FDA should be in the business of evaluating their science and not the process, unless the process used compromised the science—though in not following the FDA process, the applicant has made the job of the FDA harder, as the FDA has structured its approach to data integrity, as Dr. Pazdur pointed out, on the ability to make comparisons across national borders and look for irregularities.
I think there needs to be some additional thinking on how else, other than MRCTs, we can overcome this risk. I don’t think that’s a sufficient concern that should impact approval in this case.
The rest of the committee voted “Yes.”
Chair of the Division of Solid Tumor Oncology, George and Edith Richman Distinguished Scientist Chair, director of the GU Oncology Program at University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University
Additional trials are required prior to U.S. regulatory approval. I don’t the applicant, their data, can be applicable to our U.S. patient population. And I have to admit that I’m disappointed to hear that the lack of engagement between the applicant and the sponsor early on during the trial design. I would like to believe that, if those meetings were held, we probably wouldn’t be actually having this conversation today.
Founder of Patients for Affordable Drugs
There’s no need for regulatory flexibility, because this application does not address an unmet need. We have treatments that are safe and effective and have shown improvement in overall survival, rather than this drug, which was tested against a primary endpoint of progression-free survival, and not against current standard of care, but instead against chemo and a placebo.
At a time when the FDA and the industry are trying to increase diversity in clinical trials to ensure they are representative of the patient population to be treated, it makes no sense to move in the opposite direction with this application.
Chief of breast medical oncology, associate director of precision Medicine at Meyer Cancer Center; scientific director of the Englander Institute of Precision Medicine; Weill Cornell Medicine, Division of Hematology-Oncology
This was a single-country run study and doesn’t apply to the variety of diversity that we have in the U.S, and in other countries for that matter. We should actually support and recommend that this bit follows the beginning of the design of the initial studies. And then, of course, for the primary endpoint, there was not overall survival progression.
Associate professor, Division of Hematology, Department of Internal Medicine; medical director, Oncogeriatric Program, James Comprehensive Cancer Center
My vote reflects my concern on the clinical trial integrity, particularly as it applies to the informed consent process, and also is supportive of the prior comments regarding diversity in clinical trial inclusion.
President at Inova Schar Cancer Institute, Inova Fairfax Medical Center
I do not think it’s applicable to a U.S. population. It needs a more diverse as well as gender balanced—and in terms of the patients we have here in the U.S., doesn’t meet an unmet need. It didn’t have overall survival. I’m concerned about the inclusion of IIIb and IIIc patients. I’m concerned about the reports of underreporting of adverse events and definitely very concerned about the patients who were enrolled to the standard of care arm after pembrolizumab was approved in China. So, I voted yes, that additional studies with a diverse population are required before a final regulatory decision is made.
Primary care physician and addiction medicine specialist, The Wright Center for Community Health
I voted yes for the reasons stated previously, and in addition, because of the inclusion of IIIb and IIIc patients who could have had curative treatment, and yet were included within this trial.
Thoracic oncologist, Massachusetts General Hospital Cancer Center
The value of a well designed multiregional clinical trial—and the importance as Dr. Pazdur stated of the charge to have more diverse clinical trials, I think was central to my vote. I believe the data that were presented don’t support the applicability of ORIENT-11 findings to the more heterogeneous U.S. population and the primary endpoint of PFS, in my opinion, is a step backwards.
Professor and director of translational research, Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia
There should be additional trials required that provide a direct comparison of safety and efficacy of the proposed regimen to the current standard of care that’s relevant in the population.
Associate professor of medicine, associate director for clinical research, director of Gastrointestinal Medical Oncology Program, University of Colorado
I will echo what’s already been said—there’s no need for regulatory flexibility in this situation. The applicability, I think, is still questionable. I have no concerns regarding competence, but there was certainly a concern regarding FDA validation. I do think an additional study is warranted. I would, again, stress, I think that this is a known entity and there’s already a body of evidence that is available. I have concerns about forcing a non-inferiority, seven-plus-year study as a confirmatory study, but would hope that the FDA and the applicant would be able to work towards a potentially more feasible and efficient solution.
Associate director of clinical research, UPMC Hillman Cancer Center; director, Lung Cancer Disease Unit at UMPC; co-director, UPMC Lung Cancer Center of Excellence
I think my issues were that this wasn’t a multi-regional trial and it lacked diversity. I echo everything everyone else said. I think that maybe discussions with the FDA regarding an additional trial that would promote diversity will be useful. I think that’s it.
Saul A. Rosenberg Professor of Lymphoma, physician leader of the Lymphoma Clinical Care Program, Stanford Medicine
Basically, I echo the thoughts of my colleagues who have voted yes too, for the same reasons. Thank you.
Clinical director of the Genitourinary Malignancies Branch, NCI
This study was not intended to lead to approval in the United States. The primary endpoint, therefore, was not appropriate, in progression-free survival. So, for me, that’s a fundamental issue. And while there is OS data, overall survival data, it lacks really the necessary robust statistical design. I would also like to say that while data integrity is of utmost importance in clinical research, moral integrity is of greater importance. We really need to do a better job to make sure that, in all clinical research, but especially in large studies like this, patients have the appropriate informed consent, that is updated as needed over time. Thank you.
Associate professor of medicine, Duke University School of Medicine, Duke Adult Blood and Marrow Transplant Clinic
While I agree with Dr. Nieva that this drug probably works, that is not the question we were asked to vote on. I do believe there are problems with the process used, as others have mentioned, with the informed consent. Although there’s some discussion of the FDA regulations and procedures, I think these are the regulations in place. We are not here to change those regulations, but to advise on whether or not we think this process has been consistent with those established guidelines—and I do not think that the processes in this study were consistent with those guidelines.
Associate professor, Department of Medicine, Division of Oncology, Yale University School of Medicine
I also voted yes, for many of the reasons previously stated.
