March 9, 2022 - FDA, Global, Healthcare, Pharma, Regulatory

FDA’s Loud and Clear Message: Engage with FDA Early and Formally

Jianyuan (Yuan) Hua, FDA Regulatory and Compliance Associate in New York, contributed to the drafting of this post.

On February 10, 2022, the U.S. Food and Drug Administration (FDA) held a public Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the sintilimab application based on the ORIENT-11 trial conducted exclusively in China. Rather than following the traditional paradigm of assessing the risk-benefit profile of a single drug, the committee was, in a significant departure from typical Advisory Committee practice, asked to vote on a single question: Whether additional clinical trial(s) should be required to demonstrate applicability to the U.S. population and U.S. medical practice prior to a final regulatory decision. The committee ultimately voted 14–1 in support of the need for additional clinical trials, potentially delaying sintilimab’s approval in the United States by years. Yet, with more than 25 drug applications from China pending before the FDA, according to Dr. Richard Pazdur in his February 4, 2022 article in The Lancet, the more pressing question is whether the panel’s decision has any relevance beyond sintilimab. While there is no quick answer, the loud and clear message is that sponsors need to engage with the FDA early and formally if they seek FDA approval for their drugs.   

ORIENT-11 is a randomized, double-blind, placebo-controlled phase 3 trial assessing the safety and efficacy of sintilimab in combination with pemetrexed and platinum chemotherapy as a first-line treatment for patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). With trials exclusively in China, sintilimab’s review hinges on the FDA’s regulatory flexibility under 21 C.F.R. 314.106, which stipulates that “[a]n application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if the foreign data are applicable to the U.S. population and U.S. medical practice.” After hearing presentations from both the FDA and the sponsor, the majority of the ODAC members decided that the study was not generalizable to the U.S. population because (1) the patient demographics in ORIENT-11 do not reflect the diverse U.S. population; (2) the study endpoint and comparator arm were not the standard of care for U.S. medical practice; (3) the consent forms should have been updated when pembrolizumab was approved by the Chinese regulatory agency seven months after study initiation; and
(4) the inspections were too limited in scope to assess trial conduct and data integrity.

Despite calling into question ORIENT-11’s trial design and conduct, the FDA did not conclude that trials conducted exclusively in a single foreign country could never be approved in the United States. Instead, the FDA indicates that the agency will apply 21 C.F.R. 314.106 in a flexible manner according to the nature of the drug and data considered. For “me-too” drugs that do not address unmet medical needs, rare diseases, or novel drug classes, the agency has to determine the applicability of the foreign data to the U.S. population, the recognized competence of the clinical investigators, and the FDA’s validation of the data. Sintilimab review provides valuable insights for sponsors that seek FDA approval based on a foreign-only clinical strategy.

(1) Early engagement with the FDA. Regardless of the clinical strategy, sponsors should engage with the FDA formally and early if they want their drugs to be marketed in the United States. Relying on informal communication with the FDA can be a costly mistake. Eli Lilly and Innovent were reportedly prepared to launch sintilimab in the U.S. market when Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence, openly welcomed Chinese sponsors to bring their PD-1/PD-L1 inhibitors to the U.S. market during the March 2019 American Association for Cancer Research (AACR) meeting. Yet, on February 4, 2022, less than one week before the committee meeting, Dr. Pazdur, writing for The Lancet, argued that drug applications seeking approval based on data from a “single foreign country” need to be representative of the U.S. population in order for regulators to be flexible. Defending his change of position, Dr. Pazdur declared that “I have a right to change my mind” in an interview with STAT News four days later. During the committee meeting, Dr. Pazdur emphasized again that “comments that were made at an AACR meeting should not be viewed as regulatory policy.”

Sintilimab’s bumpy ODAC meeting sends a strong message that informal communication from the FDA should never be the basis for any business or regulatory decision. Additionally, if a product wants to enter the U.S. market, the sponsor needs to engage with the FDA during the early phases of drug development or early enough in advance of submission to have meaningful engagement with the FDA regarding the data development.

The benefit of engaging the FDA early and formally is that the FDA can provide formal regulatory advice with regard to both study design and trial conduct. This can be particularly important when conducting trials in countries with different standards of care, or regulatory structures that are different from the ones in the United States. For ORIENT-11, the FDA has now indicated that it would have advised the sponsors to conduct a non-inferiority trial, comparing sintilimab with an FDA-approved anti-PD-(L)1/chemotherapy regimen with an overall survival (OS) endpoint, rather than a placebo arm with a progression-free survival (PFS) endpoint. 

 (2) Data Integrity. Data integrity is a critical underlying concern for all clinical trials, and is especially important for foreign sites. For ORIENT-11, the FDA conducted in-person inspections of two of the forty-eight clinical sites and one remote inspection of the sponsor. The inspections uncovered some minor issues, such as under-reporting of adverse events and the use of concomitant medications. However, the FDA cautioned that its inspections and data validation are limited in scope. The agency’s concerns, expressed during the ODAC meeting, are two-fold: first, most study investigators have limited experience conducting clinical trials, and second, historical data integrity problems in China make the agency less confident about clinical data generated locally. Citing a 2016 report by China’s State Food and Drug Administration that 80% of clinical trial data from China were “fraudulent or substandard,” Dr. Pazdur asked the sponsor during the ODAC meeting to clarify whether any site investigators were previously involved in data integrity scandals. 

To mitigate the potential or perceived issue of investigator competence and prevent fraudulent conduct in clinical trials, the FDA highlighted the need for international, multi-regional clinical trials (MRCTs) with “investigators who have gained experience in regulatory submissions to the FDA.” Further, MRCTs can enable regulators to “look at sites in different countries and take a look at differences . . . in adverse event reporting, in efficacy, and compare them and to see if there is any outlier.”

(3)  Diversity. Both FDA officials and the committee members emphasized the need for trial subject diversity. Dr. Pazdur, responding to his comments at the 2019 AACR when recently questioned, stressed that “[t]he world has changed since those comments were made,” adding that the agency has to address ethnic and racial diversity concerns in clinical trials. The agency highlighted some known differences between the U.S. population with non-squamous NSCLC and the patient population enrolled in ORIENT-11, pointing out that ORIENT-11 enrolled only Chinese patients, while the U.S. racial/ethnic breakdown is 79% white, 15% Black, and 6% Asian. The FDA acknowledged that the majority of the studies approved by the agency do not reflect racial representation of the U.S. population. However, Dr. Pazdur avowed the agency’s commitment to “address ethnic and racial diversity,” adding that the agency cannot be deaf to the outcry even though it will require a major shift throughout the FDA.  

(4) Human Subject Protections. Another area of focus by both the FDA and during the ODAC meeting was the troubling consent process. Seven months after ORIENT-11 was activated, pembrolizumab was approved by the Chinese regulatory agency as a first-line therapy for NSCLC. However, the consent form was not updated to reflect the change, a severe deviation from good clinical practice (GCP) requiring that patients be informed of any new and available treatment options for their conditions. The sponsor explained that, although the written consent form was not revised, all patients were informed by their treating physicians that another treatment option was available. Further, the sponsor pointed out that pembrolizumab was never a real option for ORIENT-11 patients due to its low availability and prohibitive cost.

Informed consent is at the heart of modern clinical trials. Neither the agency nor the committee found the sponsor’s rationale reasonable. As pointed out by Dr. Ravi Madan, clinical director for the Genitourinary Malignancies branch at the National Cancer Institute, “while data integrity is of utmost importance in clinical research, moral integrity is of greater importance,” and regulatory agencies need to ensure in large studies like ORIENT-11 that “patients have the appropriate informed consent that is updated as needed over time.”

The fate of sintilimab might be jeopardized, but its review process can provide insightful messages to future sponsors who plan to use foreign data when seeking FDA approval. The loud and clear message for sponsors is to engage with the FDA early and formally if the product is intended to be marketed in the United States. Informal communication can be a great way to learn the current thinking of the agency; however, it is critically important to follow up with a formal meeting to receive formal regulatory advice. Second, the FDA clearly favors MRCTs as a way to promote diversity and data integrity. It could be very beneficial to engage with study sites that have a known reputation with the FDA, such as prior involvement in FDA regulated clinical studies. Last, but not least, all clinical studies need to be conducted ethically, with informed consent as the cornerstone of all research ethics. Sponsors need to put in the utmost effort to ensure that patients are fully informed throughout the study.