FDA Raising the Bar Higher for Cross-border Drug Approval -
The Backstory Behind Innovent/Lilly’s ODAC Meeting and Its Implications
On Feb. 10th, 2022, after a 5-hour live hearing, by a vote of 14-1, FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended against approving Innovent (HK: 1801.HK; Mkt Cap US$6.04bn) and Eli Lilly’s (NYSE: LLY; Mkt Cap US$232.5bn) anti-PD-1 inhibitor Sintilimab.
The first attempt of a China “me-too” cancer drug hoping to enter the US market based on China only data, casts a shadow over the future of China biopharma's “go global” agenda. However, China biopharma community remains positive, expressing a great appreciation towards Innovent’s efforts as a frontrunner who provided a first-hand experience that could help other Chinese companies better adjust their FDA filling strategies.
On the surface, it seems like the challenges FDA pinpointed are largely related to Innovent/Lilly’s clinical protocol and trial diversity. However, if we add the backstory into context, the underlying issues start to emerge.
What happened is that Innovent/Lilly initiated the clinical trial in 2018, which was not originally intended for FDA approval, and that is why Innovent/Lilly did not meet with FDA throughout the process.
Then in 2019, during an AACR meeting, there was a panel discussion on China’s pathways to western markets, where FDA’s OCE director Dr. Richard Pazdur attended. At that time, Dr. Pazdur was greatly concerned about the lack of price competition in the US. So, when being asked whether FDA would approve a drug based on China-only data, Dr. Pazdur said yes if the results were “quality” data.
It is important to remember, such conversations were not in a formal setting and should not be considered as FDA guidance. However, Innovent/Lilly, along with dozens of Chinese companies, went ahead and submitted China data to FDA without investing in a new clinical trial tailored for FDA approval. This kind of opportunistic approach places inherent pitfalls into Innovent/Lilly’s clinical trial practice.
During the meeting, FDA regulators criticized Innovent/Lilly for not consulting with FDA at all until the topline data readout, which inevitably led to the misalignment of a number of clinical trial designs (Table 1).
In addition to the filling process and trial design, ODAC’s concerns are largely directed at Innovent/Lilly’s good clinical practice, which put a big question mark on the quality of clinical data generated from China.
Some of these issues FDA identified are still up to debate, the MRCT (multi-regional clinical trial) experience of the investigators for instance (Table 2). However, the 2016 report of data fraudulent in China FDA cited during the debate, is outdated.
China joined ICH in 2017, before that, China’s drug market basically was all about generics. After 2017, China biopharma, as an emerging industry, went through a chain of drastic transformation. So far, >70% of ICH guidelines have been implemented in China. As a result, we have witnessed FDA’s approval of Beigene’s (NASDAQ: BGNE; Mkt Cap US$23.4bn) Zanubrutinib, a dozen of FDA breakthrough designation for innovative therapies by China biopharma e.g., Legend Biotech’s (NASDAQ: LEGN; Mkt Cap: US$5.9bn) BCMA CAR-T and Innocare’s (HK: 9969.HK; Mkt Cap: US$2.2bn) BTK inhibitor, and the landmark out-licensing deals I-Mab (NASDAQ: IMAB; Mkt Cap: US$2.0bn) and RemeGen (HK: 9995.HK; Mkt Cap: US$3.5bn) secured.
Regarding the flexibility towards foreign data, FDA’s decision is not to withdraw the possibility of FDA approval using foreign data. Instead, as FDA alluded to, there will be “regulatory flexibility” with innovative therapies. The flexibility will allow accepting bridging studies rather than mandating additional controlled trials.
However, the nature of Innovent/Lilly’s PD-1 inhibitor Sintilimab (“me-too” drug) failed to meet any of the criteria to warrant such flexibility:
Unmet medical need
Rare diseases or diseases that disproportionately affect specific ethnic groups
Novel drug class
There are more than a hundred PD-1 inhibitors under development, and seven approved in the US. Innovent/Lilly never claimed their Sintilimab to be the best PD-1, nor its approval fulfilled an unmet need - if not taking price into consideration, hence a proper MRCT is required per ICH E17 guidance.
By contrast, Junshi (HK: 1877.HK; Mkt Cap: US$9.1bn) & Coherus’s (NASDAQ: CHRS; Mkt Cap: US$880m) application for their PD-1 inhibitor toripalimab in nasopharyngeal carcinoma (a rare tumor of the head and neck with high incidence rate in China) may fall in the category of “regulatory flexibility”. Toripalimab is currently under review based on China-only data and granted an FDA breakthrough designation. It will be interesting to see FDA’s decision on Toripalimab.
To sum up, the takeaway from the ODAC meeting is that the FDA did not signal a shutdown to China drug developers but provided a wake-up call for companies working on “me-too” drugs. Such rules apply to all, ie in October 2021, since the FDA recently approved Merck’s (NYSE: MRK; Mkt Cap: US$186bn) Keytruda for the same indication, the agency recommended Agenus (NASDAQ: AGEN; Mkt Cap: US$709m) withdraw the BLA application for its PD-1 inhibitor balstilimab.
“Me-too “drug developers need to be aware that by law, FDA is not allowed to consider price for approval. So, the value of “me-too” drugs should not solely be attributed to lower prices. In fact, this is not only a US story for “me-too” drugs, ie in 2021, China’s CDE also released new guidance on oncology drug development to use the best standard of care as control in late-stage clinical trials, raising a higher bar for drugs approval.
In both US and China, the shortcut for “me-too” drugs becomes a mirage, and the journey for “me-too” drug developers from China to march into US market, by their own or through partnership, will be rocky. However, the reality is that due to domestic pricing pressure, China drug developers have to start looking into oversea markets. In facing such challenges, a number of Chinese biotechs distance themselves from the swirl of “me-too” movement, focusing on true innovations that tackle unmet medical needs, and actively engage the agency with a clearer guidance taking into action.
It is also abundantly clear that, to ensure racial and ethnic diversity, FDA highly encourages the drug developers to consider MRCT as early as phase I or II. Therefore, it is wise for biopharma to collaborate with partners in different geographies, work together on an early MRCT plan, and leverage each’s local patient resources to meet FDA’s demands on racial diversity.
Sources:
2019 AACR recording: https://webcast.aacr.org/console/player/43254?mediaType=audio&
80% of China’s clinical trial data are fraudulent, investigation finds. BMJ 2016;355:i5396
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