Japan Continues to Approve Cancer Drugs Withdrawn in US

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Japan Continues to Approve Cancer Drugs Withdrawn in US Due to Doubtful Effectiveness

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Japan Continues to Approve Cancer Drugs Withdrawn in US Due to Doubtful Effectiveness

Japan Continues to Approve Cancer Drugs Withdrawn in the US Due to Doubtful Effectiveness.

The urprising Reality: Some Cancer Drugs No Longer Used in the U.S. Remain Covered by Insurance in Japan—The Reasons Behind It.

A recent study has revealed that some cancer drugs still in use in Japan, despite being covered by insurance, have been withdrawn in the United States due to questionable efficacy.

This study, conducted by researchers from Eberhard Karls University of Tübingen and published in the international journal Clinical and Translational Science by the American Society for Clinical Pharmacology and Therapeutics, highlights a significant issue in cancer treatment: Japan lacks a system to withdraw drugs that were initially approved under the “accelerated approval system.”

The “Accelerated Approval System” in Drug Approval

Greetings, readers. My name is Shunyo Hakariya, a researcher involved in RNA drug discovery in Germany.

You might be surprised to learn that some cancer drugs still used in Japan have already had their approvals revoked in the U.S. due to insufficient efficacy.

The study I am introducing was conducted in collaboration with the Royal College of Surgeons in Ireland, the Institute for Healthcare Governance, and Lund University. It was published in Clinical and Translational Science on July 11, 2024, under the title “Continued Cancer Drug Approvals in Japan and Europe after Market Withdrawal in the United States: A Comparative Study of Accelerated Approvals.”

In cancer treatment, it is generally recommended to evaluate drug efficacy through robust scientific indicators like overall survival (OS) in clinical trials. However, evaluating overall survival can take several years, depending on the disease. Waiting for the results of such prolonged trials could mean missing the chance to save patients with severe cancer. Moreover, although pharmaceutical companies rarely emphasize it, the cost of clinical trials can be substantial. To address these issues, countries and regions like Japan, the U.S., and Europe have established a special framework for drug approval known as the “accelerated approval system,” separate from the standard drug approval process.

No System in Japan to Withdraw Approved Drugs

The key difference with the accelerated approval system is that it allows drug candidates to be approved even if the evidence of their efficacy is not fully established. In the U.S., drugs approved under this system are subject to post-marketing studies (confirmatory trials) by the pharmaceutical companies. If these confirmatory trials fail or are delayed, the U.S. Food and Drug Administration (FDA) can withdraw the drug from the market.

In recent years, the FDA has been accelerating the process from accelerated approval to market withdrawal to address the issue of “questionable cancer drugs” lingering on the market—a situation we previously reported in another medical journal (H. Hakariya et al., QJM, 2024).

A similar withdrawal system exists in Europe, but in Japan, there is no mechanism to withdraw a drug once it has been approved by the authorities.

Given this context, we focused on the regulatory status of cancer drugs under the accelerated approval system in the U.S., Japan, and Europe, which together constitute the majority of the global pharmaceutical market. Specifically, we scrutinized 23 cancer drugs that had been withdrawn in the U.S. as of April 30, 2023, and examined their approval status in Japan and Europe using data from regulatory authorities and pharmaceutical companies.

“Questionable Cancer Drugs” Remain Covered by Insurance in Japan and Europe

Our findings revealed that of the 23 drugs, pharmaceutical companies had applied for approval for 15 of them in Japan and/or Europe. Moreover, 12 of these drugs were still approved in Japan or Europe.

Japan’s regulatory authority, the Pharmaceuticals and Medical Devices Agency (PMDA), had received applications for seven of these drugs and had approved all of them by April 30, 2023. These approvals spanned various types of cancer, as shown in Table 1, and included drugs such as Mylotarg (gemtuzumab ozogamicin), Iressa (gefitinib), Avastin (bevacizumab), Fludara (fludarabine phosphate), Istodax (romidepsin), Farydak (panobinostat), and Tecentriq (atezolizumab).

Furthermore, two of these drugs, used in breast cancer treatment, were even recommended in Japan’s breast cancer treatment guidelines. Tecentriq (atezolizumab) was strongly recommended, and Avastin (bevacizumab) was recommended (according to the 2022 guidelines).

Meanwhile, the European Medical Agency (EMA) received applications for 13 of these drugs, approved 12, and rejected one. Of the 12 approved drugs, two were later withdrawn, but the remaining 10 continued to be approved as of April 30, 2023.

Drugs Remain on the Market for as Long as “11.5 Years”

We then calculated how long these drugs, which remained approved in Japan and Europe, had stayed on the market.

Starting from the date of their withdrawal from the U.S. market, we calculated the market retention periods of these “questionable drugs” in various countries and regions. Astonishingly, we found that in Europe, these drugs remained on the market for between 0.2 and 11.5 years (median 1.3 years), while in Japan, they remained for between 1.1 and 11.5 years (median 3.2 years).

Furthermore, the total market retention period for the 10 drugs that remained approved in Europe was 26.8 years, while in Japan, despite only seven drugs remaining approved, the total retention period was 36.2 years.

These periods may extend even further.

The Criteria for Efficacy Are “Looser” Than for Regular Drug Approval

So, why has this situation occurred?

The accelerated approval system was originally established to quickly deliver potentially effective drug candidates to patients in the U.S. (since 1992), Japan (since 2017), and Europe (since 2006). This system is primarily applied to cancer drugs. To assess efficacy more quickly, surrogate endpoints, such as overall response rate (ORR) and progression-free survival (PFS), are used instead of overall survival. If the drug’s efficacy is “estimated” based on these endpoints, it can receive approval and become a drug covered by insurance.

This means that the criteria for efficacy are “looser” than those required for regular drug approval.

Lack of a “Withdrawal System”

As a result, many drugs approved under the accelerated approval system suffer from several scientific shortcomings: (1) the total number of patients included in clinical trials is often small, (2) studies in specific patient populations may be insufficient, and (3) approval may be based on data from a single non-randomized trial with weak scientific robustness. In other words, the drug may be approved without “clinical benefit” being fully demonstrated, leading to problems.

If approvals are granted too easily, “questionable drugs” may be approved, potentially leading to a situation where “patients are administered drugs with no benefit, wasting national healthcare resources.” To minimize the time these situations occur, the U.S. has a withdrawal system in place. However, in Japan, only the “rapid approval” system has been implemented, without a corresponding withdrawal mechanism.

The Need for “International Regulatory Harmonization” in Cancer Drug Approval

In our study, we examined 23 cancer drugs that had received accelerated approval from the FDA but were later withdrawn in the U.S. The results showed that the approval status of these drugs varied by country and region, with some cancer drugs remaining approved in Japan and/or Europe.

This suggests that either (1) U.S. cancer patients no longer have access to drugs that should be effective, or (2) patients in Japan and/or Europe are being prescribed drugs with no clinical benefit. Considering that the FDA made its withdrawal decisions after conducting post-marketing confirmatory trials, it is more likely that the latter scenario is closer to the truth.

To eliminate these regional discrepancies, international regulatory harmonization is needed in the approval of cancer drugs.

Drugs with “Unproven Clinical Benefit” Continue to Be Used

How should Japanese doctors and regulatory authorities respond to this situation?

In Japan, especially, there is a tendency for “questionable cancer drugs,” i.e., those that received accelerated approval from the FDA but were later withdrawn in the U.S., to remain approved for long periods. Moreover, no cases were found where once-approved indications had been withdrawn.

This could be interpreted pessimistically as indicating that drugs with “unproven clinical benefit” are being used in Japan (and similarly in Europe). Therefore, Japan and European regulatory authorities may need to consider re-evaluating and withdrawing drugs with unclear clinical benefits. At the very least, authorities should provide clearer explanations for the differing approval statuses across countries and regions.

Updating Treatment Guidelines Is Also Important

Moreover, healthcare professionals, including doctors, should not simply prescribe drugs recommended by pharmaceutical representatives just because they are approved in Japan. Instead, they should stay updated on the latest international evidence and incorporate it into their daily practice.

Of course, it is not easy for busy doctors to continuously update such information. Therefore, it is important that the treatment guidelines issued by medical societies provide guidance based on the latest clinical trial information.

In conclusion, as someone involved in drug discovery research, I hope that the drugs delivered to patients are those that have been thoroughly proven to offer clinical benefits, ensuring that they truly serve the best interests of the patients.

Japan Continues to Approve Cancer Drugs Withdrawn in US Due to Doubtful Effectiveness

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(source:internet, reference only)

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