Exclusive: How the US and Japan Safely and Quickly Approve 'Life-Saving Drugs'

Recently, a cervical cancer vaccine was approved for sale in China. While the public is happy, some criticize the relevant departments for their slow approval speed, which has led to the vaccine being "late" in China. The United States and Japan are known for having the strictest and most standardized drug approval processes in the world, serving as models for many countries' relevant agencies. A reporter from "Reference News" conducted interviews and investigations regarding the drug approval processes in these two countries.

Generally, it can be completed in 10 months.

There is a consensus in the American pharmaceutical community that it usually takes 10 years and 1 billion dollars for a new drug to go from development to market, referred to as "double ten." In this regard, FDA spokesperson Lindsay Meyer pointed out: "The reason it takes so long is because of clinical trials, which usually take several years."

According to Meyer, a new drug must go through three main steps to be approved for sale in the United States. The first step is for the pharmaceutical company to conduct laboratory and animal tests. If the drug is found to be safe and effective, they can apply to the FDA to conduct human clinical trials. The second step, after obtaining FDA approval, involves conducting Phase I, II, and III clinical trials to confirm that the drug is also safe and effective in humans. All three phases of clinical trials are supervised by the FDA. The third step is to apply for market approval, submitting the data from the aforementioned trials to the FDA's Center for Drug Evaluation and Research, which forms a review team consisting of physicians, statisticians, toxicologists, pharmacologists, chemists, and other experts. If the review concludes that the health benefits of the new drug outweigh the potential risks, the drug can be approved for sale.

By the time it reaches the third step, which is when the FDA receives the market application, the time taken is actually not very long. Meyer stated that the review team at the Center for Drug Evaluation and Research will first assess whether the application documents are complete. If they are incomplete, the application can be rejected; if complete, a decision on whether to approve the market application will be made within 6 to 10 months.

Meyer emphasized: "The time required for a drug to be approved for sale depends on the complexity of the drug and whether the application materials are complete." She mentioned that before a drug is proven to be safe, effective, and of high quality, there are usually several rounds of back-and-forth communication between the FDA and the pharmaceutical company. However, "some drugs have never been approved because the pharmaceutical companies could not meet the strict standards set by the FDA."

In Japan, the new drug approval process is roughly divided into two stages: the preliminary review during the development phase and the formal approval in the later stage.

In Japan, before developing a new drug, pharmaceutical companies submit a comprehensive report to the "Pharmaceuticals and Medical Devices Agency," which assesses the feasibility of the drug. "We participate in the development phase, which helps pharmaceutical companies grasp the development findings and improve the efficiency of later approvals," said Tanaka Ohi, a staff member of the agency.

Once a new drug is produced and the pharmaceutical company submits the new drug application materials, the "Pharmaceuticals and Medical Devices Agency" will establish a review team specifically for this new drug. The review team generally consists of 15 to 20 reviewers, made up of professionals from seven fields: clinical medicine, biostatistics, pharmacology, risk control, quality control, drug dynamics, and toxicology, with two to three staff members from each field.

After the review team is established, they first conduct a collective interview with representatives from the pharmaceutical company, then begin various reviews. "To ensure fairness and impartiality, the entire process will also invite third-party experts to participate," Tanaka said. After the review is completed, the review team issues a result report. If the pharmaceutical company representatives believe the results are not in line with expectations, they can apply for a re-examination. In the re-examination phase, representatives from the pharmaceutical company can also hire their own experts to discuss issues with the review team and third-party experts. Once the final result is determined, the "Pharmaceuticals and Medical Devices Agency" submits it for approval and filing with the Ministry of Health, Labour and Welfare. New drugs that pass the approval can then prepare for market launch.

Tanaka noted that a major feature of Japan's new drug review process is standardized operations. "The 'Agency' has developed a very detailed standardized review manual to minimize the interference of human factors caused by different reviewers' standards."

Currently, Japan's new drug approval efficiency ranks among the top in the world. Authoritative data shows that in the 2014 fiscal year, the average speed of new drug approvals in Japan was 306 days.

The approval team is quite large.

Japan also faced issues with slow drug approvals in the past. Until 2005, the approval speed for new drugs in Japan was nearly 800 days, far behind Europe and the United States," Tanaka said. "Later, under public pressure, Japan made significant reforms to its drug approval agencies, which greatly improved approval efficiency."

Around the year 2000, new drugs for cancer treatment were continuously emerging in the medical field, but in Japan, these new drugs were unable to pass approval for a long time, leading to despair and death among some patients waiting for treatment. This sparked discussions in Japanese society about the drug approval system.

"In the past, Japan had several drug approval agencies, which were government departments or national research institutions. Their staffing and finances were limited by government budgets. There was a severe shortage of personnel, leading to low approval efficiency," Tanaka said.

After research and deliberation, in 2004, the Japanese government reformed the new drug approval agencies, merging several agencies responsible for drug approval to establish the "Pharmaceuticals and Medical Devices Agency." Moreover, the Japanese government specifically positioned it as an independent administrative corporation, allowing it to operate independently and not be constrained by government budgets, significantly improving personnel recruitment and financial freedom.

After the reform, the "Pharmaceuticals and Medical Devices Agency" rapidly expanded its workforce. When it was established in 2004, the agency had only 256 staff members. By 2016, the number of personnel had increased to 873. At the same time, the approval speed was significantly shortened, more than doubling compared to before the reform.

"The reform gave the 'Pharmaceuticals and Medical Devices Agency' operational autonomy, allowing it to start charging fees to pharmaceutical companies. Currently, income from fees accounts for 90% of its annual revenue, while government subsidies account for less than 10%. This is the premise for our significant expansion of the workforce," Tanaka said.

Drug approval involves huge economic interests, so how can corruption in the pharmaceutical industry be prevented after becoming independent?

Tanaka explained that the "Pharmaceuticals and Medical Devices Agency" has a dedicated internal body to supervise corruption and other issues. If any reviewer is found to have accepted benefits from pharmaceutical companies, they will face strict penalties. Additionally, the salaries of the agency's staff are aligned with those of civil servants in central government agencies, which are considered above average in Japan, achieving the goal of "high salaries to prevent corruption."

Reports indicate that up to 5,000 people are involved in drug approval work at the FDA, while only a few hundred are responsible for this task at China's National Medical Products Administration. In response, Meyer stated that the FDA is divided into six centers, with a total staff of over 20,000, the largest being the Center for Drug Evaluation and Research, which is responsible for new drug approvals. As of the beginning of the 2016 fiscal year, the new drug office under this center had a total of 1,014 full-time employees, with a cap of no more than 1,067 full-time employees. "Of course, not all of these people are medical officials; there are also statisticians, administrative personnel, and so on." The number of reviewers required for each application also varies.

The new drug application is the most "well-known" work of the FDA's Center for Drug Evaluation and Research, but in addition to new drug applications, U.S. drug applications also include new drug applications for clinical trials, generic drug market applications, and biological product license applications, among others, which are handled by other offices within this center. It is worth mentioning that in the U.S., drugs are not only limited to pharmaceuticals; fluoride toothpaste, antiperspirants, anti-dandruff shampoos, and sunscreens are also considered "drugs" and are regulated by this center. In summary, the Center for Drug Evaluation and Research is responsible for regulating all drugs in the U.S., and the total number of its employees is indeed around 5,000 as mentioned above.

Special drugs have a "green channel".

So, for particularly effective drugs, life-saving drugs, and scarce drugs for rare diseases, does the FDA have a "green channel" or special approval pathway? Meyer answered: "Yes."

The FDA mainly has four accelerated approval pathways for new drugs: Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review, all targeting serious diseases such as AIDS, Alzheimer's disease, heart failure, and cancer. Epilepsy, depression, and diabetes are also considered serious diseases.

The Fast Track is designed to address unmet medical needs, meaning that the therapy provided is either not currently available or has the potential to be more effective than existing therapies. Pharmaceutical companies can submit this application at any stage of drug development. For drugs entering the Fast Track, the FDA will intervene early to ensure that relevant issues are resolved quickly, allowing the drug to be approved for market earlier and patients to access the drug sooner.

Breakthrough Therapy refers to drugs that preliminary clinical trial data shows can significantly improve efficacy compared to existing drugs. Once a new drug is designated as a Breakthrough Therapy, it not only receives all the benefits of Fast Track drugs but also receives more intensive guidance from the FDA during drug development. The FDA sometimes proactively suggests that pharmaceutical companies submit Breakthrough Therapy applications.

Obtaining clinical results from drug clinical trials takes a long time, so in 1992, the FDA introduced the Accelerated Approval pathway, using laboratory measured indicators, physical characteristics, and other so-called "surrogate endpoints" to replace actual clinical results, approving first and verifying later. If clinical efficacy is verified after market approval, the FDA maintains the original approval; otherwise, it withdraws the approval or modifies the drug label.

Priority Review is granted to drugs that have the potential to significantly improve efficacy, reducing the review time from the standard 10 months to 6 months.

Under the premise of ensuring safety, Japan's "Pharmaceuticals and Medical Devices Agency" has also launched a green channel system for orphan drugs.

Tanaka said that in Japan, orphan drugs refer to drugs for specific difficult diseases with fewer than 50,000 patients. If a new drug meets this condition, it can apply for the "green channel." If successful, the approval speed will be accelerated. In 2014, the average approval time for drugs using the green channel was 264 days.

In addition to orphan drugs, some other drugs can also apply for the green channel, including those that are significantly more effective and safer than existing similar drugs and those for treating diseases that pose a serious threat to life.

Since 1993, Japan has introduced the green channel system and continuously improved it based on medical developments. Tanaka said that the purpose of this system is to provide better drugs to the medical field more quickly to save more lives.

Closely track the performance of newly launched drugs.

So, are drugs approved by the FDA 100% safe? The answer is no, and the reason is simple: all drugs have side effects. Meyer said that the FDA faces a "balancing act" of weighing pros and cons during the new drug evaluation process.

"If it benefits one person or a small group, will it benefit the entire population? What safety risks are acceptable to patients who may use the drug and doctors who may prescribe it? After a drug is launched and new safety data is obtained, the FDA must continuously reassess these issues throughout the drug's lifecycle."

Currently, the FDA tracks the performance of marketed drugs through a series of methods, such as a voluntary adverse event reporting system called MedWatch, which receives hundreds of thousands of adverse event reports each year. Meyer said that if unexpected health risks related to marketed drugs are discovered, the FDA will issue drug safety communications to consumers and healthcare professionals and will add relevant safety issue descriptions to the drug label. Occasionally, drugs may be ordered off the market due to serious safety risks.