For years, Sara worked in a hospital, making care possible for others. Now, after being diagnosed with breast cancer, she was the one in need of care.
The global cancer drug market is set to maintain strong growth over the next decade due to factors such as environmental pollution, population aging, and poor lifestyles that leave individuals vulnerable to cancer. Therefore, research and development in the field of oncology has also become the biggest focus for biopharmaceutical companies.
Compared with the traditional development method undergoing Phase I, Phase II, Phase III, and Phase IV stages of clinical research, these days most cancer drugs are developed via the "exploratory stage" and the "pivotal stage". For example, the approval for tidagenlecleucel (trade name: Kymriah, the first CAR T-Cell therapy drug to be approved) was based on the results from only one international multi-center study of 88 patients (final report number of patients: 63) with refractory or relapsed B-cell acute lymphoblastic leukemia (the "ELIANA" clinical trial) and two supporting exploratory clinical studies (Phase I/Ia trial & Phase II single-arm, open-label study).1
Another interesting case, is Merck's approach to the clinical development of Keytruda:1 First, Merck enrolled 655 cancer patients, making it the largest Phase I trial for a single drug to date. Subsequently, more than 700 clinical trials for different indications were conducted simultaneously. However, because China was not considered during the early drug development stage, bridging studies have to be performed before these drugs can be brought into the China market.
On the other hand, the entire medical industry is changing due to rapid advancements in science and technology. In particular, advancements in the fields of immunogenics, genomics, and epigenetics, etc., have in turn led to advancements with new technologies such as immune checkpoint inhibitors (PD-1, etc.), chimeric antigen receptor T-cell (CAR-T), and the CRISPR-Cas9 genome editing system. In addition, new models for clinical development have also emerged, including adaptive trial designs, patient-centric trials, precision medicine trials, real-world data (RWD), and so on. The emergence of these new technologies and tools makes it possible for the industry to adopt new strategies and develop new anti-tumor products.
Changes are happening in various areas, from patient needs to the science and technologies as well as the associated policies and regulations. However, the basic principle of drug approval, the benefit-risk balance (the benefits of the drug must outweigh its risks), will remain the same. Therefore, new cancer drug development strategies must be based on a solid understanding of the scientific, legal and regulatory, and ethical risks and benefits brought about by new technologies and tools. The goal is to maximize the benefits for patients and developers within the existing legal and regulatory framework.
China has made a number of changes to its drug regulations and laws in response to the needs of Chinese patients and scientific and technological advancements. Below is an analysis using a few examples:
For instance, Article 19 of the "Drug Administration Law of the People's Republic of China" promulgated in August 2019 explicitly states that drug regulatory authorities are to make a decision on clinical trial applications within 60 working days from the date of application acceptance, and that a failure to notify the applicant within this period is to be deemed as application approval by default.2 This stipulation has helped solve the longstanding problem of high regulatory barriers in China (excessively long application review time together with numerous special requirements).
In addition, it is stipulated in the "Decision on Adjustments to Matters Relating to the Administration of the Registration of Imported Drugs" issued by the National Medical Products Administration (NMPA) in 2017 that Phase I clinical trials can be run simultaneously in China and abroad; the use of multi-regional clinical trials (MRCTs) in support of registration efforts in China is encouraged; and applications for the market launch of innovative foreign drugs in China will no longer require proof of approval in overseas jurisdictions.
It is also worth noting, that there have been recent reforms in terms of the registration and classification of chemical drugs, together with the implementation of the drug marketing authorization holder (MAH) system. This stream of measures is a reflection of China's determination to integrate into the international market and to participate in international cooperation and competition.
On the technical level: China officially joined the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in June 2017, and has - either formally or in practice - adopted a number of ICH technical guidelines for the review process. In addition, with the issuance of the "Guidelines for International Multi-Center Clinical Trials (Interim)" and the "Technical Guiding Principles for the Acceptance of Data from Overseas Clinical Trials of Drugs" by the Center for Drug Evaluation (CDE), the legal and regulatory barriers for the development of drugs in China and other countries have been removed.
Regarding clinical facilities, it is stipulated in Article 19 of the new regulation that clinical trials should be conducted in clinical trial institutions with the appropriate conditions. The clinical trial institution is responsible for the implementation of record management in accordance with the specific measures that are to be jointly formulated by the drug regulatory and health administration under the State Council. The new regulation also frees up resources for clinical trials; the China clinical site numbers increased from about 700 to 1,200 in the past 4 years echo this positive regulation change. The quality of clinical trials has been greatly improved following the clampdown on irregularities in clinical trials since July 2015. In the last few years, the data generated by these clinical sites have been accepted by the drug regulatory agencies of various mainstream ICH member countries.
The two major advantages China has always had in the area of clinical development are the relatively low cost of clinical trials and the relatively fast patient recruitment rate for most indications. China-focused cancer drug development strategies are a growing priority for domestic and foreign pharmaceutical companies today.
The legal and regulatory reforms China has undertaken in recent years have brought significant benefits to the entire pharmaceutical industry. Further, the focus of these reforms has always been on the protection of the interests of Chinese patients. For example, Article 3 of the "Drug Administration Law of the People's Republic of China" states that the focus in drug-related administration should be on the health of the people. There is to be adherence to the principles of risk management, life cycle control, and democracy administration. Efforts are to be made to establish a scientific and stringent system of supervision and management to improve the quality of medicines on all fronts, and to ensure the safety, efficacy, and accessibility of medicines. Here, one highlight of the new regulation is the emphasis on "accessibility".
The issue of accessibility for patients can be better understood when we compare how new drugs are marketed here at home and abroad. In 2018, in an update provided during a regular briefing on the state of efforts to speed up the review and approval process for new drugs that have been launched overseas, the State Council noted that of the 415 new drugs launched in the United States, the European Union, and Japan in the preceding decade, only 277 had been/were being registered or clinically studied in China. According to a 2019 McKinsey report on the China pharmaceutical industry, the difference between the time when new drugs were marketed in China and in Europe and the United States (Drug lag) has decreased from an average of 8.4 years to 4.6 years between 2016 and 2019. This is a strong proof of the improvements that have been made in China's regulatory environment.
Legislation has been amended in a number of ways for the benefit of patients. For example, Article 26 states that drugs for the treatment of severely life-threatening diseases for which there is no effective treatment and which are urgently needed for public health may receive conditional approval if clinical trial data can show the efficacy and predict the clinical value of said drugs. The relevant matters should be stated in the drug registration certificate for listed drugs. Thus, the corresponding accelerated review channels "Conditional Approval", "Breakthrough Therapy", and "Priority Review" have been established in the "Provisions for Drug Registration (December 2019 draft)". Therefore, in the exploration stage, a pivotal stage development model can also be used for the development of cancer drug products that meet the above regulatory stipulations.
At the same time, Article 23 also improves accessibility for patients: Drugs for diseases that are severely life-threatening and for which there is no effective treatment and are currently at the clinical trial stage, but which are shown to be potentially beneficial through medical observation and are ethical, may be used with other patients with the same condition in the institution conducting the clinical trial following review and informed consent.
Further, Article 65 stipulates that: Health care institutions that urgently need to import a small amount of drugs for clinical purposes may do so with the approval of the drug regulatory authorities under the State Council or the people's government of province, autonomous region, or municipality directly under the central government. The imported drugs should be used for specific medical purposes in the designated health care institutions. Drugs imported for personal use (of the appropriate quantities) should be handled in accordance with the corresponding state regulations. These provisions help to ensure accessibility for patients while also providing companies with the opportunity to obtain clinical data for the China population in advance.
Parexel has worked in accordance with the various changes that have taken place with China's policies and regulations. We are committed to conducting clinical trials using innovative technologies and tools, with the patient always at the center of what we do. For instance, lately Parexel's Regulatory & Access Consulting team has noticed that new development methods such as adaptive trial designs, precision medicine trials, and the use of real-world data have been included and considered in certain guidance documents, such as the "Guidelines for the Use of Real-World Data in Support of Drug Development and Review (Interim)"4 and the "Guidelines for the Use of Biostatistics in Pharmaceutical Clinical Trials"5 issued by the NMPA.
Such inclusion and consideration provides the legal and regulatory foundation for the implementation of new cancer drug development strategies in China. Worldwide, Parexel has already completed more than 200 real-world clinical trials; these related experiences have also given us more ideas for cancer drug development, such as for how we can use real-world data to achieve expansion of indication in China. Perhaps we can even go one step further and collect Chinese safety & efficacy data through studies initiated by researchers before clinical trials or market entry have been approved by the regulators. This novel approach to cancer drug development in China will facilitate the development or approval of the first indication(s) for the China market, and may become the approach of choice.
As reforms continue apace, just how to maximize benefits for patients and developers within the framework of regulatory approval and to provide innovative drugs to patients at a quicker pace is an issue that all practitioners of drug development have to think about. Parexel's Regulatory and Access Consulting team has brought together many experts on regulatory issues who have formerly served with regulatory authorities in China, the United States, Japan, and Europe, and as such it is able to help our enterprises seize the opportunities and face head-on the challenges brought on by regulatory reforms, provide patients with better anti-tumor products, and become the model for dynamic and intrepid progress for our times!
1. FDA review report; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel; https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda
2. Drug Administration Law of the People's Republic of China; http://www.gov.cn/xinwen/2019-08/26/content_5424780.htm
3. "Decision on Adjustments to Matters Relating to the Administration of the Registration of Imported Drugs"; http://www.gov.cn/xinwen/2017-10/10/content_5230906.htm
4. "Guidelines for the Use of Real-World Data in Support of Drug Development and Review (Interim)"; http://www.nmpa.gov.cn/WS04/CL2182/373175.html
5. "Guidelines for the Use of Biostatistics in Pharmaceutical Clinical Trials"; http://samr.cfda.gov.cn/WS01/CL1434/154780.html
Q&A Project Optimus: What you need to know
Oct 11, 2022
Adoption of the ICH Q12 guideline: New Horizons for Efficient Product Supply Chain Management for a Key Global Market
Nov 13, 2023
Near-term strategies for biotech drug developers facing shifting healthcare dynamics
Feb 14, 2024
Five strategies for meeting the requirements of Project Optimus and improving the chances of approval
Nov 10, 2022
New endpoints for early-stage cancer are gaining regulatory traction
Jan 28, 2022
A hybrid model supports globally diverse site participation for a retrospective cancer study
Jul 24, 2023
Ensuring future success in a new market by delivering a robust safety database solution
Aug 4, 2023
Australia: The Regulatory and Reimbursement Environment
Aug 28, 2023
Lessons from China and the United States on the use of RWE in regulatory submissions
Jul 19, 2021
Expedited Pathways Comparisons - US EU CHN
Oct 19, 2021
Six top tips to prepare for the new EU Clinical Trial Regulation
Apr 13, 2021
Tencent-Backed Wedoctor Is Going Public: What Are the Next Steps for Chinese Digital Health Companies?
Jun 30, 2021