“How not to die eludes us: true. Meanwhile, whatever ails our mortal state we plot to thwart with clever – and successful – cures.” After Sophocles, Antigone 332-70
In the U.S., biopharma companies are tasked with developing experimental cancer drugs and conducting countless clinical trials, all of the while lacking the appropriate numbers when it comes to the amount of patients who are available for testing. In fact, sometimes only four percent of patients enroll in clinical trials, and there are hundreds of trials that compete at any given time, significantly slowing the patient enrollment process.
A recent New York Times article also highlights the discrepancy between the potential number of candidates and number of available clinical trials – for example, approximately 10,000 patients could be candidates for an experimental treatment for melanoma, most of which are cured by surgery. However, very few of these patients are offered experimental treatments from doctors at academic medical centers; rather, they are treated by doctors who are not part of the clinical trials network. One of the largest reasons that clinical trials are halted is due to insufficient enrollment.
According to the Yale Cancer Center’s chief of medical oncology, Dr. Roy Herbst, many trials are actually not addressing new research questions but are instead trying to get proprietary drugs approved, for example, multiple PD-1/PD-L1 antibody monotherapy trials in the same cancer indication. This is part of a larger problem that many trials are uninteresting from a scientific perspective. In fact, the Yale Cancer Center participates in fewer than 10 percent of the immunotherapy trials that it is asked to join.
To put it simply, the equation that applies to much of business and drug development is that time is equal to cost; an analysis from STAT found that costs can climb up to $648 million to develop a cancer drug. According to the recent Wall Street Journal article, it could cost an average of $2.6 billion to bring a new drug to market, combining all costs of capital and failed drugs. Biopharma companies can manage the cost of drug development better through managing the time that’s associated with it, and patient enrollment in clinical trials is a major factor in the overall time that it takes to develop a drug.
More Resources, Efficiency in China
China is a vast market resource when it comes to developing oncology drugs. Enrolling Phase 3 clinical trial patients at the best sites in China can even accelerate drug development, as there are no genetic differences between populations, and the standard of care is the same.
Clinical trials have become increasingly global, and this is a trend that isn’t going away. A recent analysis by STAT found that 90 percent of new drugs that were approved this year were tested, at least in part, outside of the U.S. and Canada.
Large Patient Population, Short Enrollment Time
China’s healthcare sector provides researchers with a large pool of patients. In 2015, the regional dispersion of lung cancer was as follows: Each year China has over 4 million new cancer patients – one-third of the total cancer patients in the world. Patients in China are more motivated to participate in clinical trials, as some centers see up to 50 percent of patients who are enrolling in trials, because insurance coverage is not as prevalent in China as it is in the West. Patients in China also seek to gain access to more advanced treatments even though they face inconveniences like frequent blood draws and lengthy questionnaires.
The developed healthcare delivery system in the U.S. and West allows available care to be close to home in many areas, as well. While China has undoubtedly advanced significantly, its cancer care is still highly centralized, primarily in the Beijing, Shanghai and Guangzhou areas. Cancer patients from around the country travel to these areas for care; one top Beijing hospital sees over 300,000 cancer patients a year.
Achieving Time- and Cost-Efficiency: Process & Quality Control
To generate quality data that will be acceptable to the U.S. FDA, it’s important to work with the 30 top sites in China, including Peking Union Hospital, which has a medical school that was founded by the American and British Missionaries and funded by the Rockefeller Foundation.
Figure 1.There are also costs that are associated with each site in a clinical trial, and being able to enroll more patients in fewer sites ultimately reduces a clinical trial’s cost.
The China drug development sector has been receiving increased acknowledgement for its quality. For example, Celgene announced its collaboration with Beigene, and OrbiMed/Fidelity announced new funds for Asian biotech investments. Zai Lab also had a successful U.S. IPO in September.
Chinese companies are generating drugs at an accelerating rate. With that said, there are certain preconditions that are associated with including patients who are based in China in a clinical trial – for example, there must be no genetic differences between the patient populations in China and the West, and the drug must have the same standard of care.
It can be efficient both in terms of time and cost to run a single global Phase 3 trial to support NDA approval in the U.S. and China – two of the largest markets in the world for ethical drugs.
Of course, as Ronald Reagan said, “Trust but verify.” It is essential to employ a third party to perform central data review and exercise detailed sponsor medical monitoring for every patient and audit of sites.
The process is as follows:
- With the U.S. FDA, open the Phase 3 IND after the end of Phase 2 meeting
- Apply for, and obtain from, the China FDA the Phase 3 CTA receipt
- Operate a global Phase 3 trial that enrolls patients in the U.S., China and other countries
The bar is higher to receive the CTA from the CFDA than to enroll patients in Phase 3 in the West. In addition to demonstrating safety, one also must show efficacy.
China had demonstrated that it can generate quality data that adheres to the principles of good clinical practice (GCP), which are set by the U.S. FDA. For example, NSCLC drug Afatinib was approved by the U.S. FDA in July 2013, using 72 percent of its data from China. China’s recent entry into the International Council for Harmonisation (ICH) underscores its quality standard and willingness to improve its clinical quality. However, it’s important to remember to take a “hands on” approach to control the quality of the clinical trial. Some elements of this approach include:
- A team of managers in China to oversee the trial
- Frequent visits to the sites by senior management
- The right experienced Principal Investigators in China
- The right clinical CRO with global trial experience
Additional components of the process include making a technology transfer in China and providing a chemical equivalence study of the drug that’s being manufactured in China, compared to the study of the drug from the U.S. that’s used in the trial.
As the costs can translate to $100,000 per patient in the West, in China, it can be one-third of that. Faster enrollment also lowers overall clinical trial support costs. The regulatory strategy of this approach is to submit NDA packages for approval in parallel with the U.S., submitting the China data to the U.S. FDA and China portion of the data to the China FDA.
The timeline with the China FDA may also be helped by fast-track review and approval of a drug for an indication on a national priority list. It can take six to 10 months for approval of the NDA, so it helps to have a domestic subsidiary company in China and “Thousand Talent Innovator” award winner in management.
Generating quality data in a timelier manner and receiving earlier approval can often result in longer patent life. The clinical trials lay the groundwork for commercialization, and the attention of senior management and managers of the clinical trials at the top 30 sites in the three main cities in China presells commercialization in one of the two largest markets in the world.
China’s New Drug Approval Agenda
On Oct. 8, 2017, the CFDA announced its new rules that will speed up drug approvals and shorten delays when it comes to accessing new treatments. Just a couple of days later, China’s Premier Li also announced that cancer is a national priority.
In addition, the government released a guideline, “Opinions on Deepening the Reform of the Examination and Approval System to Encourage the Innovation of Drugs and Medical Devices,” consisting of the proposed 36 specific views for practitioners to clarify the future direction of the work. This is likely just the beginning of this round of China’s drug reform.
The new regulations show how the CFDA has developed to the stage that its reviewers can make decisions on NDAs – even for global trials – independent of the U.S. FDA, European Medicines Agency or any other country’s regulator. The China FDA has also indicated that it will grant conditional NDA approval based on the trend of clinical patient benefit, rather than waiting for full data.
These new policies could lead to accelerated drug approval, especially for novel drugs that address significant unmet medical needs. In addition, the policies could potentially result in patent extension for five years to reflect the lengthy approval process for ethical drugs – and, in doing so, China would join the U.S., Europe and Japan.
These steps can greatly benefit companies with U.S. and China operations. In addition to developing innovative drug products to improve the lives of cancer patients, this business model can help to treat many more patients than any single drug.
Dr. Lan Huang is Co-founder, Chairman and CEO of BeyondSpring. Dr. Huang has more than a decade of entrepreneurial experience in the Chinese and U.S. biotechnology industry and invented and holds patents for a number of biotech products for oncology and dermatology indications. In 2009, she was the recipient of China’s “Thousand Talent Innovator Award.”
Prior to founding BeyondSpring, Dr. Huang co-founded Wuxi MTLH Biotechnology Co. Ltd., whose self-designed cancer peptide drug’s China rights were acquired in 2010 by Shanghai Pharmaceutical Group, one of the top three pharmaceutical companies in China. She also co-founded Paramax International, a clinical CRO company in China, which was sold to RPS (a global CRO), then to Warburg Pincus in 2011. In addition, Dr. Huang worked with Forward Ventures, where she led partnering initiatives between Forward’s portfolio companies and Chinese pharmaceutical companies.
Dr. Huang was trained at Memorial Sloan Kettering Cancer Center, where her breakthrough research in solving the first E2-E3 ubiquitin ligase structure involving P53 degradation was published in Science. The immense importance of this field is illustrated by the 2004 award of the Nobel Prize in chemistry to the founders of ubiquitin-mediated protein degradation. She received her Ph.D. in chemistry in four-and-a-half years from the University of California at Berkeley, where she won the graduating Ph.D. woman award from Soroptimist International. Her translational research in cancer signaling pathways involving Ras was published in two Nature papers.
Richard A. Brand, M.B.A., is Chief Financial Officer at BeyondSpring, with two decades of experience as an investment banking and capital markets professional, as well as a dozen years of experience in institutional investment management. He was Head of Robertson Stephens’ Private Capital Markets Group when its biotech practice was ranked No. 2 in the industry. He raised VC / PE firms’ equity capital as the first broker to obtain such allocations from public pension plans, as a member of the No. 1-ranked team at Merrill Lynch and as a founder of the same business at DLJ that quickly also became No 1. Earlier, Mr. Brand originated and managed Merrill Lynch’s first $1 billion deal.
In addition to his capital markets experience, Mr. Brand performed external CFO duties for a newly public company as it grew 101 percent per annum on its way to its current size of more than $6 billion in assets. He is on the boards of the University of Chicago’s New York City Alumni Club and the University of Chicago Booth School’s New York City Alumni Club and holds an M.B.A. from the University’s Booth School of Business. Mr. Brand received a B.A. from the University of Iowa.