Outsourcing Clinical Trials

The high costs of conducting clinical trials in the U.S., the difficulty in recruiting patients, and bureaucratic delays are causing small biotechnology and large pharmaceutical companies to seek clinical trials partnerships outside the U.S. “Over the past few years, there has been an absolute increase in the number of patients enrolled in countries outside of the U.S. and Western Europe,” said Pablo Cagnoni, M.D., senior vice president and global head of clinical development at Novartis Oncology, by e-mail. The reasons, he added, include faster regulatory timelines for approval of a clinical trial, improvement in quality of the investigators, and regulations stipulating that local patients must be enrolled in clinical trials for drug approval. He also noted that developing targeted therapies requires screening many patients to identify the small group with the molecular abnormality of interest. Numbers of patients enrolled in Asia and Eastern Europe have increased especially, said Cagnoni. “In Japan, for example, the government has taken steps to align their requirements with those of other countries. We have increased Russian participation due to the need to include local patients for [drug] approval in Russia.” The boom in clinical trials has perhaps been the biggest in China, owing to improvements in the medical infrastructure there. “China’s health care market is now $50 billion USD and growing at a rate of 30% a year, which will be $600 billion in 2020,” according to Lan Huang, Ph.D., CEO of Dalian Wanchun Biotechnology in China. “As of November 2010, 57 global phase III trials were being conducted in China, with companies such as GlaxoSmithKline, Bristol-Myers Squibb, and OSI Pharmaceuticals testing cancer drugs. A large amount of private investment also supports innovative drug development.” A cancer researcher trained at the University of California, Berkeley, with a postdoctoral fellowship at Memorial Sloan–Kettering Cancer Center, Huang returned part-time to her native China 10 years ago to do drug research and development and cofounded several pharmaceutical companies. She began her China–U.S. partnership when the cost for an early phase I/II clinical trial of her drug for brain cancer was $100,000 per patient in the U.S., compared with $10,000 in China under the same protocol. “The U.S. has very good drug discovery powerhouses that know clinical trial design,” said Huang. “In China, we can use clinical protocols from the U.S. to study a drug by looking at many indications in parallel rather than sequentially. Drug development costs are reduced by China’s lower medical costs: 20%–30% of those in the U.S. The time to trial completion is faster because the large clinical population speeds enrollment.” She said that patients have the incentive of free clinical trial drugs, which China’s universal health care coverage, capping at $300 per year, does not reimburse. Huang said their advantage begins at the preclinical level with a molecular diagnostic analysis of each person’s tumor. “Our highly trained researchers have access to large numbers of tissue samples, many from untreated patients, that we use to identify the right people to test for a drug. With higher success rates in early phase I/II trials, we then do trials on promising drugs in the U.S.,” said Huang, who received the Thousand Talent Innovator Award from the Chinese president. But, she warns, not every pharmaceutical company can expect a welcome in China. “The Chinese government does not like companies to use Chinese patients as testing subjects, and China is very serious about patent protection.” Her company is partnering with Nereus Pharmaceutical, a California company focused on developing anticancer compounds, to license the China and Hong Kong patents and commercial rights for plinabulin. They will start clinical trials looking at efficacy in non–small-cell lung cancer and colon cancer. Now several countries are trying to break into the clinical trial market that China, Japan, Brazil, South Korea, Poland, and Germany, among others, have entered. Government incentives and strategic partnerships are under way. New Zealand’s government is trying to become more competitive internationally by implementing recommendations to streamline their clinical trial application process. The National Health Service of Scotland and Pharmaceutical Product Development LLC in North Carolina allied “to increase the amount of clinical research conducted in Scotland.” Drug trials in India surged in 2005 after a relaxation of regulations. An estimated 150,000 people are involved in at least 1,600 trials. India’s large population, highly trained medical professionals, and inexpensive labor appeal to drug companies. But recent accusations of ethical violations, including breaches of the informed-consent process, have reverberated from the Indian courts to the European Parliament and may stall this growth. Irregularities in India’s regulatory system reported in the February 2012 Lancet prompted the European Parliament to request the European Medicines Agency to review allegations of potential safety issues for both trial participants in India and EU patients. Sandra J. Horning, M.D., senior vice president and global head of clinical hematology and oncology at Genentech, said, “Consent forms need to be made more concise and understandable. They need to clearly inform patients what they are signing up for.” Horning said that when selecting clinical trial partners, “we want to work with researchers who understand that our goal is to perform scientifically important, high-priority trials in a timely manner to get important new medicines to patients.” She said the trials need to “provide a level of quality information” required to submit the results to government regulatory agencies. “For any pharmaceutical company with a new product beginning clinical development, informative clinical trials, with each one informing the next, are critical,” said Howard I. Scher, M.D., chief of the genitourinary oncology service at Memorial Sloan–Kettering and principal investigator of the Prostate Cancer Clinical Trials Consortium (PCCTC). “If the drug is showing promise, progress should be rapid. If it does not, it may be that it is simply inactive, that the dose is incorrect, or that it is not being studied in the right patients.” Established in 2006 by the Prostate Cancer Foundation and the Department of Defense Prostate Cancer Research Program, the PCCTC is a clinical trial network of leading prostate cancer experts from 13 academic medical centers in the U.S. “Members of the PCCTC developed new standards for clinical trials conducted in this disease,” said Scher. “We take an active role in trial design at the preclinical stage to maximize what is learned about a drug’s effect on the disease and the patient so that development can proceed expeditiously. Our members have a lot of regulatory and research experience. We understand the biology, know the targets, and can provide input on biomarkers. With our members being from 13 of the leading prostate cancer centers, we can accrue patients rapidly and ensure that an adequate number are treated at each site,” he said. “All the trials are facilitated by a common infrastructure that includes standard contracts; patient consents; shared legal, financial, database, and regulatory document management; and dedicated personnel at each site.” Scher recently led the successful international trials for abiraterone (Zytiga) and enzalutamide (formerly known as MDV3100) in men with castration-resistant prostate cancer. The U.S. Food and Drug Administration approved abiraterone in April 2011, followed by approval in Canada in July 2011 and the European Commission in September 2011. The study, co-led with Johann de Bono, •••, at the Royal Marsden Hospital, also evaluated “the clinical relevance of circulating tumor cells as a potential new biomarker for measuring a drug’s effectiveness in prostate cancer,” said Scher. This achievement was followed by the completion of the large phase III AFFIRM trial of enzalutamide for castration-resistant prostate cancer (developed in the laboratories of Charles Sawyers, •••, and Michael Jung, •••, at the University of California, Los Angeles) studied in 15 countries, including the U.S. Scher presented results of its phase III trial at an American Society of Clinical Oncology Genitourinary Symposium in 2012. FDA review of enzalutamide is expected this year. Scher points to enzalutamide as the example of PCCTC’s new paradigm. “The collaboration with Medivation [the company developing enzalutamide] is the poster child of how this all works,” he said. “We aligned the infrastructure with the sponsor and were able to select the optimum dose to move forward into phase III testing after completing the phase I/II trial in 18 months. If you look at time from the first patient enrolled in July 2007 to the announcement of the phase III trial’s success, it was under 4.5 years. I am not sure too many cancer drugs have gone through that fast. Time is critical for our patients and has significant financial implications. Industry sponsors like Medivation appreciate the abbreviated timelines our unique drug codevelopment strategies enable,” said Scher. This approach has enabled the PCCTC to advance eight therapeutic candidates to phase III studies. “With its commitment to collaborative drug development, endpoint and biomarker codeveloped strategies, and centralized management of research, the PCCTC is poised to keep the drug pipeline primed with promising new agents,” Scher said. In addition to the financial boost for countries, clinical trials can offer a medical benefit for patients. Ironically, some patients can access a drug during a clinical trial only if their national health plan considers it too expensive. Abiraterone was codeveloped with scientists at the Institute of Cancer Research and the Royal Marsden in the UK. Although the drug was approved in the UK, the National Institute for Health and Clinical Excellence issued draft guidance that it was too expensive for routine use by the National Health Service (although citizens in Wales received temporary approval). For countries where new drugs are too expensive, the market for affordable copies of nonbiological complex and biosimilar generic drugs is growing fast. These ••• create another avenue for outsourcing clinical trials. However, the product review required before new versions of these medications can be introduced can be cumbersome—and costly. “There is no purpose in developing innovative copy products if they are not properly done,” said Ivana Knezevic, M.D., Ph.D., a scientist in charge of quality, safety, and standards for the World Health Organization (WHO). “There is enormous production capacity for similar biotherapeutic products in Brazil, China, Cuba, and India. But the cost of clinical trials for proving similarity to the originator products can be so high that there are no savings in making these products available. WHO requests that national regulatory agencies work together on standards to protect and advance public health,” she said. A clinical trial of a generic drug must not only prove safety and efficacy of a drug but also show that it is an almost identical copy of the “innovator” drug that a company seeks to sell at a lower price before it can be licensed. The evaluation is even more rigorous for a biosimilar therapeutic because precisely duplicating a biologic agent is not technically possible. Regulators in individual countries and regions, many in coordination with WHO, require a thorough drug investigation that includes clinical trials to demonstrate safety, purity, potency, and comparability to a named drug. Although this process continues to be refined, it has resulted in the licensing of several affordable versions of agents used in treating cancers, including biosimilar erythropoietins and granulocyte colony-stimulating factor (G-CSF) filgrastim biosimilar drugs.

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