Clinical Trials Go Global

Clinical studies for assessing the efficacy and safety of new medical treatments and drugs have traditionally been conducted in developed countries in North America and Europe. However, a study published in November 2007 in Nature Reviews Drug Discovery has identified a recent trend that highlights the migration of clinical trials to so-called emerging regions of the world, countries in Latin America, Eastern Europe and Asia. Although the traditional regions still host a majority of the clinical trials (66%), the study found that countries in the emerging regions now accounted for nearly 17% of all actively recruiting clinical sites.

Fabio Thiers, M.D., M.Sc., Ph.D., a senior author on the study and a research associate at the Sloan School of Management and the Center for Biomedical Innovation at Massachusetts Institute of Technology (MIT), US, has been studying the phenomenon of globalization of clinical trials for the past four to five years. “Back then we saw that this was an important trend but there was very little done in terms of quantification of data and much less was known about the types of trials that were being allocated to these emerging regions,” says Thiers. With a group of economists at MIT, he started looking at why and where new clinical trials were being launched, how the dispersion was progressing in terms of growth rates and how these emerging regions compared to one another. They have now created econometric models to try and understand the key drivers that have been responsible for the globalization of clinical trials, particularly in the emerging regions.

“The data shows that the size of the pharmaceutical market seems to be an important driver,” he says. This is due to large population countries such as India and China that offer a tremendous market potential for launching new drugs. Both the absolute and disease populations in these countries are fairly large and the patients are relatively naïve compared to those in the developed countries as they have access to less medical information and treatment options. “So far we have contributed more than 10% of subjects to the global clinical studies that China has participated in,” says James Cai, M.D., who was vice president R&D for AstraZeneca (AZ) China. He was responsible for AZ’s clinical development activities in China, which include overseeing regulatory, clinical operations, medical affairs, patient safety and clinical project management. He is now the vice president for Healthcare Policy Research at AZ.

Clearing the Regulatory Hurdles

Although AZ first started its clinical operations in China in 1990’s, Cai says the company has been aggressively tapping into the Chinese market only since 2005. Cai and his team have been looking to increase their participation in global clinical studies and to see how the data generated can then be used for registration and an early launch of the drug in China. “Speed in terms of patient quality recruitment in China is phenomenal,” says Cai. He gives the example of one clinical study for asthma where China started patient recruitment seven months later than its European counterpart. However, it caught up with its European counterpart in just two months and surpassed its recruitment numbers a few months later. “Speed is not an issue, it’s really the opportunity to be able to participate in,” says Cai.

One of the biggest hurdles is getting timely regulatory approval to launch a clinical trial. While it would take about three months to have a clinical trial approved in most Asian countries, it takes approximately 10 months in China. The country has additional requirements and specifications that most other regulatory agencies do not demand. Cai, who has previously worked with the US FDA, admits that the political, social and regulatory environment in China is very different from other countries. “It’s a different system and China is still trying to figure out how to effectively review and approve applications,” he says.

However, there have been significant improvements in the last five to 10 years. The Chinese government is working hard to reduce the number of days for approvals, as it looks to develop capacity and capability for conducting clinical trials in the region. Currently there are only about 200 hospitals certified to conduct clinical trials and the number of qualified clinical investigators is also fairly limited. “Finding the right physician often takes a long time,” says Merick Su, drug safety and medical information manager for Bayer Healthcare in China (BSP China). The language is a barrier since not many Chinese physicians are fluent in English and find it difficult to understand the clinical protocols, which are written in English. “A lot of companies will translate the protocols in Chinese but the physicians are still expected to fill in all the information in English,” says Su. This can be challenging. However, despite all these regulatory and personnel challenges, the number of clinical trials being launched in China is increasing.

India too offers a large patient population. When compared to China, India seems to offer more of an operational advantage for conducting trials. “The information technology (IT), data management resources, the cost and speed of patient recruitment in India are added advantages,” says Thiers. The number of large medical centers available to conduct trials, the quality of physicians and trained personnel, and the English speaking population in India pose great advantages. Some of the other countries in Asia and Latin America are also moving to the forefront in terms of offering resources and talent for launching clinical trials. Countries like Singapore, Taiwan and South Korea, have sophisticated hospitals, trained personnel and their healthcare system is fairly Westernized, which helps in harmonizing the regulatory efforts. “These are smaller countries but they are very promising,” says Thiers. “However, they have less room to grow because of their smaller population.”

A Sustainable Trend?

Clinical trials often go global when companies need a large patient population or when the types of patients or diseases being treated are not accessible locally. “We see increased participation of emerging regions in large clinical trials,” says Thiers. “The ones that are small are typically kept close to home.” The costs and speed in patient recruitment in the emerging regions so far has been very lucrative. However, some companies are now finding that costs are on the rise. Patient recruitment is also becoming difficult as health awareness and treatment options are increasing among physicians and patients. However, at the same time, local government and regulatory agencies in these countries are making a conscious effort to simplify the regulatory processes to make it easier for companies to continue to develop their clinical base in these regions. They are realizing that access to clinical trials will later offer patients access to the very latest and the best choices for medical treatment. For instance, the Chinese government has set up centers of excellence for clinical trials and it is working closely with the US FDA to foster collaboration and transfer of knowledge between the two agencies. “They have been working to improve their capabilities for evaluating clinical trial protocols,” says Thiers. Similarly the Indian regulatory agency is also going through an overhaul, increasing head count and training people. “Things will improve in the next six to 12 months but meanwhile, it is a bottleneck,” says Theirs.

Countries like Japan are also realizing the value of clinical trials going global. Even though Japan has been a part of the International Conference on Harmonization (ICH) to harmonize the regulatory guidelines, only a small minority of the clinical trials done there are global. “The Japanese government is now beginning to accept data from regional trials conducted in countries like China, Taiwan and South Korea and they are beginning to recognize that they share a common ethnic background with these countries,” says Thiers. “This probably is one of the external factors that drives the clinical trial enterprise in Asia.”

Drug companies are also realizing the benefits of conducting trials globally for getting early approvals and increasing the marketability of their drug. “The goal now is to have a concomitant registration for a global launch of the drug,” says Thiers. When clinical trials sharing the same protocol have a counterpart in another country, it sometimes gets easier to gain approval to launch a new trial. “In Latin America or Eastern Europe, it is easier to start a trial if you have a counterpart in the US or Europe,” says Thiers. “It’s the perception that the sponsor of the trial will not do anything differently in these regions than what is being planned in the more developed countries.”

Another trend being evidenced is that drug companies are trying to launch early-phase clinical trials in the emerging regions. “In the past a lot of phase III clinical trials were conducted but now companies are looking into more phase I and II trials,” says Su. The study published last year by Thiers and his colleagues also reported that early stage clinical trials were disproportionately high in North America (62%), whereas confirmatory trials were higher in the emerging regions. The study also found that post-marketing trials were disproportionately high in Western Europe compared to any other region. However, the dynamic is changing. “The challenge with phase IV studies in China is that the regulatory guidelines are not very clear,” says Su. “There are no clear definitions on how to manage the study, how to report the safety data, and how to evaluate the efficacy and safety profile of the drug.” With increasing scrutiny from outside regulators the regulations for phase IV and post-marketing surveillance, studies in China and other emerging regions are also likely to change.

Finally one cannot ignore the impact the presence of large multi-national CRO’s like Quintiles, MDS Pharma Services, Covance, EPS and others have had on the growth in clinical trials in the emerging regions. They have made it possible for drug companies to simultaneously launch a large number of clinical trials at various stages, looking at different therapeutic indications. “If we have the capability and capacity, we will keep the work in-house,” says Cai. “If we don’t have it and they can do a better job, then we are willing to outsource. For us, the most important factors are quality, speed and cost. As long as we reach an optimal balance we are happy to contract out.”

Getting Ready for Regulatory Scrutiny

The US FDA faced some tough questions recently when hundreds of serious allergic reactions and 81 deaths were traced back to an active ingredient found in the blood thinner, heparin, manufactured by Baxter International Inc. The contamination was found in an active ingredient, isolated from pig intestines in China. While the US FDA inspects domestic facilities once every two years, inspections of the nearly 3000 foreign drug facilities happen only once every 13 years. The agency has now requested more funds hoping to conduct about 500 foreign inspections this year, up from 332 conducted last year. It also plans to open its first office in China by the end of this year.

Cherif Benattia, an executive who has worked on clinical trial management and pharmacovigilance in both large and small pharmaceutical organisations in the US and in the emerging regions, advices companies to get ready for routine FDA inspections. “Doing the right thing is not enough, you have to document it,” he says. “For regulators, if there is no documentation it does not exist, even if you do it.” Drug companies that work with clinical organizations and contract research organizations (CROs) have to do their due diligence to make sure that everything is done according to the protocol, the standard operating procedures (SOPs) and good clinical practices (GCP) guidelines. Here is some advice he offers.

 All companies and personnel must be familiar with ICH guidelines and have the right procedures in place in order to be compliant. What is often missing is familiarity with the regulatory processes and the procedures. Regulators want to know how you got the data and how valid is the system for collecting the data.

 While quality of data is important, what always takes precedence is patient safety. Organizations have to be compliant by building in strong procedures not only in good clinical practices (GCP) but in safety. For instance, one of the important documents in a clinical study is the informed consent form, which is signed by the patient. This document is typically long and detailed. When translated in a different language, translators have to make sure that they have translated everything and that all the information is conveyed in the way it was originally intended and in a way local patients could understand it.

 Clinical investigators should be trained in GCPs. They should know their roles, responsibilities and the rigors of safety reporting. Reporting timelines are critical and must be adhered to. Patients have to be made aware that they have to report adverse events to the local clinician, in a timely manner, who in turn has to report it to the sponsoring company. If local companies (such as contract research organizations (CROs) and local pharmaceutical partners) are not familiar with the reporting timelines and the regulatory definitions, they may miss the deadlines and fail to be compliant.

 When working with CROs, companies have to make sure that they have safety agreements or pharmacovigilance contracts in place, which covers all the details on how safety reporting and responsibilities will be done on both sides. Problems may arise at a later stage if things are done without ironing out all the details due to the lack of time.

 Training: make sure that all staff and partners’ staff (CROs and local pharmaceutical partners) are trained in GCP, safety reporting and all training is documented.

Clinical Matchmakers

The internet is expanding the realm of matchmaking from the romantic to the clinical world, helping to link patients to appropriate treatments or clinical trials. EmergingMed, a for-profit service helps connect patients to a clinical trial by matching their personal clinical data such as age, gender, disease stage, types of treatment received to the requirements for enrollment. Drug companies and medical centers are also partnering with companies like EmergingMed to educate patients and physicians about the different treatment options that are coming up in the pipeline.

Although a fairly large number of patients are often eligible to participate in clinical trials, only a small percentage of them actually do so. There is often a scarcity of patients, especially for certain ethnicities and age groups like adolescents and children. While the fear factor plays a role, ignorance is also largely responsible for keeping patients from participating in ongoing clinical trials. Keeping up with new trials and understanding the various requirements can often be tedious and time consuming. Companies like Emerging Trials have the resources to conduct searches and find options that best fit a patient’s needs.

There are also other websites like Clinicaltrials.gov, Centerwatch.com and Searchclinicaltrials.org that offer multiple listings, news, results and reviews on various trials ongoing in different countries around the world. For patients suffering from chronic conditions or life-threatening disorders access to such information on a regular basis and availability of new treatment options that reduce side effects or improve quality of life can be very beneficial.

Types of clinical trials

Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.

Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes.

Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.

Screening trials test the best way to detect certain diseases or health conditions.

Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.

(Source: Clinicaltrials.gov)