A few years ago, Latin America and India were considered among the most promising emerging markets for conducting industry-sponsored clinical trials. Dramatic increases were predicted for both regions, and investigative sites anticipated an influx of new work. Unfortunately, growth in these markets has fallen far short of expectations.
The number of industry-sponsored global phase I-IV trials in India has dropped 22.4% annually between 2010 and 2014, according to the 2015/2016 Parexel Biopharmaceutical R&D Statistical Sourcebook’s analysis of the ClinicalTrials.gov database. The volume of new clinical trial starts declined by more than 70%. In South and Central America, clinical trial activity declined 10.7% and 3.8%, respectively, during this same period compared to an overall decrease of 1.1% in the more mature markets of the U.S., Western Europe, Canada and Japan.
Potential growth was held back by the global economic crisis, which forced sponsor companies to reconsider global outsourcing strategies, along with long study startup timelines and unpredictability in the regulatory processes that made Latin America and India less competitive compared to other emerging regions.
In India, many pharmaceutical companies and CROs have either pulled back their clinical trial operations or moved out completely since 2010 due to domestic concerns about adequate protection of study volunteers and increased regulatory scrutiny.
“Because of the many negative aspects of clinical trials in India, people are shying away. We are not getting many trials,” said Manju Sengar, M.D., D.M., a medical oncologist and principal investigator at Tata Memorial Hospital in Mumbai, India.
As the volume of clinical trials in Latin America and India has become more volatile and unpredictable, investigators in those regions find it increasingly difficult to attract study opportunities and support their clinical trial infrastructures. The number of investigators conducting FDA-regulated trials dropped at the fastest rate in India, where there was a 16% decline between 2009 and 2013, while other experienced investigators have struggled to keep their sites open by conducting biosimilar work, observational studies, academic research or trials regulated by local authorities.
“In the beginning, there was a lot of interest from pharmaceutical companies and CROs because we showed them that we have the patient population, the experience, the knowledge and the training. But it’s gone. It disappeared,” said Sergio Guerrero, M.D., president and CEO of Accelerium Clinical Research in Monterrey, Mexico, who has more than 18 years of experience in clinical research and serves on the Drug Information Association’s Board of Directors representing Latin America.
Impact of slowdown on investigators
In Latin America, industry-sponsored clinical trials between 2010 and 2014 declined significantly in three of the major clinical trial markets—Brazil (14.5%), Argentina (8%) and Mexico (9%). The slowdown in research activity made it difficult for many investigators to sustain or build any kind of infrastructure for conducting clinical trials. The burden has been particularly acute for investigators who have heavily invested in recent years.
Accelerium Clinical Research in Mexico, for example, was founded five years ago by Guerrero in anticipation of the increase in industry-sponsored clinical trials predicted for the region. Guerrero built an extensive research operation to conduct global phase I-IV trials. The operation has a 32-bed phase I unit, a network of 120 investigators and 26 full-time employees, including coordinators, pharmacists, regulatory personnel and administrative personnel.
Last year, for the first time, Accelerium had fewer confirmed clinical trial projects on the books than the previous year. Guerrero fears he may need to cut staff if work doesn’t pick up. The number of clinical trials that sponsors have contracted to conduct at Accelerium has dropped by 50%, from about 50 to 60 a year to 25 to 30. Since the phase I unit was opened in 2011, only two early phase trials have been conducted at the facility. Accelerium responds to about 200 requests from global biopharmaceutical companies for proposals each year, but they rarely lead to work. When Guerrero inquires about the status of these feasibility proposals, in most cases, the sponsor companies say that Mexico or Latin America were not selected for the study.
“If sites had more studies, if they had volume and patients, they would be able to support the infrastructure and add staff to their clinical teams. A lot of the work is administrative. If you don’t have people to do the administrative part, then you get lost,” said Guerrero, who works with international organizations to develop clinical trial opportunities in Latin America. “There is a lot of pressure in getting patients, getting data and getting everything ready to be submitted to the FDA or another regulatory agency. Sometimes investigators say, ‘I don’t have time to do this.’”
Some sites in Latin America continue to work for CROs and global sponsors supporting studies for registration, but other investigators maintain their businesses by conducting biosimilar work, observational studies or small clinical trials for local biopharmaceutical companies. As is the case in India, some investigators have left the enterprise and closed sites because they can no longer support the infrastructure needed to run successful clinical trials. Two of the largest site management organizations in Mexico have shut down during the past two years. Three countries in the region with long-established clinical trials markets have seen a decline in the number of investigators conducting FDA-regulated studies between 2009 and 2013: Argentina (10%), Brazil (8%) and Mexico (6%).
“It has been challenging for investigators in Latin America to sustain their teams due to the economic burden associated with the decrease in activity. Most of the region’s key principal investigators consistently continue to work with CROs and pharma companies despite the challenges. Some investigators have closed sites, but in my experience it has been a limited number. There are still investigators, including new investigators, very interested in clinical research, but they need continuity and a workable regulatory framework,” said Sylvia Zieher, M.D., vice president of clinical development, Latin America Operations for INC Research.
Meanwhile, the ability to support and build clinical research infrastructure in India also has been impaired by the cutback in industry-sponsored studies in the country. In India, which accounts for only 1% of clinical trials registered at ClinicalTrials.gov, the majority of clinical trials are conducted in large hospitals and health centers, run either by the government or private sector, since strict government requirements for conducting clinical trials in India make it nearly impossible for physicians to run small, independent sites. Nevertheless, major medical centers typically rely on income from industry-sponsored trials to help maintain their clinical trial infrastructure.
“It does help to get industry-sponsored trials, which helps us build our clinical trial team and keep pace with the rest of the world in terms of quality,” said Tata Memorial Hospital’s Sengar, who has extensive clinical trial experience and currently serves as the principal investigator on six trials, which include three regulated clinical trials and three investigator-initiated trials.
As industry-sponsored clinical trial activity has slowed in India, investigators have continued to perform India-centric research about certain cancers or diseases common in local populations that foreign pharmaceutical companies are unlikely to study. While new trial starts in the country have stalled, many investigators have continued working on existing trials and also have conducted work with local pharmaceutical companies and academic institutions.
“While there has been an exodus of big companies out of India, local biotech and pharma are still doing trials even though there has been a decrease in the volume of studies,” said Alan Ong, executive vice president, Asia Pacific for INC Research.
Sengar and her colleagues worry that the decline of industry-sponsored clinical trials in India, particularly the important phase III trials for promising treatments, limits the ability for physician-investigators to gain experience with important new medications and restricts access of innovative drugs for their patients.
“When we get drugs in later phase clinical trials that are newly discovered and really promising, we look forward to participating. Our patients benefit. Plus, we can provide a prospective from a different ethnicity about how our patients respond to a particular drug in terms of benefit and side effects,” Sengar said. “If we don’t get to participate in these clinical trials, our patients are ultimately being denied access to these drugs. That is the worst part when these trials stop coming.”
Unique needs for sites in emerging markets
A 2015 CenterWatch poll of investigators from emerging markets found that sites in these regions have unique needs and operating challenges that impact their ability to conduct clinical trials efficiently. Delays in obtaining ethics and regulatory approvals, which lead to long study startup times, were among the top concerns reported in the survey.
Timelines are a particular challenge in Latin America, where the Tufts Center for the Study of Drug Development has found that the mean time from pre-visit through site initiation is 14.2 months, compared to 8.4 months in the Asia Pacific region and an overall global rate of eight months. Long timelines and complex regulatory requirements have been one of the primary barriers for growth in the more established Latin American markets, which include Brazil, Argentina and Mexico.
“A central problem in getting trials for Latin America is that often our regulatory timelines are extensive. However, if our countries are included at the very start and not as rescue countries, we can certainly compete with the rest of the world,” said Marlene Llópiz-Aviles, M.D., president of the Association of Medical Specialists in the Pharmaceutical Industry and president of the Mexican Chapter of the Association of Clinical Research Professionals.
Investigators from emerging regions, in both the CenterWatch survey and in interviews, also identified patient recruitment as an immense problem and major source of study delays. While patient recruitment is one of the most significant clinical trial challenges for investigators worldwide, sites in emerging regions encounter unique problems in finding patients to meet complex protocol requirements since many countries lack diagnostic equipment or comparator drugs that might be required to qualify patients for a particular study. A clinical trial for Crohn’s disease or colitis, for example, might require that potential study volunteers undergo an endoscopic exam before beginning the study. This would be a fairly routine procedure in the U.S. or Europe, yet in an emerging region, the necessary diagnostic equipment might not be available. The local standard-of-care could call for physicians to diagnose patients clinically, rather than with an endoscopic image, which would make it nearly impossible for patients to meet the protocol’s inclusion/exclusion requirements. Study protocols also might require access to novel medications, such as biologics, which are expensive and not widely available in an emerging market.
“The CROs and the pharmaceutical companies bring us studies that are not feasible to do. We have the patient populations, but they don’t meet the requirements because the standard-of-care is quite different from the U.S. or Europe,” said Guerrero. “That hurts the sites or the investigators, because we are not meeting the patient recruitment objectives.”
In India, were there has been substantial debate about the ethics of clinical research, informed consent forms and processes have come under intense scrutiny and present distinct challenges for investigators. Investigators need access to consent forms that are country-specific and translated into multiple languages. Social values and practices also put additional responsibility on investigators to obtain a meaningful informed consent in many settings since patients generally trust their physicians and the medical system, but typically don’t understand the clinical research process. Investigators often must spend a great deal of time thoroughly explaining the risks and benefits of clinical trials to study volunteers. Local customs also require patients in some regions to discuss participation with family and community members before making a decision.
Consent issues have become even more complicated for Indian investigators in recent months after the government instituted new guidelines that require an audio-video recording of the consent process for study subjects entering a clinical trial. Investigators remain unclear about which studies are subject to the new law and the industry will need to address changes in infrastructure, cost implications and how to maintain confidentiality of study volunteers.
“This is something that is quite drastic when we talk about industry-sponsored or any regulatory trial that must be approved by a drug controller in India,” said Sengar.
Clare Grace, Ph.D., vice president of Site and Patient Access, INC Research, said publication policies are another important issue to investigators in the Asia Pacific region, particularly for physicians in Taiwan and Korea who are trying to establish their reputations, build up their research practices and hire new staff.
“One of their biggest challenges, because they are still in an academic environment, is the publication policies that limit their ability to participate in the major primary publications. It’s very hard to publish because of the academic environment they’re in, but most of the time the main PI is based either in the U.S. or Europe. We need to look at how we can support investigators and what we can do as an industry to broaden the publication policy to include sites in other regions,” said Grace.
Investigators in emerging regions also experience delays in receiving investigational drugs and other clinical trials supplies, according to the CenterWatch survey, and indicated that protocol amendments create additional burdens for sites. Ultimately, the biggest challenge for investigative sites in emerging regions is the lack of study opportunities that are appropriate.
“What we are now doing is ensuring a close working relationship with the sites to understand their challenges and support them to ensure they can maintain their teams and prevent high turnover. The financial aspect is really critical for them,” said INC Research’s Zieher. “The investigators need CROs and sponsors to pay on time, for example. We need to understand the sites’ financial burdens and make sure that contracts are taken into consideration when defining site study budgets and frequency of payments.”
Signs of activity improving
There are signs that activity will pick up in these emerging markets. Both Latin America and India are expected to be an integral part of global programs sponsored by major drug developers going forward. In order to support investigators as activity picks up in these regions, sponsors and CROs need to understand the struggles sites have experienced during the past five years and the unique challenges they face in conducting global clinical trials.
“Here is the reality: Clinical research is hard. There are a million different things that have to happen in each country and they all have to go perfectly. Every country has its ups and downs and quirks of what may be challenging at a particular time,” said PRA Health Sciences’ Kent Thoelke, executive vice president, Scientific and Medical Affairs, Safety and Commercialization Services. “But there is still a definite need for and a desire to work in global emerging markets.”
In India, the government has taken steps to address regulatory and ethical concerns by amending regulations and creating new compensation guidelines. A few principal investigators funded by the U.S. National Institutes of Health (NIH) have restarted studies in India, CROs have made new investments in the region and global sponsor companies have expressed renewed interest in conducting studies in the country.
INC Research’s Ong said one of its largest sponsors has asked for help with their India strategy. “They feel now is the time to take another look at doing trials in India,” he said.
“Definitely we see more interest in biopharmaceutical companies bringing work to India as well as the domestic innovators within the pharma sector who were forced to take trials outside and institutions like the NIH. It’s good news, but we would like to see more numbers,” said Suneela Thatte, president of the Indian Society for Clinical Research, an association of industry professionals formed to build awareness about clinical research in India and facilitate its growth.
In Latin America, proposed changes in Mexico, Argentina and Brazil could lead to shorter timelines for clinical trial approvals, more predictability in regulatory processes and stronger support for clinical trials. The region also sees new Latin American countries moving into the research arena, including equatorial counties, Panama, Dominican Republic and Costa Rica.
“In the last 18 months, we’ve seen sponsors pushing studies wider and ensuring that we have a mix of ethnicity and countries in the regulatory framework for approvals,” said INC Research’s Grace. “They are looking at the capabilities of the site and infrastructure as opposed to looking at countries where they haven’t been to before. We are seeing a move back to those regions that almost stalled through the economic crisis.”
Thoelke said sponsors and CROs want to place studies in Latin America since the patient populations and large, centralized healthcare systems can be beneficial for trial recruitment. Since timelines are typically longer in this region, he said sponsors tend to choose programs for the region that have timelines longer than 18 to 24 months. This strategy has impacted clinical trials in Brazil and Argentina, which have among the longest timelines in the region; however, there has been growth in places like Peru and Columbia where regulatory timelines are more manageable.
“We tell clients they have to be willing to explore all of the potential benefits that these countries offer against some of the challenges that are included. There are so many positive aspects to conducting trials in these countries. They have very good populations and they have extremely good, qualified GCP-trained physicians. If the timeline can sustain it, they should always be considered as part of big, global trials,” Thoelke said.
Based on CenterWatch interviews, it appears that most established sites in Latin America and India will be able to survive the recent slowdown in industry-sponsored studies. As activity increases in these regions, sponsors and CROs will need to develop closer relationships with sites to understand their distinctive needs in conducting clinical trials and develop ways to support investigators and improve operational efficiencies.
“I see tremendous opportunity,” said Accelerium’s Guerrero. “It’s just a matter of the industry looking in this direction and seeing that we can provide expertise in clinical trials.”
Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master of Science degree from the Columbia University Graduate School of Journalism.
Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master of Science degree from the Columbia University Graduate School of Journalism. Email firstname.lastname@example.org.
This article was reprinted from Volume 23, Issue 03, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>