March 15, 2008 (Vol. 28, No. 6)

Outsourcing Veterans Reveal Advantages and Drawbacks of Offshore Trials

Biopharma companies are increasingly turning to developing nations as sites for clinical trials, driven by a ready supply of patients, the ability to tackle diseases that are rare in industrialized nations, and large potential markets.

“Competition for available patients in industrialized nations is a major challenge in new product development,” notes Joe Shan, executive director of clinical and regulatory affairs at Peregrine Pharmaceuticals. Developing nations, however, offer less competition from other clinical trials and plenty of patients and investigators who are eager to participate.

Gregg Sweet, vp of strategy and development at Integrated Clinical Trials Services (ICTS), recounts one 500-patient Alzheimer’s trial in Eastern Europe that reached full enrollment within days. The recruitment phase for the U.S. phase of the same trial lasted more than 18 months without reaching its enrollment goal.

In patient screening, “input can be several-fold higher in developed countries than in industrialized nations,” according to Steve King, Peregrine’s CEO. Patients specific to a region are often funneled into a few hospitals, so there’s also a more concentrated population for a given condition, he explains.

“Additionally, many of the physicians were trained abroad and want to continue activities such as clinical trials research,” says Christophe Tournerie, M.D., executive director of clinical research at PharmaNet.

In Dr. Tournerie’s experience, these researchers deviate less from the trial protocols than other researchers. Some also see trials participation as a way to bring Western medicine to their patients. “It offers a unique opportunity to work with drugs they would otherwise have no access to,” adds Jeff Thomis, Ph.D., president of global clinical development for Quintiles.

Access to More Diseases

Another potential benefit for companies is the prevalence of diseases that rarely appear in the West. “Certain indications are in scarce supply in the West,” John Rothman, Ph.D., vp of clinical development at Advaxis, cites cervical cancer, which has declined in the West because of early screening but is prevalent in countries in which PAP smears and HPV tests are not routinely administered. Other diseases like malaria and leishmaniasis are simply more common in the developing nations of Asia and Africa than in the industrialized world.

Conducting a clinical trial in Beijing or Bangalore is not the same as conducting a clinical trial in London or Los Angeles. But, it doesn’t have to be different, either.

Peregrine executives, for example, travel to the proposed sites to ensure the infrastructure is adequate and to meet with CRO site personnel and government officials, King says. “The reality sometimes differs from the paper picture, so we have a global development strategy that we implement early in the process.”

One of the success strategies used by biopharma firms and CROs planning to conduct trials in the developing world is to conduct trials in cities, rather than rural areas.

If you do studies in Indian cities, for example, “you find very little difference between studies in the West. They have good hospitals, the proper equipment, and well-trained doctors,” according to Dr. Thomis. “However, we didn’t find that in rural areas,” he adds. Therefore, it’s vital to conduct the studies in the right institutions.

Despite many physicians’ Western training, Dr. Thomis continues, “you may need to train them as clinical investigators,” emphasizing such standards as good clinical practice (GCP). ICTS minimizes the need for investigator training by working extensively in the former Eastern bloc. Investigators in those nations are accustomed to following GCP, Sweet remarks.

Overestimating the population’s education is one of the most common issues in clinical trials in the developing world. Therefore, Dr. Thomis says, companies need to ensure that patients truly understand that to which they are consenting and what that means in regard to their care.

In Latin America, for example, it’s common for companies to develop simplified, plain-language consent forms that are signed and witnessed, in addition to the more detailed forms. The form typically used in industrialized countries is simply insufficient when working with less-educated populations.

“For most cases, you don’t need to design the trials differently,” Dr. Thomis says, “but you do need to ensure that the institutions and investigators have the necessary experience.” For instance, in interventional cardiology, Western personnel generally have a fair amount of experience with stents. Yet, in developing nations, stents are expensive and are not as common. That difference can lead to poor placement which, in turn, generates poor endpoints that may be attributed to the drug but are, in fact, caused by the stent.

In another example, investigators for Advaxis’ oncology trials in Serbia, Mexico, and Israel did “very good clinical work,” according to Dr. Rothman. The problem came in the lab because technicians lacked the necessary expertise in clinical immunology methods. Also, the regulatory authorities in those nations weren’t familiar with the concept of nominal doses, and so used a different procedure requiring multiple vials of the product, and a somewhat variable process. “We amended the protocol to get back to the doses we intended,” he says.

Cultural Issues

Besides ensuring that the professional experience is available, companies also need to ascertain that the disease is actually recognized as a local morbidity. In many countries, mental illness, insomnia, and depression, for example, are seen as character weaknesses rather than as illnesses.

Likewise, central nervous system disorders often rely on patient input through questionnaires like the Hamilton Depression Rating Scale, where failure to account for cultural influences in any translations can make huge differences in responses. “Pay attention not only to the wording, but also to its tone,” Sweet recommends.

“We can take U.S. material and translate it to the local language and miss the boat,” he says. “It has to be an in-culture translation.”

Cultural issues may affect the trials negotiation, too. Sweet recalls one negotiation that had proceeded smoothly for six months. “Suddenly, the conversations became cold. Negotiations stopped dead.” Once the parties determined that a misunderstanding was conveyed in the tone of an e-mail, they were able to get negotiations back on track.

How medicine is practiced in developing countries also varies and may affect the speed of the trials. Serbia, for example, may use a team of physicians rather than referring patients to a succession of specialists. So, Dr. Rothman explains, if any one member of that team is unavailable, the patient visit is rescheduled, which can unduly extend the timeline of the trial.

Quality Concerns

Dr. Thomis insists that “the patient quality is the same, if not better, than that coming from Western countries.” One reason, he says, is that “patients are extremely compliant.” They still listen to their physicians and are truly motivated. The FDA has done a significant number of audits of investigator sites outside North America and Western Europe and discrepancies have been minor.

There are some concerns, though. Researchers are trying to determine whether differences in genetic distribution between regions affect the outcome or the method of action of the drug in question. For example, Dr. Thomis postulates, “if patients respond the same way, are they metabolizing the drug the same way?” There are also questions regarding the nutritional status of patients and how that may affect outcomes.

And, in some countries it’s easy to find family physicians but harder to find specialists. In Russia, for example, Sweet says he can find any specialist he needs for almost all trials, but some indications aren’t recognized by the old Soviet system and so have fewer practitioners.

If a regulatory agency isn’t convinced the drug will change a disease state, it may request a placebo trial. But, in some countries, trials involving placebos are illegal or considered unethical for untested treatments.

Advaxis conducted dosing trials in Israel, Serbia, and Mexico for Lovaxin-C, a therapy targeted at cervical and head and neck cancers. Because of the nature of the product—a living pathogenic microbe that is administered intravenously—“it made sense not to get into a speculative discussion with Western regulatory authorities that could have led to multiyear conjecture,” explains Dr. Rothman.

The company chose to conduct dosing studies abroad, working with Pharm-Olam International, a CRO with European headquarters in the U.K. When it met with the FDA, it presented results from initial clinical trials, thereby providing actual data for regulatory consideration as well as stretching its limited funds and perhaps shaving months off its development timeline.

Bureaucratic concerns exist, too, and vary by country. For example, “regulatory agencies may not be the most experienced (with a given study design), so may defer to local ethics committees,” Shan says.

Transparency and speed are also concerns. “For example, regulatory processes in China are challenging. But when we understand the environment well and we have a good relationship with the local regulatory authorities, we manage to overcome the challenges,” Dr. Tournerie says.

Globally, researchers report time lags that add months to studies, while some studies are actually approved faster than in industrialized nations. The upside, they say, is the high patient-recruitment potential, which can overcome any lags and actually help get products to market faster.

Decision Factors for Partnering with a CRO
For companies looking to establish outsourcing partnerships to support pharmaceutical and clinical development in 2008 and beyond, the key factor in the decision process should be quality, first and foremost, according to Vikki Renwick, sales manager, Tepnel Research Products & Services. Is the CRO suitably qualified for GMP, GLP, GCP, and GxP?

Good communication is also vital, which will preferably be through a dedicated, single point of contact such as a project manager. Capacity and sufficient resources are critical in terms of both technical staff and equipment to ensure the project can be delivered on budget and within the required project timelines.

Project cost is important as well, but one should ask if the CRO is adding value. In the instance of tactical outsourcing, for example, is it utilizing a CROs knowledge and experience? Finally, the company’s financial stability is key, particularly for clinically related projects.

The decision process to outsource is multifaceted and business strategy has a large influence on this process. Developing a partnership, however, can be a rewarding, successful, and cost-effective relationship when coupled with excellent communication, flexibility, and the sharing of technical capabilities between both parties.

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