Building Relationships Around the Globe

Wyeth’s Joan Shen examines the benefits of choosing international locations for clinical trials.

As Medical Director for neuroscience at Wyeth, Joan Shen is used to working with people from around the world. She is currently focused on conducting global trials for phase II and phase III, for indications including schizophrenia, bipolar and depression. "My day-to-day job is to work with clinical scientists to generate protocols and select the countries, and then conduct trials and analyze the data to get the results," she explains. "We coordinate with the other project management functions and propose to upper management what we think the best strategy is to move forward with a certain compound."

Clinical trials are becoming ever more complex, with larger patient groups, and are often conducted internationally, meaning it can be challenging to conduct trials in a timely and cost-effective manner. Shen points out that the main things to keep in mind are speed and quality. "Wyeth has been back and forth in terms of what are the best methods, and in the last two years we have generated a group called country visibility. We call it the site management group, as distinct from the study team.

"This group helps us to facilitate the selection of countries and the visibility of studies company-wide. Once we get approval to move forward with a study and get a budget in place, we have a study mobilization meeting with all the functions,  including the management group. That needs to be planned six to nine months ahead of time.

"We generate a synopsis of the study and a questionnaire about the site country's visibility, and the special site management group takes them and sends them all over the world, wherever Wyeth has attachments. They collect the feedback on what is required, such as the number of patients or disease areas or placebos needed. They then give feedback to us and based on that information we select which site we want to go to. That helps us get collective information and from that we can generate a database based on site performance in the past, and the regulatory environment changes."

Shen points out that the downside of this is that the quality of the site may not get as much consideration as it should. She believes a joint effort works best, between country visibility groups and the study team to look into the specific capacity of and the quality of the sites.

International benefits

Shen leads trials in various sites around the globe, including China, India, Japan, South Africa and Eastern Europe. While big pharma companies have been criticized for choosing these locations based on cost, and have been accused of 'taking advantage' of unsophisticated local populations, Shen explains that there are legitimate reasons to site trials abroad.

"We need a diversified patient population, which is very important for development if you are marketing all over the world; and secondly the trend toward placebo results and so-called failed trials is increasing in the US. That means we are getting 'fake' patients or treatment resistant patients, or patients who have been recycled from other studies. We can't see the true treatment facts if we repeatedly use the same population, and the commercial treatment sites who try their best to get patients don't necessarily provide the best quality.

"We can lower the placebo rates because we know going to countries like China, India and South Africa you see many more patients who have not been exposed to clinical trials and to second generations of certain drugs; for example, psychotics. It then becomes much easier to see the true effect.

:I remember one of the studies I was involved with in the US in which we had no effect on the treatment between the two populations, but we were able to identify the drug effects with Russian subjects. Overall, it was statistically significant, but if you put aside the Russian patients you didn't see it. We were able to discuss this with the FDA and they agreed with our data. The quality of the data speaks for itself."

Of course there are disadvantages to international clinical trials. One of these, as Shen points out, is that some countries require a much longer time for regulatory approval. "Some countries are quite fast, while others are very slow. For example, in China in my experience once you hit the 'yes, go', they are able to really move very, very quickly. In one of the trials I remember in China, they had already finished their enrollment but some other countries were so behind that we asked China, 'Can you increase the number of patients to finish up all the studies?' And they did."

While Shen feels comfortable running trials in the US, apart from the issues with patient quality, she prefers to go where there is a bigger potential patient population. "It's also the market that we're looking for. The regulatory requirements for most of those regions ask for the particular patient population from their region. If early on you know you're targeting those populations, it makes life easier when you submit to the FDA and to get market approval. That's one of the incentives we are moving towards with these global studies."

Different regulations

Regulations also vary between countries. Shen has found that India has an excellent regulatory environment. She anticipates a three to four month approval period there, because the board of health is relatively easy to work with. "As long as the ethic group committee agrees with your proposal, you have no problem. This is not always the case in other countries.

"In Japan, the PMDA is really strict on what they do. Usually they ask for phase I data before you can move forward, and the other problem is slow enrollment, but I think the PMDA is now much more open-minded. They like open dialogue, so the study team has to put a lot of effort in to support this. We send our experts over there to talk to them so they have a whole picture of the safety data, and then they feel comfortable.

"Right now we anticipate novel chemicals getting approval in eight or nine months, but again this is a regulatory bottleneck. There's a huge potential for markets so we usually don't give up; we'll keep trying."

According to Shen, South Africa also has an excellent regulatory environment, with an approximate three to five month approval period. The downside is that it's on the other side of the world, and to travel there is difficult. "It depends on disease areas. Some of the diseases are much easier to conduct studies in; some are not; it depends on the availability of the treatment.

"Ethics committees in other countries sometimes also ask a lot of questions about placebo: why you want it and can you do it without it. Eastern European countries are stricter now about placebos as well. Originally countries like Poland were pretty open to clinical trials but now the psychiatric committee there has issues with some kind of consensus.

"As long as there's available treatment they do not suggest that we use placebo in the studies, so we had to withdraw our applications. We don't know the trend but it looks like as a company we are moving towards more Asian and South American locations instead of Eastern European countries, although Russia is currently has a pretty good regulatory environment."

Patient quality

Patient recruitment methods also differ depending on the country in which the trial is being carried out. Shen says she is strongly opposed to the notion that patient recruitment should be conducted based on speed alone. "I want to recruit patients quickly, but I also want to emphasize the quality of the patient. We also face challenges with patient trust in some regions.

"For example, in China and Taiwan the method of recruiting patients largely depends on the relationship with the site. In those countries patients need therapeutic alignment with the physicians, so if they trust the physician they come to the studies and stay with the treatment, but if they don't it's hard retain them or get them to come to clinical trials because it's still a relatively new concept in those regions.

"You have to have a very good relationship with the site. I cannot emphasize that enough because that's one of the things our company is doing. I've currently initiated this in China, to try to build long-term relationships with the key opinion leaders there, as well as the PIs. To better understand their needs we help to train them. We help them to obtain the disease knowledge to get the best quality from the clinical trials.

"Those regions are looking for collaboration. They don't want to be treated just as a site: give us patients and we're done. They want to be treated with mutual respect and also have long-term collaborations. They also like to have a co-author on the publication."

In Shen's view, it's about building a long-term relationship. "Many big pharma companies have been operating in countries like China for a long time, so they already have good reputations there. This can mean that when they have four or five trials they prioritize ours, which can be significant factor in enrollment rates. As a big company, what you need to do is build up a relationship with local government. If you get their support, things are much easier.

"Those are the differences in terms of Asia and the US, because in the US you don't need to deal with these things as long as you have incentives for the PIs. We also have good relationships with India and many other countries, and this does make a huge difference. We as a study team go to visit the sites. We exchange scientific information and then make ourselves available if they have problems or questions. Once you start the trial, you can't just throw that out and leave them on their own.

"In those regions they are still learning to ensure study quality. For this reason, I would strongly suggest providing a refresher or other visits to rejuvenate the study's energy and to refresh the memory of what's needed, otherwise quality could deteriorate throughout the study, especially if it's long. That's how I feel about the energies we need to put in to help get recruitment as we need it."

Another important aspect of building relationships with international sites is education. As Shen explains, training at sites is very important, as well as training the company site managers. It's not a matter of setting up the trial and leaving them to get on with it. "You can't just give it to the region and wait for results. That never works very well.

"We need to educate people, to help them understand that if they want to have those medications available for the local population, they need to make sure patients understand that joining studies helps them and will help others in the future to get medicines early on. That's also the selling point for the government when they say, 'You're trying to test our population.' Then we'll say, 'This is the only way we can get this on the market early so everybody can have this available.' Those are the things we want to see not just for clinical trials, but also for long-term patient benefit."

Joan Huaqiong Shen is Medical Director for neuroscience at Wyeth. She began her career as a surgeon, then obtained a PhD and training in psychiatry. Shen, who is board-certified in psychiatry and eligible in clinical pharmacology, worked for Eli Lilly before moving to Wyeth in 2005. She leads clinical trials to China, India, Japan, South Africa and Eastern Europe.

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