Learn and Confirm

In response, Wyeth Pharmaceuticals has launched a clinical development initiative called Learn & Confirm, which replaces the traditional phases 1, 2 and 3. And the company is building a small global network of clinical sites aimed at streamlining all of its processes for conducting phase 2 (Learn) trials.

“Through repetition, added surveillance and added training we will be able to accomplish our goal”
-Sheila Ronkin

Novel study designs have helped Wyeth to strengthen its pipeline. It received the accolade of “Best Central Nervous System Pipeline” as part of R&D Directions magazine’s annual “Top 10 Pipeline Report”. This follows “Strongest Primary-Care Pipeline” in 2005 and “Pipeline to Watch” in 2004.

It all goes back to Robert Ruffolo, who joined Wyeth in 1999 and became Head of Research and Development in 2000. He instituted Wyeth’s new R&D productivity model. “Previous to this model, there was not a large number of products going on development track or making it to the IND stage, so we decided that we needed to fill the pipeline,” says Bob Maguire, Vice President of Clinical Development at Wyeth. “There were a lot of industry-wide issues necessitating more shots on goal to guarantee two major submissions a year.”

Most of those issues are challenges that all pharmaceutical companies face at the beginning of the 21st century. A decreasing number of new drug approvals combined with decreasing clinical trial success rates, increasing costs of R&D, stronger pricing pressure for prescription drugs, greater involvement of state and federal governments, stronger regulatory and compliance requirements, and greater consumer choice, to name but a few.

“There is tremendous pressure to increase productivity and efficiency on the development side because of these issues,” explains Maguire. “Most major companies are now thinking about what it is that makes the whole clinical development process more productive and efficient, from things done internally to consideration of non-core capabilities being conducted by others. We have designed our own R&D productivity model, to guarantee a minimum of 15 development track products and 12 INDs every year.” In order to handle this large number of clinical candidates, Wyeth needed a more efficient development model – thus, Learn & Confirm.

Not the old Wyeth anymore
The model has proved successful over the past five years. Last year, Wyeth even upped the number of products to go on development track to 15 instead of 12. And the success story continues. “We are actually at a point now where we are hitting two plus major submissions a year. We fill our pipeline with lots of compounds but not just any product. A ‘me-too’ isn’t making it there. There is a focus on innovation in the pipeline,” emphasizes Maguire. Wyeth is now the fourth largest biotech company in the world, based on its biotech commercialized products and manufacturing capability. “It is not,” reflects Maguire, “the old Wyeth anymore.”

The focus on innovation has strengthened Wyeth’s pipeline, increased the number of submissions and, in a word, lead the company to success. So what is this new R&D model all about?

The concept of Learn & Confirm emerged from Wyeth’s discussions with the Food and Drug Administration and from a paper published in 1997 by L.B. Sheiner. In this paper, Sheiner identified two distinct activities in clinical development, learning and confirming. The goal of learning is to focus on how to use a drug in representative patients to make an acceptable benefit/risk profile likely, while the goal of confirming is to demonstrate, in a large and representative patient population that an acceptable benefit/risk profile is achieved. Wyeth’s Learn phase will replace phase 1 and phase 2 in the traditional approach while the Confirm phase will replace the traditional phase 3.

The new model has increased levels of collaboration and feedback between discovery and the clinic adopting discovery studies during the phases. “Phases 1, 2 and 3 are not going to go away but we are trying to think of them as one process rather than separate processes. We have created Learn teams led by a core group of project management, discovery, clinical pharmacology, and medical individuals. Together, they are now devising development strategies from late discovery through to the end of Phase 2,” says Maguire.

Instead of looking at clinical outcomes some time down the line of the trial, the Learn phase is designed to enable learning from the trial as it is going on, so that drugs make it to the Confirm phase with the highest probability of success. Maguire explains: “In the early phases we are trying to quickly and efficiently kill drugs that don’t work and make our investments in drugs that do work at the right doses and in the right patient populations.”

This requires a new way of thinking regarding the use of biomarkers and adaptive or flexible study designs, believes Maguire. “We are initially recruiting a minimum number of patients across a broad range of doses to establish a good exposure response curve. After we have achieved this, we start dynamically randomizing patients based on what doses are working well, often within pre-specified safety parameters. Then more and more patients will be put on effective doses while other doses drop out. In the end, you are likely to have gathered a lot more information about the right dose.”

Once established at what dose and in what patient population a drug has the best chance of working, it is possible to narrow the patient population and the number of drug groups in the Confirm phase. “Even in a standard phase 3 design,” Maguire predicts, “things will move faster, they will be less expensive and patients will receive doses that they have the best chance of doing well on. It’s a win-win for everybody.”

Even the regulatory authorities, often blamed for stiffening pharmaceutical company’s attempts to be innovative, are supportive of Wyeth’s new study design – at least in phase 1 and phase 2, the Learn phase. In phase 3, there are still some concerns, which is due to the potential problem of biased results. “When you are conducting adaptive trials the computer is continually looking at data. The possibility that investigators or patients are influenced by somebody knowing that data is a problem for FDA. So when we get to the pivotal studies, they are concerned about continual analyses and ongoing decision-making during the trial,” explains Maguire.

Wyeth believes this issue is addressable in the long-run. Maguire is optimistic that frequent communication with the regulatory authorities will help to reach common ground in the next few years. “It won’t work for every drug and it won’t happen yesterday, but we have an increasing number of studies under consideration for novel designs and the sentiment around here is that this is the way to go. The future’s bright, the pipeline’s full, and there is lots to work on.”

A global network of clinical sites
Naturally, there are challenges that Wyeth faces, and these challenges are directly linked to their success. As the company found itself with an increasing number of innovative compounds, it also realized that the time it took to get through the Learn phase was increasing. A first solution was to identify a larger number of clinical sites. However, this did not turn out to be a good solution.

“What we found was that up to 40 percent of these sites contributed only one patient or even no patients at all. We were also faced with the increasing operational cost of maintaining these non-contributing sites. So we had to look for a better way to run trials in face of a larger and larger number of compounds that we knew would be entering the development track,” says Sheila Ronkin, Assistant Vice President of Clinical Development, heading the Early Clinical Development Center Initiative. The resulting program, Wyeth hopes, will be a better way to run trials.

The Early Clinical Development Centers group, which reports to Maguire, seeks to build a small global network of clinical sites associated with hospitals or institutions committed to research that draw on large patient populations in multiple therapeutic areas. “Our goal,” says Ronkin, “is to conduct a portfolio of early phase clinical studies through this network. We want to streamline all of our processes and activities so that we can actually conduct our clinical trials more efficiently with a better eye to timeliness and quality.”

Wyeth has pre-negotiated long-term master agreements with its partnering sites. Because of the volume of studies at any particular place, the company has on-site monitoring presence to a much greater degree than in the old model, where a monitor visited every six to eight weeks. Ronkin adds: “We also learned that this network is a good way to pilot innovative new processes; processes addressing reducing cycle time but also addressing quality. And it’s a good network to work with our adaptive trial design section because drug supply is more manageable and we have greater contact in this effort of partnership.”

The company reached its goal of a 10-site network by the end of 2006. The sites are located in Asia, Europe, US and South America. “We are conducting studies at most of these sites right now,” says Ronkin, “and we are getting good results. We intend to contract five additional sites during the first half of 2007 and we have discussions in place right now in the US, the UK and South East Asia to do this.”

Up to 80 percent of Wyeth’s clinical trial participants used to come from core countries. Today, the company is moving closer to the industry wide average of about 55 percent, which they are planning to recruit in the US and Western Europe. The remainder of patients will come from Latin America, Central and Eastern Europe and Asia Pacific. Wyeth’s Asia Pacific Research Organization group, which includes China, Hong Kong, Taiwan, Korea, Australia and New Zealand, last year doubled the number of newly enrolled patients in that region. This is also the goal for 2007.

The problem of regulatory approval times
Many sites in non-core countries have a lot of experience, understand the trial process and have good investigators. However, there are challenges involved in conducting trials. “The biggest challenge, especially in specific countries, is clinical trial regulatory approval times. We have major issues with regulatory approval times in some Latin American countries and in China. Most of the rest of the world’s countries are okay, they are within three to four months start-up-time, but in China it can take nine months, sometimes longer,” says Maguire. “That’s a problem for us.”

A problem Wyeth is addressing by changing its internal processes to have clinical trial submission packages ready earlier than in the past. The company also has early frequent discussions with the regulatory authorities in China. This raises hopes at Wyeth that there will be some movement on the part of the regulatory authorities in China to decrease regulatory clinical trial approval times.

Other challenging issues Maguire addresses are related to finding talent in the region. “We have got about 60 people between our full-time and contracted people in the East Asia region and more in Japan and India. We found all the talent we need for now but it will be an issue as we expand because there is lots of competition for talent.”

Ronkin agrees that conducting clinical trials in non-core countries is challenging but is convinced that there is benefit: “The credentials and experience of the investigators we found to work with are exceptional. In addition, many of these investigators really do view early phases as the most exciting parts of the development process, when we find out whether drugs work or don’t work. They are anxious to contribute to protocol design and program design, much more than I had anticipated, and their input is really appreciated and excellent.”

Robert Maguire
With 24 years experience in the biotech and pharmaceutical industry, Bob Maguire has worked his way from medical monitor to multitherapeutic area head and is now VP of Clinical Development and Chief of Operations at Wyeth.

Sheila Ronkin
Sheila Ronkin, a maternal foetal medicine sub-specialist, worked as a medical monitor in Women’s Health Studies at Wyeth before she moved over to the development side, where she heads the Early Clinical Development Centers program.