The New Risk Management Paradigm

Jill Robinson and Mary Ellen Turner of the Global Safety Surveillance, Epidemiology, and Labeling Group at Wyeth Research discuss their approach to risk management.

Risk management has always been an intrinsic part of the world of pharma – with the decisive calculation of benefit-risk for each medicine serving as the ultimate determinant for drug and patient safety.

While the rigorous adherence to drug safety hasn’t changed over the years, there has been a noticeable shift in the approach to risk management as companies have begun to implement more standardized, formal processes in light of the new requirements and challenges around drug safety.

Increased pressure from regulators, including stricter compliance guidelines for transparency, has placed greater accountability on pharma to identify and make visible the true benefit-risk associated with each medicine. Clinical trial registries have become standard, and recent federal law has even expanded the national clinical trials database to include trials on all drugs and devices, excluding those in phase I trials.

The increased transparency of clinical trial data serves to enhance stakeholders’ knowledge around the complete benefits and risks of medicines to enable more informed decision-making and, ultimately, to improve medical outcomes. In addition, greater visibility into clinical trial data should also help to restore public confidence in the industry.

However, the multi-faceted challenges stemming from the new drug safety standards require a more formalized approach to risk management. “The industry has always had a high standard for safety and efficacy of their products and a high standard for patient safety,” says Jill Robinson, Vice President of Global Pharmacovigilance Operations for the Global Safety Surveillance, Epidemiology, and Labeling Group at Wyeth Research.

She adds: “What has changed in the new paradigm is a bigger scope where more formalized processes and communication plans in place are needed to talk to all the stakeholders – including patients, doctors, regulators and advocacy groups.”

People and processes
Wyeth has responded to the new requirements by implementing an integrated risk management system that runs from drug development throughout the product lifecycle.
“We’ve tried to make sure we have standardized processes and policies in place around risk management and that we have clearly defined roles for clear decision-making – who is making what decision, what kind of information needs to be available, and then making sure that we have the right technology,” Robinson explains.

Within Wyeth’s risk management system, the implementation of more standardized processes is geared to help better define roles and identify the information and technologies needed for clearer decision-making around risk management.

“True risk management is a process and it involves risk identification, evaluation and characterization of that risk,” explains Mary Ellen Turner, Vice President of Risk Management. She continues: “It involves developing interventions to minimize that risk, developing a strategy to communicate that risk to the appropriate stakeholders, and then developing a plan to evaluate the impact of whatever intervention or communication plan you’ve chosen.”

Integration is a major element of Wyeth’s risk management system. Not only are their formalized processes applied from the beginning of drug development throughout the product lifecycle, they have also brought together the individuals who handle adverse events, medical surveillance, labeling and epidemiological studies into one multi-disciplinary group for a truly integrated approach to risk management.

With a cast of knowledgeable individuals assembled together who possess expertise across all areas of the entire product lifecycle, it ensures a strong and broad knowledge of the impact of risk management. Wyeth has already experienced immeasurable benefits from the formation of its Global Safety Surveillance, Epidemiology and Labeling group.

“What we have found to be very helpful is bringing in people like our epidemiology group early during this planning process because when you’re looking at your strategy around benefit-risk assessment, it’s important to know the characteristics of the population who will be taking the drug and what you can anticipate happening in that population,” Robinson says. “That kind of early contribution from epidemiology can help you with decisions about positioning your drug in a way to minimize risk and maximize benefit.”

It’s obvious that while clearly outlined, integrated processes are vital; at the heart of Wyeth’s risk management system are people. Turner admits that in order to make all the pieces of their risk management system come together expertise must be leveraged from all around the company. “You have to draw on the expertise from other areas of the company to help you effectively communicate those risks and to develop interventions and get those out to the healthcare professionals and the patients.” In addition, full buy-in from senior management has been key to successfully carrying out risk management initiatives.

Executing the right approach
While people and processes are critical for sustaining a successful risk management system, one overriding aspect of importance is timing, and planning should be initiated as early as possible in development.

“Having a process in place for early detection of risk is key, and bringing the right expertise to the table is really important,” Turner says. “In terms of best practices, if we have some identified risk or potential risk during clinical development, starting to think about that sooner rather than later is important, even before you start planning your clinical trial.”

At Wyeth, teams are encouraged to start discussing the benefit-risk profile of a product even before it reaches the clinical trials stage to better understand the safety profile and identify the potential safety issues as far in advance as possible.

Early planning ensures that when a red flag or an issue arises, the standard tools, processes and well-defined roles are already in place to mitigate the issue. One prime example relates to standardized data collection methods such as with capturing electronic data from clinical trials and reporting adverse events. By formulating a standardized way to collect safety information, information will be more complete and reported as correctly and quickly as possible.

One overriding aspect of a successful risk management approach is that it should concentrate on each product rather than the individual phases of a product lifecycle. “Risk management is more related to the product, the treatments that the product is going to be used for and the patient population,” Robinson says. “For example, if we’re doing a vaccine for children and we’re putting a drug into healthy children, the risk level that people are willing to take is usually a lot less than if we were treating someone with a malignant cancer disease.”

In addition to the applicable patient population, other factors that need to be taken into consideration include whether it’s first in class to help determine the extent of information related to benefit-risk needed to satisfy regulators, doctors and patients, and whether it’s a short-term or long-term use product to better understand timing and impact.

Identifying the stakeholders and understanding their level of knowledge related to a drug is another crucial component. “For example, when HIV became prevalent in the 80s, you were dealing with patients who were very knowledgeable about their disease and the drugs on the market,” Robinson says. “How you handled that was much different than, for example, if you were giving something today to an Alzheimer’s patient, where we’re still studying the research and trying to figure out how everything works.”

Communication is obviously another major factor in successfully carrying out a risk management strategy. “The key to all of this is to plan early and keep an eye on what’s going on as your clinical trial progresses. It’s important to have good communication throughout your organization so that you’re flexible enough to change course if you need to and to rely on all of the scientific tools that you have at your disposal, including some of the newer pharmacoepidemiology techniques to help develop your strategy.”

Ultimately, all of these components of formalized methods will lead to better safety strategies in development and, in the end, better medical outcomes. Still, Turner emphasizes that safety needs to move up on the priority list to make it even with efficacy.

“In the past, clinical trials obviously have defined the product with regard to its efficacy and how they’re going to test it. They’ve always collected adverse events. The new message now is we need to study safety as rigorously as we do efficacy.” While the length or size of clinical trials may limit the desired extent of statistical analysis able to be conducted on various safety issues, today pharma has many tools at their disposal – i.e. pharmacoepidemiology – to help to better understand clinical trial findings.

Every pharmaceutical company is being called to participate in more rigorous, formalized risk management processes, but for the big pharma companies, risk management entails a bit more complexity. Global companies have to take into account every country and ensure that risk management plans suit each local culture. “For the major global companies, you have to be looking at the whole global environment – all the external forces make it more challenging because there are different standards of care and different acceptable ways to communicate benefit-risk within these different communities,” Robinson explains.

An evolving process
Given its nature, risk management is a constantly evolving process and pharma companies can only look for ways to improve their approach to and execution of risk management plans.

“We all look for ways to continue to ensure that the right product is given to the right person for the right reason at the right dose,” Robinson says. “There has been a lot of collaboration and everyone – including regulators – are going back and looking at what we can do better. The industry does a very good job when you look across our record but there’s great opportunity to improve our processes.”

One major identified area for improvement is risk communication. “In talking with regulators globally and with our colleagues across the industry, I think we all agree that one big unmet need is to do more research into risk communication,” Turner says. “There’s a real need to communicate clearly and effectively to healthcare professionals and, most importantly, to patients the risks of medicines.”

While recent initiatives – such as the FDA’s work to make important information more prominent on labels – have touched on communication needs, there’s still a ways to go in terms of refining communication methods to physicians as well as patients to raise awareness of the full extent of the benefits and risks of medications.

A number of exciting changes and directions are already underway that will impact the industry with respect to risk management. Robinson predicts a shift from spontaneous surveillance to more active surveillance to obtain better quality data. And personalized medicine is one big arena that’s enabling the optimizing of treatment so patients can experience greater benefits from medicines. “Going back to clinical development, there are all kinds of initiatives in the area of pharmacogenomics and trying to identify through scientific means which patients are benefiting and which ones are not benefiting from medications, so that we can really get the medicines to people who will have the best outcome,” Turner explains.

Technology is another huge area that’s quickly evolving, as companies and regulators are turning to new technology tools to aid in the risk management process. Electronic capabilities have certainly opened the doors for more opportunity to improve risk management initiatives. “As healthcare systems switch over to electronic medical records, we have large insurance claims databases – and everybody is looking at all of those sources of information as potentially sources of data that we could use to do research in safety and risk management,” Turner says.

As companies begin to embrace more formalized risk management plans, they’ll need to keep in mind the widening stakeholder arena, which calls for a more comprehensive scope of risk management. Stakeholder involvement is only expected to increase, especially as patients are taking on more active participation in earlier stages of the process. “I don’t think it will be the case anymore that a company decides what they’re going to discover, what they’re going to market and that it’s good for the patient,” Robinson says. “Patients are becoming more educated and I think they’re going to have a larger voice in what risks they’re willing to take for what benefit.”

It’s obvious that the rules of the game, so to speak, around risk management have undergone a significant change. With expanding regulatory pressures, widening stakeholder involvement, rapidly advancing technology, and even more complicated products due to the maturation of biotechnology, risk management is an entirely new challenge and companies can only expect to need to adapt to meet such shifting requirements. “The good thing about the benefit-risk management process is that it is a continuous process – it is a process that you always get to go back and see if you’re doing the right thing and measure any outcomes so I think that we’ll always find better ways,” Robinson says.

Dr. Jill E. Robinson is VP of the Global Pharmacovigilance Operations area at Wyeth Research in Collegeville, PA. She is responsible for directing and managing human and material resources for the Global Pharmacovigilance Operations area. Other responsibilities include the timely and accurate reporting of all adverse medical event information for clinical development and marketed products to all global regulatory agencies and the development and compliance of the Safety Surveillance and Labeling databases.

Dr. Mary Ellen Turner is currently VP of Risk Management, Global Safety Surveillance and Epidemiology at Wyeth Research. She is responsible for the development and implementation of Risk Management Strategies for Wyeth’s investigational and marketed products. Prior to this she worked at Zeneca Pharmaceutical Co. in the department of Drug Safety and Epidemiology.