Product development requires the incorporation of clinical expertise in the assessment of safety issues, stressed John Ayres, MD, Sr. Medical Director, Eli Lilly, at the GMP Links to Pharmacovigilance Interest Group meeting held during the 2013 PDA Visual Inspection Forum in early October. He emphasized the benefits that can be gained from the mutual involvement of on-staff medical experts and development teams.
Product development requires the incorporation of clinical expertise in the assessment of safety issues, stressed John Ayres, MD, Sr. Medical Director, Eli Lilly, at the GMP Links to Pharmacovigilance Interest Group meeting held during the2013 PDA Visual Inspection Forum in early October. He emphasized the benefits that can be gained from the mutual involvement of on-staff medical experts and development teams.
“I think as a clinician in this business that there is a real opportunity to take all of the good science and the work that’s been done and to bring in physicians in your businesses and to get them trained in what you do,” he said. “This has to be something that physicians in our industry get engaged [with],” and added that physicians also need to “understand the portfolio in your development process.”
A former practicing physician himself, Ayres was also involved in founding the interest group, which was established in 2012 for the specific purpose of facilitating clinical expertise and patient experiences into the GMP quality system, forcing companies to consider the impact of certain attributes, such as quality attributes and product attributes, on safety and efficacy.
“This forum was established, as you can see, to consider how we assess CQAs [clinical quality attributes] for their impact on safety and efficacy, evaluating these attributes through the lifecycle,” he explained, pointing out the group’s other goal involves communicating “to the broader pharmaceutical community and industry, the value and limitations of safety surveillance.”
As an example of a safety surveillance limitation, Ayres pointed to the U.S. FDA’s Adverse Event Reporting System database.
“You have to understand the limitations of that dataset relative to some of the questions that are being answered, and you can’t rely wholly on that information coming through,” he explained as the dataset relies heavily on waiting for an event to be reported but many events are most likely not recorded in the database. In addition, the information gained from the database is only as useful in how it is utilized.
“As you think about these attributes, you’re really asking the question ‘are the changes that we see over two years—how are those translated into issues that they are relative to the performance of a patient and pharmacovigilance tools for monitoring these attributes?’” Ayres said.
Returning to the pressing issue of greater physician engagement, he then explained that Eli Lilly involves clinical staff at each milestone of the development process as part of a continuous review process. At each milestone, any signs that have been picked up from assessment data are discussed and examined as far as relevance.
“I like this milestone approach, because I think that we all pause at these decision points and have a discussion around the attributes that we’re seeing…we’re collecting data along the way, and what I’m suggesting is that you look at your clinical data,” he said.
Furthermore, each group that meets for one of the milestones uses a special tool he called an impact score.
“Each of those milestones has a group that gets together,” Ayres said. “We’re looking at these elements as well as a few others, but asking ourselves ‘are we getting information here relative to this specific product?’”
For example, a high impact score might mean that the team needs to gather additional information or develop a more rigid control strategy. The impact score serves to drive discussions and result in a specific response addressing the issue.
Safety signals and pharmacovigilance was another area where Ayres felt called for greater physician involvement. According to him, adverse safety signals present the threat of being misinterpreted, resulting in loss of product, unless there was clinical input.
“What we don’t want to have happen is that we put a lot of work into developing and manufacturing a drug product that has beneficial properties to patients,” he said. “And you don’t want to have it trashed because you start getting a safety signal that’s not related to the drug product, and regulators start reacting to that, [then] you start reacting to that. “
Moving on to product safety assessments, he identified two types of assessments: prospective and retrospective. Retrospective safety assessments occur following a deviation, such as a product complaint or an adverse event. Prospective safety assessments involve conducting analysis and review in anticipation of an event, and for Ayres are “where I want to live, primarily because I think this gets me earlier into the product lifecyle, and it could be more anticipatory of the types of events you might want to see, and to recognize that much of what’s relevant to safety is predicated on a quality culture and control strategies and capability.”
But he urged audience members to continue focusing on the GMP environment, no matter the type of assessment.
“If it’s GMP, keep it GMP. But try to get safety in as a proxy to make those decisions,” he said, and to ask if “the changes that we make in our manufacturing environment, whether it’s a site change or a change control, is it really having any impact downstream on the patient?”
During the Q&A following his presentation, Ayres addressed how a company could engage physicians during the development process.
“I think that you have to be patient with your physicians,” he admitted. “This is an emerging process. I think it’s a two or three year process. And you just have to get them at the table.”
Additionally, he emphasized the fact that physicians who can write well are a prime asset as they will need to draft various assessment reports.
Ultimately, the interest group plans to explore additional ways companies can elevate the role of physicians in pharmacovigilance. Other topics to be addressed by the interest group include extraneous particulate matter assessments, data mining methods and utility, manufacturing investigations for adverse events, portfolio risk assessments to prevent counterfeiting, clinical assessments and the design space, and the impact of pharmacovigilance legislation on quality.
Ayres stressed that the interest group will continue to push to facilitate expansion of medical expertise in the pharmacovigilance lifecycle.
“This has to be something that physicians in our industry get engaged and understand the portfolio in your development process,” he stressed. “The FDA and the EMA, they can’t police this...this is a self-regulated industry…and it’s up to us to put these systems in place and demonstrate we’re on the same page as they are.”
If you are interested in joining the GMP Links to Pharmacovigilance Interest Group, please contact PDA’s Volunteer Coordinator at [email protected]
[Editor’s Note: See Ayres’ remarks about CDER Director Janet Woodcock’s presentation at the 2013 PDA/FDA Joint Regulatory Conference on p. 42.]
About the Expert
John Ayres, MD, serves as the Health Hazard Evaluation physician and Sr. Director, Product Safety Assessments for Eli Lilly. In this role, he works closely with the company’s development functions, manufacturing, quality, and pharmacoviligance to evaluate the human safety risk potentially associated with product quality attributes, manufacturing deviations, linked to product complaints, or related to anticounterfeit medication issues.