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Detection of nitrosamine impurities in some marketed drugs highlights need for standardized, consistent approach to systematically monitor risks of drugs throughout their lifecycles, CDER’s Janet Woodcock says. Safety monitoring overhaul is lagging behind new drug review modernization effort, but implementation is expected to begin in 2020.




The detection of nitrosamine impurities in a growing number of approved drugs highlights the need for an integrated postmarketing safety surveillance framework at the US Food and Drug Administration, the agency’s Janet Woodcock said.

At last month's FDA/CMS Summit hosted by Pink Sheet parent company Informa, the Center for Drug Evaluation and Research director and other agency officials discussed plans to modernize the agency’s postmarketing safety evaluations by creating a standardized, consistent approach to systematically monitor the risks of drugs throughout their lifecycles.

The initiative – which will establish a more robust and unified postmarketing safety system – will span the Office of Surveillance and Epidemiology, Office of New Drugs and other offices within CDER, Woodcock said.

“The very high-profile, recent safety problems we’ve been having, such as the nitrosamines and others, have helped I think make people realize this isn’t just an OSE thing or an OND thing,” Woodcock said. “We need expertise from all over. We need some kind of overall governance of postmarketing safety across all these different units.”

Cross-Disciplinary Safety Assessments
Woodcock has previously signaled plans to streamline the agency’s approach to drug safety reviews, with an eye toward having one process for all kinds of safety issues across CDER. (Also see "CDER Safety Overhaul Planned As Review Process Modernization Continues" - Pink Sheet, 8 Jul, 2018.) The ongoing concerns around nitrosamines in marketed drugs may shine a brighter light on the agency’s plans in this regard.

Potentially carcinogenic nitrosamines have been found in some formulations of angiotensin II receptor blockers, which are used for treating hypertension, and the heartburn drug ranitidine, leading to product recalls and warning letters. (Also see "Mylan Warning Letter Exposes Challenges In Valsartan Supply Chain Chemistry" - Pink Sheet, 12 Nov, 2019.) More recently, impurities have been found in formulations of the diabetes drug metformin. (Also see "Global Scare Over Nitrosamine Impurities Extends To Diabetes Medication" - Pink Sheet, 6 Dec, 2019.)

The FDA has said advances in analytical methods is enabling the detection of even trace amounts of impurities in drug products and may be the reason why more drugs have been found to have low levels of N-nitrosodimethylamine (NDMA). The discovery of nitrosamines in some drugs has led the FDA to focus more attention in reviews and inspections on where and how process-related impurities may form in the manufacturing process. (Also see "US FDA Scrutizes Process Risks After Finding Nitrosamines In ARBs" - Pink Sheet, 29 Aug, 2019.)

Such safety concerns have demanded the type of cross-disciplinary attention that underpin the agency’s postmarketing safety modernization plan.

Khushboo Sharma, OND’s deputy director for operations, told the FDA/CMS Summit the plan is to create a standardized, postmarketing drug safety framework that will include:

>   Cross-disciplinary, collaborative, science-focused assessments;

>   Clear roles, responsibilities and governance;

>   Information technology-enabled processes to enhance knowledge management and fit-for-purpose analytic tools to promote optimal evaluations; and

>   Policies and processes (such as standard operating procedures, charters and templates) that support this framework.

FDA officials said the timeline for launch of the postmarketing safety management initiative is lagging behind that of the new drug review modernization effort, although the agency hopes to roll out some pilot programs and begin phased implementation in 2020.

“We knew this would take longer … to try and figure out how to pretty significantly reconfigure how we do our postmarket safety evaluations,” Woodcock said. “It took a long time to get it to gel, but we have a plan now.”

Keeping Track Of Applications During The OND Reorg
Woodcock and Sharma also provided updates on the new drug review modernization program, including the OND reorganization, the integrated review template for marketing applications, and the investigational new drug review management streamlining initiative.

In September, the agency received congressional approval to restructure OND in a way that flattens the organization and brings more of a disease-focused structure to review divisions. (Also see "US FDA's Office Of New Drugs Reorganization Approved, But Not Happening Overnight" - Pink Sheet, 26 Sep, 2019.)

The number of OND clinical offices is increasing from six to eight, and the number of clinical divisions from 19 to 27. Six nonclinical review divisions have been established as well as several cross-functional support offices, including program operations, administrative operations, regulatory operations, new drug policy and drug evaluation sciences.

The breakthrough therapy and expanded access programs now are located in the program operations office, while the drug evaluation sciences office houses the clinical outcomes assessment staff and biomarker qualification programs.

The reorganization of the clinical offices and review divisions within OND is proceeding in a phased process, with the third of four phases currently scheduled for January. (Also see "US FDA Office Of New Drugs Reorg: Phase 3 Pushed To January" - Pink Sheet, 3 Dec, 2019.)

“That’s how we have to do it so that we don’t lose anybody’s INDs or lose track of an NDA review,” Woodcock said of the phased implementation. “We’re staging these very carefully.”

Review Template Adoption Complicated By IT Issues
CDER also is staging implementation of a new integrated review process and template for marketing applications. (Also see "US FDA 'Uni-Review' Rolls Out: Psychiatric Division Is Among Early Adopters" - Pink Sheet, 22 Oct, 2019.) The initiative is aimed at promoting streamlined, issue-based reviews that foster interdisciplinary collaboration while also reducing redundancies and low-value work and enabling better knowledge management.

Woodcock described the integrated review document as a “huge cultural change.”

“Instead of having each individual reviewer write kind of a treatise on the file with a lot of cut and paste from an application put in there, we have a template for a multidisciplinary assessment based on the problems that are identified in the file,” Woodcock said. “So is there a problem with efficacy, is there a problem with multiplicity, is there a problem with an endpoint … it will tell a story of how that was resolved.”

Nevertheless, technological challenges have complicated adoption of the new process.

“We might have 20 people on the team each working on this in SharePoint, and you can generate a lot of versions,” she said. “We’re using an obsolete version of SharePoint … and so this might crash sometimes. This doesn’t make people feel warm and fuzzy about this new process.”

However, CDER reportedly is getting a modern version of Sharepoint “and then we are going to move into a new workflow management tool … that will enable this process a lot better,” Woodcock said.

The new integrated review process also involves a new tracking tool that will be used from pre-NDA through the end of the review cycle. New positions for clinical data scientists and medical editors have been added to enable reviewers to focus on the science and regulatory aspects of applications.

In addition, the new review process incorporates scoping working meetings to get leadership involved early in discussions of known benefit and risk issues, and joint assessment meetings that focus on specific review issues, Sharma said.

Some review divisions have fully adopted the new template and process, while others have not yet begun using it. All divisions are expected to begin using the new process and template in 2020.

“Each month we bring some more people into the fold and as we get completed cycles done we’ll do an assessment – what worked, what didn’t work, and how can we improve this … template and this process,” Woodcock said. “But generally we don’t have a lot of tremendous hostility to this idea anymore. Everybody is on board with moving along, it’s more the technical challenges.”

Updating IND Review And Management Practices
The agency also is working to streamline reviews and management of the IND program to address variable practices across review divisions and reduce redundant documentation practices.

The initiative involves creating issue-based templates that foster interdisciplinary collaboration, establishing procedures to standardize the review process, clearly defining roles and responsibilities, and developing a risk-based approach to categorizing incoming protocols and amendments to identify those of higher priority that should receive a more expeditious review, Sharma said.

“We’re going to template our review of all the clinical protocols that come in. That will then allow us to capture information about what those protocols are really about,” Woodcock said. “That’s also being rolled out in a staged implementation.”

Woodcock acknowledged the reorganization and modernization initiatives are “a lot of change to throw at people.”

“Reorg, a new workflow management system, totally new review processes, and new documentation templates. This is what we did to the generics folks and it was very stressful for awhile,” Woodcock said, referring to a recent overhaul in the generic drugs program. “But we’re explaining everything to people … and moving along.”

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