Executive Summary

Amid concerns Office of New Drugs reorganization will result in sponsors receiving conflicting advice, new director offers several items already contemplated to prevent such problems.

The US FDA’s Office of New Drugs wants external stakeholder oversight to accompany standardization and other internal efforts to ensure reviewer consistency after its reorganization.

Peter Stein, announced as OND director on Dec. 7 (see sidebar), recently listed four items that should help avoid a surge in confusing or conflicting information flow once OND implements its new flatter structure.

Stein made his remarks on consistency during the Biopharma Congress IV, sponsored by Prevision Policy and the Friends of Cancer Research, on Nov. 14, after he had been chosen to head OND but before the pick was officially announced. (Also see “US FDA Office Of New Drugs Likely To Be Headed By Deputy Director Stein” – Pink Sheet, 20 Nov, 2018.)

Stein said centralized activities within the OND, such as project management and policy development, will increase consistency, but he also asked industry to call out FDA when it does not give consistent advice or a similar regulatory interpretation.

Stein’s Four Steps For Stronger Consistency

• Centralizing regulatory project management staff
• Developing Office of Policy
• Forming Medical Program and Policy Council
• Having industry flag apparent inconsistencies

Sponsors already call him asking about why advice they received was different given to similar development programs in similar situations, and Stein wants to encourage such inquiries.

“I think industry has a role in flagging where we are clearly inconsistent,” he said. “I think that’s where there’s a legitimate scientific question and really clear information to suggest that there’s really been a disconnect between how things have been done before or how things are done in one division versus another, I think flagging that is perfectly legitimate.”

Stein suggested that sponsors direct questions to the division and office director first before contacting him or Center for Drug Evaluation and Research Director (and then acting OND Director) Janet Woodcock. Stein also reiterated that he and others at FDA “do not hold grudges.”

“Getting those calls is in no way problematic,” Stein said. “We think that’s part of your role and our role to make sure we’re making the right decisions for patients.”

The proposed OND reorganization would add more divisions and offices to better balance the workload and increase the focus on therapeutic area. (Also see “Office Of New Drugs Reorg Is Bigger Than Expected: US FDA Adds 11 Review Divisions ” – Pink Sheet, 4 Jun, 2018.)

The new structure is expected to open many new leadership positions, which FDA officials already are discussing how to fill. (Also see “CDER Recruitment Wins Begin Outnumbering Losses” – Pink Sheet, 26 Nov, 2018.)

Consistency Concerns Temper Reorg Enthusiasm

Sandra Milligan, Merck & Co. Inc. SVP of global regulatory affairs and clinical safety, raised the consistency question during the conference. She said that while the reorganization will create more “scientific opportunity,” the company is “a little bit hesitant and it’s a wait and see attitude” about the move because it could lead to inconsistency in the advice offered to sponsors.

“Sometimes we do experience some inconsistency and the inconsistency could be in advice that we receive even within division with different reviewers but more particularly what comes to fruition and observation for us is between sponsors who may have similar molecules going through similar development programs,” Milligan said.

Peter Stein”We also depend on that consistency in the advice that we receive because it’s difficult to advise a certain pathway or certain probability of success for a molecule on a pathway that we are expecting that other sponsors are also going down if indeed sponsors are treated differently, whether it’s in a review, whether it’s in development advice they get, or more importantly in the labeling,” she added.

Former OND Director John Jenkins, now a principal at Greenleaf Health, said consistency across divisions has always been a challenge, and will be heightened by the growth in OND structure. Jenkins also said the shift to focus on therapeutic area may further heighten the problem.

“You really have to rely on the division leadership, you have to rely on the office leadership to provide oversight and guidance to try and ensure consistency,” he said.

“It’s one of my areas of concern, by moving to such a [therapeutic] area of focus division structure that it may actually foster more inconsistency because people will be more focused on their therapeutic area and being part of OND than being part of a regulatory organization that is bound by laws and regulations and precedents,” he added.

“I think it’s going to be a real challenge to manage that larger structure moving forward.”

Indeed, new reviewers often do not have a full grasp of FDA’s interpretation of laws and regulations or its expectations for approval, which can cause problems giving advice.

When the agency’s Office of Generic Drugs added more than 1,000 new employees following the launch of the generic drug user fee program, for example, there were complaints that new filing reviewers were not following the regulations correctly. (Also see “ANDA Refuse-to-Receive Challenges Become More Common – And More Successful” – Pink Sheet, 20 Jul, 2015.)

Policy and Program Review Council Helps Apply Precedent

Stein highlighted several planned changes expected to improve consistency that are part of the reorganization. Chief among them are centralized project management and the new policy office.

He said moving project managers out of the review divisions should help alleviate problems where sponsors with similar products receive differing advice.

“Creating a central organization was intended to have a common perspective on how we do things as well as how regulatory decisions are being made, what’s being asked of sponsors, how labeling is going forward,” Stein said.

The new OND Office of Policy, which is expected to include about 50 people at capacity, also will give division directors an outlet for questions and help ensure a common message coming out of the agency.

“I can tell you that I send emails every day to the policy group saying can you help me figure out what I’m supposed to do here and the division directors are doing the same,” Stein said. “And by coming to that common organization for how we apply policy I think that supports consistency.”

The OND policy office is headed by Keith Flanagan, who had been head of a similar group in the Office of Generic Drugs. (Also see “New OND Director Could Be Hired Within Six Months, Woodcock Says” – Pink Sheet, 7 May, 2018.)

In addition, OND also created the Medical Policy and Program Review Council, which meets weekly to discuss pressing policy and regulatory issues. The council includes high-ranking OND officials, as well as clinical-pharmacology, biostatistics and surveillance and epidemiology representatives who can relate precedents if necessary.

“What I realized very early is sorting out policy that’s programmatic is very complicated and now we don’t have to figure it out any more,” Stein said.

Woodcock has said that the OND reorganization also is focused on modernizing operations. Central project management and other changes also are expected to streamline the administrative burden of application reviews.  (Also see “CDER Safety Overhaul Planned As Review Process Modernization Continues” – Pink Sheet, 8 Jul, 2018.)

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