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Final Guidance on Expedited Drug Programs Details New Flexibility in Manufacturing and Quality Data

May 30, 2014

The FDA can exercise flexibility on the quality manufacturing information it requires drugmakers to present under expedited drug approval processes, says a final guidance.

This flexibility is a new element in the guidance, released Thursday, that provides details of the FDA’s four expedited programs and aims to help drugmakers determine whether their products are likely candidates for them. They are:

  • Fast track designation, which provides more frequent meetings with the FDA to discuss a drug’s development plan and ensure the collection of appropriate data to support approval;

  • Accelerated approval, which bases approval not on a clinical endpoint but on an agreed upon surrogate marker, such as  blood test or urine marker believed to be indicative of a disease state and treatment effect;

  • Priority review, which has the FDA act on a drug application within six months instead of 10 months for standard review; and

  • Breakthrough therapy designation, which provides the same benefits of a fast track designation as well as a commitment from FDA’s review staff to work closely with the sponsors through drug development and review process.

The final guidance follows a June 2013 draft guidance.

While sponsors must ensure the availability of quality product at the time of approval, the FDA said it will provide some leeway on certain manufacturing information, including stability updates, validation strategies, inspection planning and manufacturing scale-up.

The level of flexibility the FDA will offer when considering manufacturing and product quality submissions will be determined on a case-by-case basis, and include factors such as: (1) product characteristics, (2) seriousness of the condition and medical need, (3) manufacturing processes, (4) the robustness of the sponsor’s quality system, and (5) the strength of the sponsor’s risk-based quality assessment.

Other changes in the final guidance include clarifications on qualifying criteria for breakthrough therapy designations, as well as examples of surrogate and intermediate-clinical endpoints used to support accelerated approval.

To support a breakthrough therapy designation, the preliminary evidence must show that a drug demonstrates substantial improvement over available therapy or has an important advantage, the FDA said.

The final guidance also includes a new definition for demonstrating substantial improvement. It states, “If there is no available therapy, the new drug shows a substantial and clinically meaningful effect on an important outcome when compared with a placebo or a well-documented historical control.”

Examples of surrogate and intermediate-clinical endpoints to support accelerated approval include:

  • Clearance of bacteria from the blood stream as evidenced by a laboratory measurement has been considered reasonably likely to predict the clinical resolution of infection; and

  • Radiographic evidence of tumor shrinkage in certain cancer types has been considered reasonably likely to predict an improvement in overall survival.

In addition, the guidance details FDA’s thinking on submissions of portions of an application.

“FDA has determined that it is appropriate for a drug designated as a breakthrough therapy to be able to obtain rolling review,” the guidance says. “Therefore, if FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a breakthrough therapy product may be effective, the agency may consider reviewing portions of a marketing application before the sponsor submits the complete application.”

Janet Woodcock, MD, director of CDER, touted the final guidance and the FDA’s success with the expedited programs. The breakthrough designation, created under the 2012 FDA Safety and Innovation Act, has been a “virtually overnight success,” she wrote in a May 29 blog posting.

As of May 5, the agency has received 186 requests for the designation and granted 48 of them, she said. Six drugs have been approved, including a late-stage lung cancer drug that gained clearance four months ahead of its target date by using evidence from a trial with 163 patients, Woodcock said.

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