Hello Regulatory Scientists,

Today, let’s explore the journey of Qsymia (phentermine and topiramate extended-release) from receiving an FDA Complete Response Letter (CRL) to gaining approval. This case offers valuable insights and lessons that can be applied by companies developing new drugs today.

Regulatory History and Initial Submission

Drug: Qsymia (phentermine and topiramate extended-release) Mechanism of Action: Combination of phentermine, an appetite suppressant, and topiramate, an anticonvulsant with weight-loss side effects Indication: Obesity management in conjunction with a reduced-calorie diet and increased physical activity Initial Submission Date: December 2009

The Complete Response Letter (CRL)

CRL Date: October 2010

CRL Concerns:

1. Cardiovascular Safety: Concerns about potential cardiovascular risks, including increased heart rate and blood pressure.
2. Teratogenicity: Risks related to birth defects, given topiramate’s known teratogenic effects.
3. Long-term Safety Data: The need for more extensive long-term safety data to fully understand the drug’s profile.
4. Post-Marketing Requirements: The FDA required a robust plan for post-marketing studies to monitor safety.

Resubmission Strategy

Vivus, the company behind Qsymia, implemented a strategic plan to address the FDA’s concerns:

1. Additional Clinical Trials: Conducted further studies to gather more data on cardiovascular and long-term safety.
2. Risk Management Plans: Developed comprehensive risk management strategies, including restricted distribution and patient education to mitigate teratogenic risks.
3. Labeling Revisions: Made labeling changes to reflect the safety concerns and usage guidelines accurately.
4. Engagement with Advisory Committees: Leveraged FDA Advisory Committee meetings to review and discuss the data and strategies.

Resubmission Date: October 2011

Outcome

Approval Date: July 2012 Qsymia was approved with a Risk Evaluation and Mitigation Strategy (REMS) to manage the identified risks, particularly focusing on teratogenicity and cardiovascular safety.

Lessons Learned

The Qsymia resubmission journey highlights several key lessons for drug developers:

1. Addressing Safety Concerns Head-On: Vivus’s success was largely due to their proactive approach in conducting additional safety studies and developing robust risk management plans.
2. Importance of Risk Management: Developing and implementing comprehensive risk management strategies is crucial, particularly for drugs with known safety concerns.
3. Effective Communication: Maintaining transparent and ongoing communication with the FDA helps align resubmission efforts with regulatory expectations.
4. Utilizing Advisory Committees: Leveraging advisory committees can provide critical insights and help validate the approach to addressing FDA concerns.

Relevance for Current Drug Developers

For companies developing drugs today, the Qsymia case underscores the importance of strategic planning and risk management in the regulatory process. Here are some takeaways to help avoid a CRL and achieve first-cycle approval:

1. Thorough Pre-Submission Preparation: Ensure all safety and efficacy data is robust and comprehensive before submission.
2. Proactive Risk Management: Identify potential risks early and develop strategies to mitigate them effectively.
3. Engage with the FDA Early and Often: Regular interactions with the FDA can provide valuable guidance and help steer the development process.
4. Utilize Advisory Committees: Seek feedback from advisory committees to validate data and address potential concerns.
5. Invest in Quality Data: Prioritize the collection of high-quality, long-term safety and efficacy data to support the submission.
6. By learning from the Qsymia resubmission experience, current drug developers can better navigate the regulatory landscape, avoid common pitfalls, and increase the likelihood of a successful first review cycle approval.

Stay strategic and proactive,

CERES Regulatory Services