Monday, September 27, 2021

Advancing the Development of Pediatric Therapeutics (ADEPT) - FDA Workshops on Pediatric Drug Developments

Each year, the FDA's Division of Pediatrics and Maternal Health in collaboration with the University of Maryland CERSI organized an annual public workshop to discuss the issue related to pediatric drug development. Starting in 2014, it has organized 7 public workshops (no event for 2020 due to Covid-19). 

           Advancing the Development of Pediatric Therapeutics (ADEPT)



Complex Innovative Trial Design

"Advancing the Development of Pediatric Therapeutics Innovative Trail Design"



Pediatric Patient Perspectives


Pediatric Clinical Trial Endpoints for Rare Diseases With a Focus on Pediatric Patient Perspectives

NOVEMBER 12, 2019



Pediatric Pharmacovigilance

Advancing Pediatric Pharmacovigilance Public Workshop

AUGUST 13, 2018



Big data


Application of "Big Data" to Pediatric Safety Studies



Long-Term Pediatric Safety Studies

Successes and Challenges of Performing Long-Term Pediatric Safety Studies:

Pediatric Drug Development Regulatory Considerations

International Collaborations in Pediatrics: FDA and EMA growing together

International Considerations for Pediatric Master Protocols




Long-term Neurocognitive Development in Pediatrics

Evaluation of Long-term Neurocognitive Development in Pediatrics



Pediatric Bone Health


For this year (2021), the 2-day public workshop was titled “Advancing the Development of Pediatric Therapeutics Complex Innovative Trial Design”. The purpose of the workshop was to discuss opportunities for leveraging complex and innovative trial designs, understand the challenges with their applications, and develop solutions on how challenges in the designs can be overcome. 

The workshop specifically focused on two topics of interest: 
  • bridging biomarkers in pediatric extrapolation 
  • Bayesian techniques in pediatric studies. 
In addition, the workshop allowed for an open dialogue around the use of these approaches among regulators, industry, academia, and patient organizations.

The presentation slides & webcast video links from the workshop are now all available.

SEPTEMBER 1 - 2, 2021


Saturday, September 11, 2021

Afghan Withdrawal and Accelerated Approval for Aduhelm

These two topics seem to be irrelevant at all, but have one thing in common: changing the subjects when the decision is questioned.

For the US withdrawal from Afghanistan, the decision to withdraw from two decades of war is the right decision and welcomed by the majority of the Americans. However, the execution of the withdrawal was a disaster. The execution of the withdrawal is not properly planned, botched, entirely a failure no matter how the Biden administration tries to spin and change the subject. When questioned by the reporters, the Biden administration keeps mentioning how correct the decision of withdrawal from Afghanistan is and avoids mentioning why the execution of the withdrawal goes so wrong.
Changing the subject is also the theme in the controversial approval of Aduhelm for the treatment of Alzheimer's disease through the 'accelerated approval' pathway. The full story of the Aduhelm approval is very well captured in a New York Times article "How an Unproven Alzheimer's Drug Got Approved" and ‎NEJM Interview: Dr. Gil Rabinovici on the FDA’s controversial approval of a new treatment for Alzheimer’s disease. on Apple Podcasts

'Accelerated approval' is a valid pathway for approving a drug based on the surrogate endpoint without waiting for the results from the lengthy confirmatory trial to demonstrate the clinical benefit.  "Accelerated approval" was one of the regulatory approval pathways listed in FDA's guidance for industry "Expedited Programs for SeriousConditions – Drugs and Biologics"

Facing the mounting criticisms, FDA officials published the papers to defend their decision - Approval of Aduhelm through the 'accelerated approval' pathway is the right decision. They changed the subject here. Rather than arguing if approval of Aduhelm is the right decision, they argued if 'accelerated approval' is an appropriate approval pathway. 
The controversy is not about 'accelerated approval', it is about how the 'accelerated approval' is used in the approval of Aduhelm. 

Accelerated approval is appropriate if the following qualifying criteria are met: 
  • Serious Condition
  • Meaningful Advantage Over Available Therapy
  • Demonstrates an Effect on an Endpoint That Is Reasonably Likely to Predict Clinical Benefit
In Aduhelm's situation, the third criterion was not met. The two confirmatory trials had already been completed and indicated the inclusive results in clinical benefit. There is no evidence to conclude the biomarker (beta-amyloid) will be 'reasonably likely to predict clinical benefit.' 

'Accelerated approval' is a valid pathway for drug approval for a serious condition, however, it can't be applied to a drug approval:
  • as a remedy approach (when clinical benefit had been shown to be inclusive)
  • retrospectively applied (when the lengthy confirmatory trials had already been completed)
  • against the pre-specification rule (i.e., accelerated approval pathway had been discussed and agreed with the agency prior to the BLA/NDA submission)
  • for pivotal studies that had been discontinued early due to futility 
  • based on results largely from the post-hoc, sub-group analyses
  • against the consensus objection from the FDA advisory committee members. 

No wonder there are so many controversies after FDA's decision to approve Aduhelm, The story is continuing,...
The New York Times (9/2, Belluck) reports two congressional committees “investigating the controversial federal approval of Biogen’s Alzheimer’s drug, Aduhelm [aducanumab], demanded extensive information and documents from the Food and Drug Administration in a letter released on Thursday, making it clear that the committees’ leaders are troubled by unusual actions the agency took in the course of evaluating and approving the drug.” The letter said the agency “granted accelerated approval for the drug despite concerns raised by experts – including the agency’s own staff’ and members of its independent advisory committee. ... We are also concerned by reports of unusual coordination between F.D.A. and Biogen throughout the drug’s approval process.” The Times adds, “While some Alzheimer’s experts did support the approval, given that there are so few therapies available for the devastating condition, many are concerned that the evidence does not convincingly show the drug can provide any benefit. There is also concern because the medication can cause brain swelling or brain bleeding.”
Afgan Withdrawal: the decision is right, execution is not!
Aduhelm Approval: accelerated approval is a valid pathway, the application of accelerated approval in Aduheml approval is not!