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Perspectives on Off-Label Use of Therapeutics in Rare Diseases

19 Mar 2025
Biochemical/Metabolic and Therapeutics
  • Accredited:
    • Accredited
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
FDA-approved specific therapy is not available to over 95% of rare diseases despite the success of the 1983 Orphan Drug Act (ODA) which provides fast-track FDA approval, marketing protection, tax incentives, and funding for clinical research in rare diseases. As a result, patients with rare genetic diseases often rely on off-label prescriptions, a prevalent practice in pediatrics. The examples include benzoate and dextromethorphan for glycine encephalopathy, albuterol for Pompe disease and empagliflozin (sodium-glucose co-transporter-2 inhibitor) for glycogen storage disease type 1b. Insurance coverage of off-label prescriptions varies widely. Some insurers may agree to cover the off-label use based on a published compendium or published evidence. However, they may deny coverage even when the use aligns with clinical guidelines. Moreover, some medications with proven effects in rare diseases, such as the chaperone therapy ambroxol (EMA-approved for mucolytic expectorant) for Parkinson’s disease, mucopolysaccharidosis type III (San Filippo disease) and Gaucher disease type 3, are not FDA-approved and cannot be prescribed or available in the US.

Drug repurposing is an attractive application of the ODA due to its lower development costs and shorter development time. However, off-label use in rare diseases without data collection mechanisms, such as a registry, would compete with the valuable opportunity to collect evidence for drug repurposing and may eventually harm the rare disease population.  

We will orient the audience on the practices of off-label use in rare genetic disorders, ODA and drug repurposing, followed by a debate (World Schools Style format) of for and against the practice of off-label prescription and finalizing with an “ask the expert” section lead by the moderators, clinicians and FDA officials:
  • An introduction to Off-label use (Mari Mori, MD)

  • Debate: Off-label use of FDA-approved drugs.

    • Pro (for off-label prescription)

      • Eva Morava, MD, PhD.

      • Jennifer Malin, MD.

      •  
      Against

      • Dwight Koeberl, MD, PhD.

      • Ameet Sarpatwari, PhD, JD 

      •  
      Ask The Experts.

      • An open forum and round table discussion between the audience, the clinicians involved in the debate and regulatory body officers.

        • Kerry Jo Lee, MD. Associate Director for Rare Diseases, Center for Drug Evaluation and Research (CDER).

        • Catherine Pilgrim-Grayson, MD, MPH. Acting Director, Division of Rare Diseases and Medical Genetics, CDER


          •  
      Consistent with ACMG’s commitment to Diversity, Equity, and Inclusion, the presenters are from varying institutions across the United States, of both genders and varying ethnicities, and include senior and junior faculty members and important stakeholders within the field.

      •  
    NOTE: This session is on behalf of the ACMG Therapeutics Committee.

Learning Objectives

  1. Recognize the status of drug repurposing for rare diseases
  2. Discuss the limitations encountered when considering off-label drug use for rare diseases
  3. Differentiate the benefits and risks when considering off-label drug use for rare diseases
  4. Distinguish the differences between drug repurposing and off-label use
  5. Outline the needed data when considering a project involving drug repurposing or off-label use
  6. Summarize the steps towards the process of drug repurposing through regulatory entities
  7. Apply the skills obtained towards a more efficient drug repurposing process

Agenda

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