FDA committees conclusions on the open meeting on achondroplasia

On the 11th May 2018, the FDA (US Food & Drug Administration) held an open session with the Pediatric Advisory Committee (PAC)

and the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to identify and discuss important elements of drug development programs for products intended for the treatment of achondroplasia (ACH).

The meeting was divided into two sessions, one closed to the public and the other open for public participation. In the closed session, the committees discussed the clinical development program for a specific investigational new drug. In the open session, the committees discussed general considerations for ACH drug development programs, including clinically meaningful outcome measures, the age of patients who might benefit most, study designs, and duration of pivotal trials. The open session included an open public hearing and Fundación ALPE participated and presented a statement in this open session, by Estefánia González. The report of ALPE participation can be read here



Image 1. Aiden Cockrell, a young boy from the USA, before speaking at the open session


Minutes of the meeting

Recently, FDA published the full document of the minutes of the open meeting and these were the more relevant conclusions for the questions asked:


Question 1. Considering the various manifestations and complications of abnormal bone growth in ACH, discuss potential clinically meaningful study endpoints in the development of drug product(s) for ACH.

  • The annualized growth velocity (AGV) is a reasonable primary endpoint for clinical trials in ACH, but that data on final adult height should be obtained to validate long-term clinical efficacy.
  • Strategies for obtaining these data were discussed, such as implementing a post-marketing study requirement or a registry.
  • Proportionality should be assessed as a secondary objective.
  • Height is the simplest and most reliable measure.
  • The inclusion of validated instruments to assess improvements in quality of life and activities of daily living as important outcome measures.
  • Secondary endpoints would need to be stratified by age

Question 2. Comment on whether there is a pediatric age-specific subpopulation that should receive priority for investigation of drug treatment. If no, provide rationale.

  • The sub-population of children less than 2 years of age with ACH should be the priority for study.
  • The greatest benefit for patients with ACH may be through improvement in early growth parameters.
  • Conducting trials in younger children during a critical period of growth may be the most informative and impactful.
  • If AGV is targeted, the duration of study may be shorter and sample sizes smaller, given that growth occurs rapidly in this age group.
  • IS very importance acquiring comprehensive and consistent post-marketing data to assess long-term safety.
  • A consensus was reached on conducting parallel studies, rather than sequentially studying each age group. For example: conducting a phase 2 study in younger children simultaneously with a phase 3 study in older children.

Question 3. Discuss the design(s) of clinical trial(s) that will generate a robust evaluation of the efficacy and safety of study drug(s) in the intended population(s). Consider whether a randomized placebo-controlled trial is required to allow for such evaluation(s). Discuss the strengths and limitations of the proposed trial design(s).

  • The committee reached a consensus that a randomized, blinded, placebo-control trial design is critical for the evaluation of efficacy and safety for products intended to treat ACH.
  • Approving a product without a placebo-controlled, blinded trial that categorically establishes efficacy would be unethical and would be a disservice to the ACH population.
  • For the placebo-controlled trial, the Committee suggested using specific design elements, such as 2:1 randomization or cross-over after an appropriate (but unspecified) interval to help mitigate patients’ concerns regarding prolonged placebo.

Question 4. Considering the discussions above (in particular, selection of efficacy endpoint(s) and trial design), comment on the required duration of a clinical trial(s) that will allow for an adequate assessment of long-term efficacy and safety of the drug. In your discussion, consider durations for core, extension and post-marketing phases of the trial(s).

  • The duration of the study should be at least 2 years to obtain adequate growth data.


After this FDA open session, in which both committees heard from patients, relatives, clinicians and patient organizations about what is in fact, to live with achondroplasia and what are the major concerns on clinical trials for ACH, the Committees have withdrawn the previous relevant conclusions. We look forward that these conclusions and indications will positively influence FDA next deliberations towards the preparation and design of the next clinical trials for medicines for achondroplasia.