ACoP7 Pre-conference Survey: “The Challenging Course of Pediatric Drug Development: What is the Role of Clinical Pharmacology and Pharmacometrics in Bringing New Medicines to this Special Population?”

[isoplinks]

ISoP is developing a pre-conference session focusing on the unique challenges and opportunities facing model-based approaches in guiding pediatric development programs for new medicines. We would like your feedback to help us understand what the key issues are facing the pharmacometrics community involved in pediatric drug development.

We have prepared a short survey that will help us understand your key issues.

1. How many years of post-graduate experience in pharmaceutical sciences do you have?

• None (currently a student)
• < 5 years
• 5 to 10 years
• 10 to 20 years
• 20 years or more

2. In which sector did you spend most of your post-graduate experience in pharmaceutical sciences?

• Academia
• Industry
• Regulatory
• CRO
• Other

3. How many pediatric development or pediatric clinical pharmacology programs have you been involved in?

• 0
• 1
• 2
• 3
• 4
• 5 or more

4. How many pediatric programs have you prepared “Pediatric Study Plans” or “Pediatric Investigation Plans” for?

• 0
• 1
• 2
• 3
• 4
• 5 or more

5. Among the pediatric programs you have been involved with, how often were pharmacometrics approaches employed?

• Always
• Often
• Sometimes
• Rarely
• Never

6. What types of pharmacometric analyses were used in your pediatric programs? (choose all that apply)

• Population pharmacokinetic analysis
• Quantitative Systems Pharmacology
• Physiologically based pharmacokinetic modeling
• Population pharmacokinetic-pharmacodynamic analysis using a biomarker
• Exposure-response analysis using clinical endpoint
• Disease-progression modeling
• Health Economic/Outcome Research
• Other

7. How often do the pediatric studies you are involved with fail to enroll completely?

• Always
• Often
• Sometimes
• Rarely
• Never

8. How often do you experience resistance to using pharmacometric approaches in your pediatric programs?

• Always
• Often
• Sometimes
• Rarely
• Never

Below is the pediatric study decision tree from the Dunne paper published in 2011 [Pediatrics 2011;128:e1242–e1249], which was adapted from “Guidance for Industry: Exposure-Response Relationships: Study Design, Data Analysis, and Regulatory Applications. Washington, DC: Food and Drug Administration; 2003”

9. Since the publication of Pediatric Study Decision Tree in 2003, roughly what percentage of your pediatric programs used each option described

Option A. No Extrapolation

• 0%
• 20%
• 40%
• 60%
• 80%
• 100%

Option B. Partial Extrapolation

• 0%
• 20%
• 40%
• 60%
• 80%
• 100%

Option C. Full Extrapolation

• 0%
• 20%
• 40%
• 60%
• 80%
• 100%

10. For the pediatric programs that were based on “Option A: no extrapolation”, what type of safety and efficacy trials were conducted in children? (multiple Choices allowed)

• Non-inferior efficacy study
• Superior efficacy study
• Non-inferior safety study
• Superior safety study
• other

11. Is the concept of “extrapolation” in the Pediatric Study Decision Tree according to the FDA or EMA guidelines, clearly understood by the pediatric team members within your organization?

• Yes
• No

12. If you answered “no” to the question above, please provide further details on what area(s) would benefit from further clarity (click reply and type your input below).

13. What area(s) should be updated in Pediatric Study Decision Tree published in 2003 based on emerging science and knowledge? (click reply and type your input below)

14. Are there any key topics or challenges in pediatric drug development or pediatric clinical pharmacology research that you would like to include at this pre-conference? (click reply and type your input below)

15. What is the most frustrating issue you’ve faced in developing or studying drugs in children? (click reply and type your input below)

Thank you for your time and help!

Wonkyung Byon, PhD
Brenda Cirincione, PhD

[Brian]

15. What is the most frustrating issue you’ve faced in developing or studying drugs in children? (click reply and type your input below)

One frustrating element is the difficulty in enrolling pediatric patients in a timely manner,and for some age groups, inability to enroll at all. In many cases, given the paucity of data that eventually is available for some age groups, model-informed estimates are the best that can be done.

[n.holford]

Key challenge is the failure of pediatricians and pharmacometricians to recognize that children are small adults.

[janet.wade]

Relucatnce to measure biomarker in paediatric study. Reasons cited were cost and time it took to turn round biomarker assay so that biomarker results were not available in time to influence future dosing in paediatric study.

[paul]

ating issue you’ve faced in developing or studying drugs in children? (click reply and type your input below)

The requirement by regulators of properly powered studies (and placebo controlled?) in a challenging to recruit and vulnerable patient population with ethical considerations that do not sit well together

[amukherjee10]

• The extrapolation tree and study design requirements need to be applied consistently across disease areas
  -the requirement of placebo control places a signfiicant enrollment challenge. from a parent’s perspective there is no reason to enroll a child with active disease in a trial where they may get placebo when they can be prescribed active drug

[jingliu2012]

Concur with others comments on the challenge of pediatric subject recruitment for placebo controlled trials. Clin Pharm and Pharmacometrics can play an important role in evaluating the extrapolation of efficacy from adults to pediatrics with concerted efforts from regulatory, sponsors and academic and health insitutions. Currently the extrapolation has been established in very few limited indications, and it should be expanded to other disease areas.

[jingliu2012]

Re Pediatric Study Decision Tree, it seems that under all the options, the pediatric PK study is a default. From ethnic point of view, the pediatric PK study provides limited benefit to the subjects. In addition, the pediatric PK study may add a few years to the pediatric drug development and patient acess timeline. Given the progress in pediatric PK understanding, e.g. confidence in PK extrapolation to adolescents and PK extrapolation for renally eliminated compounds, could the PK extrapolation be the supporting evidence in stead of a Phase I pediatric study for all options in the decision Tree?

[anasuya.hazra]

Agree with Jing’s comment on challenges associated with a dedicated PK study. From time to time however, we’ve heard (presentations from the agency) that such studies are not absolutely necessary as long as sponsors are able to show that PK in children can be well predicted from adults with further corroboration from a small PK cohort within an efficacy study. Thus, examples of such cases would be greatly appreciated emphasizing that the latter approach can be well accepted.

Within a same topic, but with a bit different direction; if PK of a drug candidate in pediatric population is different (CL in a 70 kg adolescent is different than CL in a 70 kg adult), should we label this case as not “extrapolatable”? Assuming extrapolation of efficacy is still reasonable i.e. it is believed that potency of the compound in adult vs. children did not change based on literature data.