Clinical Trials for Diabetes  Yeong-Liang Lin, MD, MS Center for Drug Evaluation
Background <ul><li>Metabolic disorder characterized by hyperglycemia, relative or absolute insulin deficiency and developm...
Type 1 Diabetes <ul><li>Insulin deficiency </li></ul><ul><li>Result from a cellular autoimmune destruction of  β  cells of...
Type 2 Diabetes <ul><li>Insulin resistance and relative deficiency </li></ul><ul><li>Most patients have obesity-related in...
Present treatment <ul><li>Insulin  </li></ul><ul><li>Sulfonylureas </li></ul><ul><li>α -glucosidase inhibitors </li></ul><...
Clinical Trials  <ul><li>Studies concerning blood sugar </li></ul><ul><li>Long term outcome studies </li></ul>
Consideration  <ul><li>Efficacy endpoint </li></ul><ul><li>Patient population </li></ul><ul><li>Inclusion/exclusion </li><...
Efficacy Endpoint <ul><li>Hemoglobin A1c </li></ul><ul><li>Fasting plasma glucose </li></ul><ul><li>Responder rate  </li><...
HbA1c <ul><li>Most widely accepted measure of long-term control of blood glucose </li></ul><ul><li>Average glucose levels ...
Plasma Glucose <ul><li>Real time measurement </li></ul><ul><li>8-point plasma glucose profile </li></ul><ul><li>Detection ...
Responder Rate <ul><li>Proportion of subjects achieving a pre-defined HbA1c value </li></ul><ul><li>7% frequently used </l...
Responder <ul><li>Reduction of 0.7% units in HbA1c  </li></ul><ul><li>Decrease of fasting glucose of 30 mg/dL from baselin...
Reduction in Insulin Dose <ul><li>Rate of elimination of insulin use </li></ul><ul><li>Reduction in insulin dose accompani...
Insulin Antibody <ul><li>Proportion of subjects developing insulin antibody </li></ul><ul><li>Related to efficacy </li></ul>
Population <ul><li>Clinical trial population representative of the target population </li></ul><ul><li>Body mass index def...
Inclusion <ul><li>Types  </li></ul><ul><li>Body mass index,  </li></ul><ul><li>HbA1c, usually  ≥ 6.5% and ≤ 11% </li></ul>...
Exclusion <ul><li>Pregnant or nursing women </li></ul><ul><li>Daily insulin doses too high, e.g. 100U </li></ul><ul><li>Tr...
Duration <ul><li>Run in period, usually 4 weeks </li></ul><ul><li>- to ensure subject eligibility </li></ul><ul><li>Titrat...
Long Term Effectiveness <ul><li>Improvement of HbA1c durable for 12 months </li></ul>
Control <ul><li>Use of placebo  </li></ul><ul><li>- duration not jeopardizing patient safety </li></ul><ul><li>- low start...
Withdrawal Criteria <ul><li>Withdrawal due to inadequate efficacy </li></ul><ul><li>- Plasma glucose higher than a pre- </...
Concomitant Medication <ul><li>Antihypertensive drugs </li></ul><ul><li>Lipid lowering drugs </li></ul>
Confirmatory Clinical Trials <ul><li>Randomized </li></ul><ul><li>Double blind </li></ul><ul><li>Placebo controlled  </li>...
Safety  <ul><li>Safety monitoring according to individual safety profile </li></ul><ul><li>Hypoglycemic episode – severity...
Insulin <ul><li>Hypoglycemia </li></ul><ul><li>Insulin antibody </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Tumor...
OHA <ul><li>Hypoglycemia </li></ul><ul><li>Liver dysfunction  </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Heart f...
Hypoglycemia <ul><li>Symptomatic hypoglycemia </li></ul><ul><li>Severe symptomatic hypoglycemia </li></ul><ul><li>Nocturna...
Demonstration of Efficacy  <ul><li>Efficacy will be demonstrated by </li></ul><ul><li>Noninferiority of study drug to appr...
Demonstration of Safety <ul><li>Safety will be demonstrated by </li></ul><ul><li>Incidence of TEAE, especially SAE, compar...
Conclusion <ul><li>Efficacy including long term efficacy </li></ul><ul><li>Safety </li></ul><ul><li>Other supportive evide...
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Clinical Trials For Diabetes

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Clinical Trials For Diabetes

  1. 1. Clinical Trials for Diabetes Yeong-Liang Lin, MD, MS Center for Drug Evaluation
  2. 2. Background <ul><li>Metabolic disorder characterized by hyperglycemia, relative or absolute insulin deficiency and development of vascular diseases </li></ul><ul><li>Two major types with several less common forms </li></ul><ul><li>Diagnosed by random plasma glucose greater than 200 mg/dL, fasting plasma glucose greater than 126 mg/dL or 2-hour glucose greater than 200 mg/dL in 75-g oral glucose tolerance study </li></ul>
  3. 3. Type 1 Diabetes <ul><li>Insulin deficiency </li></ul><ul><li>Result from a cellular autoimmune destruction of β cells of the pancreas </li></ul><ul><li>Islet autoantibodies </li></ul>
  4. 4. Type 2 Diabetes <ul><li>Insulin resistance and relative deficiency </li></ul><ul><li>Most patients have obesity-related insulin resistance </li></ul><ul><li>Others have increased visceral adiposity </li></ul><ul><li>Genetic predisposition </li></ul><ul><li>Risk factors include age, obesity and gestational diabetes </li></ul>
  5. 5. Present treatment <ul><li>Insulin </li></ul><ul><li>Sulfonylureas </li></ul><ul><li>α -glucosidase inhibitors </li></ul><ul><li>Thiozolidinediones </li></ul><ul><li>Biguanides </li></ul>
  6. 6. Clinical Trials <ul><li>Studies concerning blood sugar </li></ul><ul><li>Long term outcome studies </li></ul>
  7. 7. Consideration <ul><li>Efficacy endpoint </li></ul><ul><li>Patient population </li></ul><ul><li>Inclusion/exclusion </li></ul><ul><li>Duration </li></ul><ul><li>Control </li></ul><ul><li>Withdrawal criteria </li></ul><ul><li>Safety monitoring </li></ul>
  8. 8. Efficacy Endpoint <ul><li>Hemoglobin A1c </li></ul><ul><li>Fasting plasma glucose </li></ul><ul><li>Responder rate </li></ul><ul><li>Reduction in insulin dose </li></ul><ul><li>Lipid profile </li></ul><ul><li>Body weight change </li></ul><ul><li>Insulin antibody </li></ul>
  9. 9. HbA1c <ul><li>Most widely accepted measure of long-term control of blood glucose </li></ul><ul><li>Average glucose levels in previous 2 to 3 months </li></ul><ul><li>Strongly associated with vascular complications </li></ul><ul><li>Effect size </li></ul><ul><li>Margin </li></ul>
  10. 10. Plasma Glucose <ul><li>Real time measurement </li></ul><ul><li>8-point plasma glucose profile </li></ul><ul><li>Detection of hypoglycemia and adjustment of treatment dose </li></ul><ul><li>Secondary endpoint </li></ul>
  11. 11. Responder Rate <ul><li>Proportion of subjects achieving a pre-defined HbA1c value </li></ul><ul><li>7% frequently used </li></ul><ul><li>If other values are used, pre-define by the applicant </li></ul><ul><li>Secondary endpoint </li></ul>
  12. 12. Responder <ul><li>Reduction of 0.7% units in HbA1c </li></ul><ul><li>Decrease of fasting glucose of 30 mg/dL from baseline </li></ul>
  13. 13. Reduction in Insulin Dose <ul><li>Rate of elimination of insulin use </li></ul><ul><li>Reduction in insulin dose accompanied by improvement in symptoms </li></ul><ul><li>Secondary endpoint </li></ul>
  14. 14. Insulin Antibody <ul><li>Proportion of subjects developing insulin antibody </li></ul><ul><li>Related to efficacy </li></ul>
  15. 15. Population <ul><li>Clinical trial population representative of the target population </li></ul><ul><li>Body mass index defined </li></ul><ul><li>Range of HbA1c specified, determined by the efficacy evidence </li></ul><ul><li>Range of fasting plasma glucose </li></ul><ul><li>Severity of disease defined </li></ul><ul><li>Pre-study treatment </li></ul>
  16. 16. Inclusion <ul><li>Types </li></ul><ul><li>Body mass index, </li></ul><ul><li>HbA1c, usually ≥ 6.5% and ≤ 11% </li></ul><ul><li>Duration of diabetes, must be examined at the analysis stage </li></ul><ul><li>Fasting C-peptide </li></ul><ul><li>Pre-study treatment </li></ul>
  17. 17. Exclusion <ul><li>Pregnant or nursing women </li></ul><ul><li>Daily insulin doses too high, e.g. 100U </li></ul><ul><li>Treatment with steroids </li></ul><ul><li>Impaired liver function, e.g. ALT 2.5 times ULN </li></ul>
  18. 18. Duration <ul><li>Run in period, usually 4 weeks </li></ul><ul><li>- to ensure subject eligibility </li></ul><ul><li>Titration period </li></ul><ul><li>- titrate according to plasma glucose to </li></ul><ul><li>achieve normoglycemia </li></ul><ul><li>Maintenance period, 12 weeks or longer </li></ul><ul><li>- to evaluate efficacy and risk of </li></ul><ul><li>hypoglycemia </li></ul>
  19. 19. Long Term Effectiveness <ul><li>Improvement of HbA1c durable for 12 months </li></ul>
  20. 20. Control <ul><li>Use of placebo </li></ul><ul><li>- duration not jeopardizing patient safety </li></ul><ul><li>- low starting HbA1c </li></ul><ul><li>- clear withdrawal criteria </li></ul><ul><li>Use of active control </li></ul><ul><li>- longer duration allowed </li></ul><ul><li>- more severe patients allowed </li></ul><ul><li>- clear withdrawal criteria </li></ul><ul><li>- selection of control </li></ul>
  21. 21. Withdrawal Criteria <ul><li>Withdrawal due to inadequate efficacy </li></ul><ul><li>- Plasma glucose higher than a pre- </li></ul><ul><li>defined value, e.g. higher than 400 </li></ul><ul><li>mg/dL </li></ul><ul><li>Withdrawal due to safety concern </li></ul><ul><li>- Frequent hypoglycemia episode </li></ul><ul><li>- Development of LVH by ECG </li></ul><ul><li>- Decline of pulmonary function </li></ul>
  22. 22. Concomitant Medication <ul><li>Antihypertensive drugs </li></ul><ul><li>Lipid lowering drugs </li></ul>
  23. 23. Confirmatory Clinical Trials <ul><li>Randomized </li></ul><ul><li>Double blind </li></ul><ul><li>Placebo controlled </li></ul><ul><li>Demonstration of superiority of the study drug over a placebo in a study of no less than 3 months duration, using HbA1c as the primary endpoint </li></ul>
  24. 24. Safety <ul><li>Safety monitoring according to individual safety profile </li></ul><ul><li>Hypoglycemic episode – severity and frequency </li></ul><ul><li>Cardiovascular function – QT interval </li></ul><ul><li>Laboratory findings – liver function </li></ul><ul><li>Other adverse events </li></ul>
  25. 25. Insulin <ul><li>Hypoglycemia </li></ul><ul><li>Insulin antibody </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Tumor formation, unlikely to be monitored by clinical trials </li></ul><ul><li>Lung function </li></ul>
  26. 26. OHA <ul><li>Hypoglycemia </li></ul><ul><li>Liver dysfunction </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Heart failure </li></ul><ul><li>Lactic acidosis </li></ul>
  27. 27. Hypoglycemia <ul><li>Symptomatic hypoglycemia </li></ul><ul><li>Severe symptomatic hypoglycemia </li></ul><ul><li>Nocturnal hypoglycemia </li></ul>
  28. 28. Demonstration of Efficacy <ul><li>Efficacy will be demonstrated by </li></ul><ul><li>Noninferiority of study drug to approved drugs, based on change in HbA1c </li></ul><ul><li>Equivalent glycemic control to the comparator with long term administration </li></ul><ul><li>Efficacy maintained irrespective of BMI, age, sex and race </li></ul>
  29. 29. Demonstration of Safety <ul><li>Safety will be demonstrated by </li></ul><ul><li>Incidence of TEAE, especially SAE, comparable in pooled study drug and pooled comparator groups </li></ul><ul><li>Incidence of hypoglycemic event, sequelae of hypoglycemic event including seizure, diabetic ketoacidosis, injection site reaction, systemic hypersensitivity </li></ul>
  30. 30. Conclusion <ul><li>Efficacy including long term efficacy </li></ul><ul><li>Safety </li></ul><ul><li>Other supportive evidence </li></ul>

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