1. Diabetes Management: a Regulatory view
Luca Pani
10-11 giugno 2013

2. Public Declaration of transparency/interests*
Interests in pharmaceutical industry NO
Currently
Last 2 years
More than 2 years but less than 5 years ago
More than 5 years ago
(optional)
Direct interests:
Employment with a company X
Consultancy for a company
Strategic advisory role for a company
Financial interests
Ownership of a patent
Indirect interests:
Principal investigator
Investigator
Individual’s Institution/Organisation receives a grant or other funding
CME Courses
*Luca Pani, in accordance with the Conflict of Interest Regulations approved by AIFA Board of Directors ( ) and published in the Italian Government Official Journal on according to 0044 EMA/513078/2010 on the handling of the conflicts of interest for scientific committee members and experts
Note: For this presentation I am not receiving any compensation

3. Diabetes: not only a clinical problem
Type 2 diabetes is the most common metabolic disease in Italy and in developed countries.
It is the sixth leading chronic disease by diffusion with a crude prevalence of about 4.9%.
It is estimated that about 3,500,000 Italians suffer from this pathology.
The WHO estimates that every ten seconds a person dies for a disease related to diabetes

4. Incretin-based therapies
The new class of Incretin-based therapies entered the arena, but their place in therapy remains difficult to determine because of limited long-term clinical data on both effectiveness and safety, and the high cost of therapy.
Both GLP-1 receptor agonists and inhibitors of DPP-4 produce an improvement in glycemic control similar to other second-line therapies, but show some additional advantages with respect to weight gain and overall hypoglycemia.

5. Incretin-based therapies expenditure
According to the OsMed report January-December 2012 on “The use of medicines in Italy”, the Incretin-based therapies expenditure is significantly increased.

6. Efficacy
Incretin-based therapies have a innovative mechanism of action but they have not demonstrated a better efficacy than therapeutic alternatives, as shown by meta-analysis or clinical studies.

7. Safety
In the clinical studies were reported ADRs including gastrointestinal symptoms (nausea, vomiting), hypoglycemia, increase of pancreatic enzymes and pancreatitis, rhinitis, nasopharyngitis and kidney damage.

8. Safety

9. Safety

10. Safety

11. Safety

12. International recommendations
The main recommendation is to differentiate the target of HbA1c according to the characteristics of the patient (less stringent in the complex/fragile patient) and use the most appropriate hypoglycemic drug.
Inzucchi SE et Al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. Vol 35. June 2012.

13. International recommendations
The appropriate use of Incretin-based therapy, in dual or triple therapy, concerns patients with a HbA1c level between 7.5% and 8.5%. In the complex/fragile patient a less stringent HbA1c level can be considered.
Incretin-based therapies have not a better efficacy than therapeutic alternatives with a HbA1c reduction of about 0,5-1%.
Inzucchi SE et Al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. Vol 35. June 2012.

14. RCTs ≠ Real Life Data
Real life data are essential to correctly assess the risk/benefit and benefit/cost ratio

15. Real life data concernig antidiabetic drugs
The experience of AIFA Monitoring Registry
Data collected by the AIFA Monitoring Registry from February 2008 to April 2012 concerned exenatide, sitagliptin, vildagliptin and, from 2010, saxagliptin and liraglutide. AIFA Monitoring Registry has the objective to monitor appropriateness of use, safety profile and effects on metabolic control.

16. Clinical and anthropometric baseline data
84,476 cases from the AIFA Antidiabetic Monitoring Registry were analyzed. DPP-4 inhibitors (saxagliptin, vildagliptin and sitagliptin associated or not with metformin) were prescribed in 47,566 cases and GLP-1 analogues were used in 36,910 cases.

17. Measures of therapeutic effect
The mean change of HbA1c ranged from to -0.80%.
The proportion of cases never reaching HbA1c ≤7% ranged from 37.5% to 62.7%.

18. Total treatment costs and mean cost per patient
The total economic NHS burden of cases selected from the Registry was 83,9 Million €: 42% for DPP-4 inhibitors and 58% for GLP-1 analogues. The daily mean cost per patient related to the drugs monitored in the Registry was around € 3.16.

19. Antidiabetics Italian NHS expenditure and consumption
(DDD) data ( )

20. Real-world clinical practice
Incretin-based therapies are a concrete example of the importance of evaluating a drug's efficacy and safety in real-world clinical practice in order to define the correct risk/benefit and benefit/cost profiles.
AIFA Monitoring Registries have identified “niches” of inappropriate prescription of Incretin-based therapies considering the current national and international scientific evidence.

21. What are the AIFA's priorities?
Supporting the prescription appropriateness and NHS sustainability considering the clinical evidence reported in the national and international guidelines and real life data.
Reimbursement (without conditions)
Refusal
Outcome based MEAs
Monitoring registers
AIFA notes
Therapeutic plans
Payment by results
Risk sharing
Oncologicals
Antidiabetics
Psoriasis
Orphans
Cardiovascular
Antireumatics
Volume agreements
Managing uncertainty relating to clinical benefit and cost-effectiveness
Managing budget impact
Managing utilisation to optimize performance
Non-Outcome based MEAs
Cost sharing
Budget cap

22. Valorization of innovation
AIFA’s new domains
Innovation
Pathology
Drug
Safety
Efficacy
Cost/Efficacy
Innovation must represent a therapeutic advantage
Innovation must be "measurable“ on:
Population selection. Robustness of endpoint(s). Choice of comparators. Duration of therapeutic effect
Innovation should be valued against the National context
Innovation must meet pharmaco-economic studies and HTA standards in order to determine the ratio of incremental cost-effectiveness compared to the standard reference standard
AIFA’s new algorithm on innovation

23. Conclusions
There is a need to compare the clinical trials data with the real life data to confirm the value of potential innovation. The AIFA Monitoring Registry provides the scientific community with the elements required to make choices targeted to the real needs of public health.
The therapeutic effect of drugs monitored in the Italian real-world clinical practice in terms of HbA1c mean reduction are similar to those recorded during phase 2-3 registration trials but with an high proportion of patients never reaching the clinical HbA1ctarget suggesting the need to better characterize the subset of patients in which these treatments are effective.
Data collected through the Registries are being used to evaluate the safety profile of Incretin based therapies which are today under closed scrutiny. 23