IHS Global Insight Perspective | |
Significance | According to the IQWiG, two levels need to be discerned in the consideration of surrogate endpoints: the validity of the surrogate and the correlation between the surrogate and patient-relevant endpoints. |
Implications | IQWiG's paper suggests that demonstrating a relation between the surrogate and the clinical endpoint will be insufficient to convince the Institute of the validation of a surrogate. |
Outlook | The present report provides useful hints about what IQWiG is expecting manufacturers to prove as part of reimbursement applications for cancer drugs in Germany. |
The Institute for Quality and Efficiency in Healthcare (IQWiG) has issued a report (available here) whereby it analyses the validation of surrogate endpoint for the benefit assessment of cancer therapies. The recommendations given by the Institute refer to two levels:
- The validity of surrogate endpoints; and
- The effect of the surrogate on patient-relevant endpoints.
Assessment of Validity of Surrogate
IQWiG considers that "if no data on surrogate validation are available, or if the data available only show low reliability, no conclusion about the patient-relevant endpoint can be drawn on the basis of the results for the surrogate". It means that no proof of an effect on the patient-relevant endpoint can be deduced. The goal of surrogate validation is to determine what conclusions about patient-relevant endpoints can be drawn from surrogate endpoints. For IQWiG, the validity of the surrogate is directly correlated to the reliability of validation studies and to the correlation of the effects on the surrogate and patient relevant endpoint.
Conclusions About Patient-Relevant Endpoints Drawn from Effects on Surrogates
If data on surrogate validation are available, IQWiG recommends to first assess their reliability:
- Low reliability: no proof of an effect on the patient-relevant endpoint can be deduced from results for the surrogate;
- High, limited or moderate reliability: conclusions about patient-relevant endpoints depend on the degree of correlation of the effects on the surrogate and the patient-relevant endpoint in the validation studies.
Based on the correlation between surrogate and patient-relevant endpoint in the validation studies, the following conclusions can be drawn from results for the surrogate endpoints in the benefit assessment of cancer drugs.
Conclusions: Effects on Patient-Relevant Endpoints | ||
Reliability | Correlation | Conclusion |
Low | - | No proof of an effect on the patient-relevant endpoint can be deduced from results for the surrogate. |
High | High | At most proof of an effect on the patient-relevant endpoint. |
High | Medium | Effect on the surrogate in the benefit assessment needs to be compared with the surrogate threshold effect (STE). |
High | Low | The surrogate is deemed to be not valid. |
Limited | High | There is at most an indication of effects on patient-relevant endpoints. |
Limited | Medium | If the STE < 95% CI of the surrogate, there is at most an indication of an effect on patient-relevant endpoint. |
Limited | Low | No proof of an effect on the patient-relevant endpoint. |
Moderate | High | There is at most a hint of an effect. |
Moderate | Medium | If the STE < 95% CI of the surrogate, there is at most a hint of an effect. |
Moderate | Low | No proof of an effect |
Source: IQWiG, 2011 | ||
Outlook and Implications
IQWiG's paper suggests that demonstrating a relation between the surrogate and the clinical endpoint will not be sufficient to convince the Institute of the validation of a surrogate. As part of the new regulation, IQWiG is set to conduct the early benefit assessment of most new drugs upon request of the Federal Joint Committee (G-BA). Such early benefit assessment shall be completed at the latest three months after commercialisation date. In light of the difficulty to prove an effect of new cancer drugs on patient-relevant outcomes at such an early stage, IQWiG is likely to receive a majority of dossiers based on surrogate endpoints. The present report will be very useful to manufacturers seeking to file for reimbursement in Germany, especially in the field of oncology. There are still many questions surrounding the new German process and any information from German healthcare authorities is clearly a step forward.
As part of the new reform, any drug bringing an "additional patient-related outcome" will qualify for price negotiations with the statutory health insurance (GKV). On the contrary, new drugs deemed to bring no added value will be automatically transferred to Germany's reference pricing system. The following benefits are considered as valid patient-related outcome by the G-BA:
- improvement of health conditions;
- shortening of the duration of the disease;
- improvement in overall survival;
- reduction in side-effects;
- improved quality of life.