The Use of Surrogate Endpoints in Regulating Medicines for Cardio-Renal Disease: Opinions of Stakeholders

Aim There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. Methods We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Results Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Conclusion Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them.


Introduction
First, we would like to know a bit more about your background and your general experience with the use of surrogate endpoints.

What is your gender?
2. What is your age?
3. How long have you been professionally active in the pharmaceutical field?

Who is your main employer?
FDA n m l k j EMA, or a regulator on a national level within the EU n m l k j Other n m l k j 6. What are your areas of specialization? (providing multiple answers is possible) 7. Have you been professionally involved in the development or marketing authorization of drugs targeted to the following surrogate endpoints? We continue with questions on the use of surrogate endpoints in marketing authorization.
8. Drug registration based on surrogate endpoints might be beneficial for a wide range of stakeholders in the drug development process. In your opinion, who benefits most from the use of surrogate endpoints? Please use the dropdown menu to rank the groups from most benefit (1) to least benefit (4).
Note: answers change position while indicating your preferences.  In the remainder of the survey we are interested in your opinion on the use of surrogate endpoints in the cardiovascular field. The predictive accuracy of surrogate endpoints is being debated in this field due to a number of unexpected results from hard clinical outcome studies. A wellknown example is rosiglitazone that due to its HbA1c lowering effect was expected to decrease the risk of cardiovascular complications in diabetes patients. However, a postmarketing hard clinical outcome study revealed an increase in cardiovascular risk resulting in the withdrawal of the drug from the European market.
10. Please indicate whether you consider yourself knowledgeable to answer questions on the use of surrogate endpoints in the cardiovascular and/or diabetes field. n m l k j n m l k j n m l k j n m l k j n m l k j In current registration practice, many cardiovascular drugs are approved based on efficacy on a single marker (e.g. blood pressure in case of an angiotensin II receptor blocker (ARB) for the treatment of hypertension), to which we will refer in this survey as the ontarget marker. At the same time, these drugs may have an effect on other biomarkers to which we will refer in this survey as offtarget markers. Such offtarget markers can contribute either in a positive (e.g. albuminurialowering effect) way or a negative (e.g. hemoglobinlowering effect) way to a drug's efficacy/safety profile. An example is visualized below, showing how the ARB Losartan has an effect on the ontarget marker blood pressure and the offtarget markers albuminuria, potassium and hemoglobin.
Predictions of longterm treatment effects may be different when taking into account changes in both ontarget and offtarget markers as compared to changes in the ontarget marker alone. To provide insight in these differences, we have developed a novel risk score that predicts the effect of a drug on hard clinical outcomes based on changes in all measured ontarget and offtarget markers.
On the next page, a case will be presented that illustrates the use of the risk score.
Drug effects on multiple biomarkers Background information for the remain...
A drug application was submitted for a novel blood pressurelowering agent called Drug X. Below you will find the most important details of the conducted clinical trials to establish safety and efficacy of Drug X.
The details of 2 registration studies for efficacy: Treatment: Drug X versus placebo Duration: 12 weeks Study population: 900 hypertensive patients drawn from the general population (450 in each group) Measurements: blood pressure and several additional markers A one year openlabel study with drug X indicated no suspicion of a detrimental effect on cardiovascular hard clinical outcomes.
These studies showed that drug X was well tolerated and any side effects were similar to existing blood pressure lowering agents.
The effects of drug X on multiple on and offtarget markers are summarized in the table below.
13. Based on the information given above, should this drug be approved for market authorization?
Yes, no postmarketing studies involving hard clinical endpoints are required n m l k j Yes, but postmarketing studies involving hard clinical endpoints are necessary to validate the cardioprotective effect of Drug X n m l k j No, followup studies with hard clinical endpoints are necessary before the drug can be registered Given the observed changes in biomarkers, the following predictions were made concerning the treatment effect of Drug X on cardiovascular outcomes (stroke, MI and cardiovasular death), relative to placebo:  You have completed the survey. We thank you for your cooperation. Should you have any further comments, please let us know by using the text box below.