A review of the regulatory landscape pertaining to surrogate endpoints in clinical studies.

1. Surrogate Endpoints: a regulatory review Tim Felgate 8 June 2010

2. Tim Felgate: European regulatory intelligence consultant

3. regulatory drivers requirements guidelines… assessments… expectations practices interpretation precedents information (available to anyone) experience & analysis

4. Definitions Biomarker: objectively measured and evaluated indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Pharmacodynamic marker reflects a pharmacologic response Clinical endpoint: a characteristic or variable that reflects how a patient feels, functions, or survives. Surrogate endpoint: a biomarker that is intended to substitute for a clinical endpoint; it is expected to predict clinical benefit (or harm or lack of benefit or harm). Source: Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 2001 Mar;69(3):89-95.

5. How they relate Source: EMEA/CHMP Workshop on Biomarkers, 16 December 2005; Daniel Brasseur, CHMP atEMEA http://www.ema.europa.eu/pdfs/human/biomarkers/01BRASSEUR.pdf

6. The use of biomarkers is not new

7. EMA on biomarkers December 2005: EMEA biomarkers workshops with academia and healthcare professionals December 2006: EMEA biomarkers workshops with the EFPIA and with all stakeholders July 2008: First EMEA-FDA joint biomarkers qualification process Source: Human Medicines - Medicines and Emerging Science - Biomarkers [Internet]. [cited 2010 Jun 3]; Available from: http://www.ema.europa.eu/htms/human/mes/biomarkers.htm

8. Some relevant EMA guideances Guideline on clinical trials in small populations (CHMP/EWP/83561/2005) Note for guidance on clinical investigation of medicinal products in the treatment of lipid disorders (CPMP/EWP/3020/03) Concept paper on the need for an addendum on the clinical investigation of medicinal products intended for treatment of glucocorticoid-induced osteoporosis (EMA/CHMP/EWP/15912/2010) Guideline on medicinal products for the treatment of alzheimer’s disease and other dementias (CPMP/EWP/553/95) Note for guidance on clinical investigation of medicinal products in the treatment of hypertension (CPMP/EWP/238/95) Note for guidance on clinical evaluation of new vaccines (CPMP/EWP/463/97) Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis (CPMP/EWP/784/97) Guideline on the evaluation of medicinal products in the treatmentof primary osteoporosis (CPMP/EWP/552/95)

9. Guideline on clinical trials in small populations (CHMP/EWP/83561/2005) “surrogate markers as substitutes for a clinical endpoint may be considered” “The term ‘surrogate endpoint’ should only be used for biomarkers, which have been validated.” “selection of a surrogate marker as study endpoint requires it to be reasonably likely – based on epidemiologic, pathophysiologic, or other evidence – to predict benefit” “Considerations should include: How closely changes in the surrogate endpoint are causallylinked to changes in a clinical endpoint or symptom. How much risk is associated with the therapy What other therapies (if any) are available for the same condition.” “surrogate markers cannot serve as final proof of clinical efficacy or long-term benefit” “Surrogate endpoints may be acceptable but need to be fully justified. Their relation to clinical efficacy must be clear so that the balance of risks and benefits can be evaluated.”

10. Note for guidance on clinical investigation of medicinal products in the treatment of lipid disorders (CPMP/EWP/3020/03) Although ideally a new lipid-modifying agent is expected to demonstrate an effect on the prevention of cardiovascular morbidity and mortality, a relative reduction in LDL cholesterol is acceptable in patients with primary hypercholesterolemia as a valid surrogate endpoint, provided that no claims are made regarding morbidity and mortality. However, an isolated effect on these parameters is in principle not expected to be the sole basis for the demonstration of the efficacy of a new lipid-modifying agent, but should be seen in conjunction with the effect on non-HDL cholesterol and the underlying mechanism as well. A new lipid modifying agent is only acceptable for registration when there is no suggestion of a detrimental effect on both cardiovascular and non-cardiovascular mortality and morbidity.

11. Concept paper on the need for an addendum on the clinical investigation of medicinal products intended for treatment of glucocorticoid-induced osteoporosis (EMA/CHMP/EWP/15912/2010) Points to be addressed in the addendum include: the need to use placebo-controlled studies with fracture as a primary endpoint or to use bone mineral density, or even other biochemical endpoints, as an acceptable surrogate endpoint;

12. Note for guidance on clinical investigation of medicinal products in the treatment of hypertension (CPMP/EWP/238/95) The goal of treating hypertension is to prevent morbidity and mortality associated with high blood pressure. Reduction in blood pressure has usually been accepted as a valid surrogate endpoint in order to assess whether this goal can be achieved by an antihypertensive agent. Notwithstanding, even if an antihypertensive effect has been proven, a new antihypertensive agent is only acceptable for registration when there is no suspicion of a detrimental effect on mortality and cardiovascular morbidity.

13. Guideline on medicinal products for the treatment of alzheimer’s disease and other dementias (CPMP/EWP/553/95) To be accepted as a surrogate endpoint such a biomarker ideally should respond to treatment, predict clinical response and be compellingly related to the pathophysiological process of the dementing condition. However, careful and sufficient validation of the proposed biomarkers as a potential surrogate endpoint is a prerequisite for acceptanceby regulatory bodies.

14. Note for guidance on clinical evaluation of new vaccines (CPMP/EWP/463/97) Vaccine efficacy may be evaluated and assessed either on the basis of clinical (protection) endpoints and/or validated serological surrogate endpoints whenever appropriate. When efficacy assessment in equivalence trials is based upon immunological surrogate parameters the relationship between the surrogate endpoint and the clinical endpoint must be taken into consideration, since this does not necessarily have to be a linear relationship.

15. Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis (CPMP/EWP/784/97) MRI measures may be an acceptable surrogate endpoint when their clinical relevance has been shown.

16. Guideline on the evaluation of medicinal products in the treatmentof primary osteoporosis (CPMP/EWP/552/95) Alternative surrogate endpoints like biochemical markers of bone turnover should also be used in bridging studies after a thorough analysis of historical studies showing a good correlation between pharmacokinetic exposures, the pharmacodynamic response and the reduction in fracture risk. To avoid having to conduct separate fracture studies, the time-course of changes in surrogate markers should recapitulate the time-course observed for the original dosing regimen. This should apply to any surrogate endpoint that is known to be associated with fracture risk, such as BMD and/or a biochemical marker.

17. The ENHANCE trial:MHRA statement (2008) The results showed that patients assigned simvastatin plus ezetimibehad significantly lower mean LDL cholesterol than did those assigned simvastatinplus placebo at the end of the study (3·65 mmol/L [SD 1·36] vs 4·98 mmol/L [SD 1·56]; difference between groups 16·5%, p<0·01). However, mean change in intima–media thickness of the carotid artery did not differ significantly between groups (0·0111 mm [SE 0·0038] vs 0·0058 mm [SE 0.0037], respectively, p=0·29). To date, no data from large clinical outcomes trials are available for ezetimibe. The ongoing IMPROVE-IT trial (IMProved Reduction of Outcomes: VytorinEfficacy International Trial) is evaluating the clinical benefit—in terms of cardiovascular morbidity and mortality—of ezetimibe combined with simvastatin compared with simvastatinalone in about 10 000 patients with acute coronary syndromes. However, the results are not expected to be available in the next 4 years. The MHRA, together with other regulatory agencies in the European Union, is currently reviewing the results of the ENHANCE trial to establish their clinical significance and potential effect on the balance of benefits and risks for ezetimibe. We will inform healthcare professionals of any changes to prescribing advice as soon as these reviews have been completed. A couple of useful links: http://j.mp/cjyk5p; http://j.mp/aeOS47

18. FDA on surrogate endpoints 21CFR314.510 (April 2009) Subpart H: Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.

19. So what does all this mean? There is much uncertainty – lots of maybes Surrogate endpoints must be predictive of intended clinical benefit Surrogate endpoints must be fully justified Surrogate endpoints must be adequately validated Further evidence is often required (e.g. post-marketing studies) Because of uncertainties Scientific Advice or Protocol Assistance are essential hint: “For more information on biomarkers, see: Scientific Advice and Protocol Assistance”

20. A view from the EMA Decisions taken during the process of marketing authorisation of medicinal products are always uncertain. Evidence that is “beyond doubt” never exists. Long life to the biomarkers.Bruno Flamion, Chair, Scientific Advice Working Party (SAWP) at the 2005 workshop

21. Questions? tim@reg-info.com europeanregulatory.com reg-info.com