Clinical trials and the impact Clinical trials and the impact of regulations of regulations of regulations of regulations Cytel Conference Cytel Conference Octobe Octobe October 12, 2012 October 12, 2012 , , 0 0 David L DeMets, PhD Department of Biostatistics & Department of Biostatistics & Medical Informatics U i University of Wisconsin-Madison it f Wi i M di
Topics Topics • Proliferation of multinational trials • Regulatory Guidelines & their • Regulatory Guidelines & their interpretation • Adverse event reporting for safety Ad t ti f f t • One site monitoring • SOPs & SAPs • DMCs DMCs • Adaptive Designs • New Guidelines for Diabetes Drug N G id li f Di b t D Approval
Regulatory Guidelines Regulatory Guidelines Regulatory Guidelines Regulatory Guidelines • Over the past 20 years, there are more large phase III trials done by industry • As a result, there are more regulatory , g y guidelines on the design, conduct and analysis of clinical trials (Eg ICH, FDA, y ( g , , EMA) • Are the recent regulatory guidelines on Are the recent regulatory guidelines on the design, conduct and analysis of industry sponsored trials making trials industry sponsored trials making trials better?
Opinion Opinion • Clinical trials are not necessarily better today than 20 years ago today than 20 years ago • The guidelines are generally consistent with clinical trial fundamentals ith li i l t i l f d t l • The problem is in the interpretation of those guidelines and practice • Industries have been built up on the p interpretation and implementation of regulatory guidelines g y g • Not getting a better bang for the cost!
Globalization of Investigators Globalization of Investigators Percent of Total 1572s Filed Average Number of Countries Average Number of Countries Where Clinical Trials Conducted (2010) Phase I Studies 2 Phase II Studies 13 Phase III Studies 34 2005 2005 1997 1997 2001 2001 2009 2009 Source: Tufts CSDD 5
Adult Non Adult Non- -US Trials US Trials • More than doubled in previous 10 years • One-third of clinical trials by 20 largest One third of clinical trials by 20 largest US-based companies are conducted solely outside the US solely outside the US • US Inspector General Report – 80% of drugs approved had non-US sites 80% of drugs approved had non US sites – 80% of subjects from non-US sites – Trials of good quality generally T i l f d lit ll • Ref: Glickman et al, NEJM 2009 R f Gli k t l NEJM 2009
US Situation US Situation • Sponsors often view US sites as p – Too slow to get studies approved – Too expensive p – Too slow to enroll • US investigators often view trials as • US investigators often view trials as – Competing with pressures to see patients – Regulatory overhead more costly than Regulatory overhead more costly than actually taking care of the patient – Not enough academic currency Not enough academic currency
Estimated Costs of Drug Estimated Costs of Drug Estimated Costs of Drug Estimated Costs of Drug Development ($Millions) Development ($Millions) Fee R: The cost of clinical trials. Drug Discovery and Development Webcast. March 1, 2007 DiMasi JA et al: The price of innovation: new estimates of drug development costs. J Health Economics 2003; 22:151-185 p g p ; DiMasi JA: New drug development in the United States from 1963 to 1999. Clin Pharmacol Ther 2001; 69:286-96
Multiple Countries / Regulatory Multiple Countries / Regulatory Multiple Countries / Regulatory Multiple Countries / Regulatory Agencies / regulations Agencies / regulations • Sponsors want their produce approved in multiple countries – especially large p p y g markets • Want to abide by each country’s Want to abide by each country s regulations for approval • Not all countries have same regulations • Not all countries have same regulations • Sponsors feel the need to meet lowest common denominator d i t
International Conference on International Conference on Harmonization (ICH) Harmonization (ICH) • Attempt started in early 1990’s to make Att t t t d i l 1990’ t k regulatory guidance between US and Europe more consistent, also with E i t t l ith Japan • Many guidelines developed on design, conduct, analysis, reporting for submissions • Guidelines generally support good g y pp g principles (E.g. ICH-E9 Statistical )
Regulatory Side Business Regulatory Side Business • Many companies (CROs) have been developed to help sponsors & developed to help sponsors & investigators interpret the various regulations avoid problems & pass regulations, avoid problems & pass audits • Similarly, companies developed to Similarly companies developed to conduct audits for regulatory compliance compliance • Sometimes the same company • All of this activity adds substantial cost
Clinical Trials Transformation Clinical Trials Transformation I iti ti I iti ti Initiative (CTTI) Initiative (CTTI) (CTTI) (CTTI) • Collaborative effort between US FDA, Collaborative effort between US FDA, EMEA, academia and drug/device industry industry • Centered at Duke University • Governed by an Executive Committee, Governed by an Executive Committee & operated by a Steering Committee • Identified some practices that were Id ifi d i h costly, perhaps not effective, and areas f for streamlining li i
CTTI Projects CTTI Projects Two examples Two examples Two examples Two examples • SAE Reports – Copies from a trial shipped to all participating sites Copies from a trial shipped to all participating sites – Not unblinded & so not useful to sites – Not required by US federal regulations – A costly tradition, not very informative A l di i i f i – Use DMC process, either internal or external – FDA has new IND safety reporting guideline y p g g • CRF Complete Auditing – Line by line on site auditing by CRA’s – Very costly to sponsor and investigators Very costly to sponsor and investigators – Two natural experiments suggest errors in NIH (academic) type approach are small • GUSTO GUSTO • Breast Cancer Trial / Montreal Site Fraud
Clinical Safety Clinical Safety • Many possible AEs and SAEs • Some can be prespecified, e.g. – LFTs – QT Interval • Unexpected events challenging Unexpected events challenging • Rare events challenging • Some adverse events are deal breakers S d t d l b k • Multiple comparison problem • Short term vs long term surveillance
Coronary Drug Project Coronary Drug Project Mortality Results Mortality Results Mortality Results Mortality Results Life-table cumulative mortality rates, Life table cumulative mortality rates Coronary Drug Research Project Group
Coronary Drug Project Coronary Drug Project “ “ “Unreliability of small numbers” “Unreliability of small numbers” f f Placebo Superior Clofibrate Superior z values for clofibrate-placebo differences in proportion of deaths by calendar month since beginning of study by calendar month since beginning of study (Month 0 = March 1966, Month 100 = July 1974)
AE Standard Coding Systems AE Standard Coding Systems AE Standard Coding Systems AE Standard Coding Systems • AE’s often collected from patient complaints, text recorded & coded • Several adverse event coding systems g y • Often organized by body systems • Subcategorized into events as reported • Subcategorized into events as reported by investigator/patient • Safety committees often review these in S f t itt ft i th i tabular form by treatment arms • (AE listings not helpful after awhile)
AE Standard Coding Systems AE Standard Coding Systems g g y y • Generally these tables not helpful • At one level, too granular and tables filled At l l t l d t bl fill d with small number of events – difficult to interpret interpret • At higher level, too many critical and non critical events pooled together – also difficult to interpret • DMCs often need to select critical events and create new safety variable(s) best not to be create new safety variable(s), best not to be done post hoc • Need to sharpen our safety focus on Adverse Need to sharpen our safety focus on Adverse Events of Special Interest (AESIs)
CTTI/FDA AE Reporting CTTI/FDA AE Reporting I iti ti I iti ti Initiative Initiative • As a result, FDA has issued updated As a result, FDA has issued updated guidelines on AE reporting: IND Rule • Focus on AE s that matter • Focus on AE’s that matter • However, – Global regulatory agencies may not agree Gl b l l t i t – Tradition is hard to break – Many jobs depend on the current practice – What trial wants to be the “first” ? • Industry struggling to deal with new rule
Site Monitoring Site Monitoring Site Monitoring Site Monitoring • Regulations & good practice suggest that CTs need to establish that trial had – Real patients – Relevant disease – No allocation bias / randomization – Intervention applied without bias – Unbiased Outcome ascertainment – All relevant outcomes reported – Consent forms signed Consent forms signed
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