Phase III Clinical Trials, what are they good for?
Session 4: Clinical Trials Tuesday 12th February 2019
Professor Alan Boyd FRCP FFPM Immediate Past President, Faculty of Pharmaceutical Medicine, RCP CEO, Boyd Consultants Ltd Standard Drug Development Process
Risk Management Plan - Decision to Pharmacovigilance Develop Product: Research & IMPD/CTA Phase Phase File MMA Post-Approval Selection of Pre-Clinical Phase Filing I II + NDA Clinical Studies Compound Research & III Toxicology,
Manufacturing Health Technology Assessments
20-100 Healthy 100-300 300-3000+ Volunteers &/or Patients: Patients: Patients: Assess Safety & Assess/Confirm Assess Safety Efficacy Safety, Efficacy & Effectiveness Origin of Phase III Clinical Trials
• Phase III Clinical Trial is typically a prospective Randomised Controlled Trial that investigates the effects of an experimental treatment compared with a control treatment (an approved therapy, standard care or placebo) • Concept of RCTs not established till 1948 – MRC Study of Streptomycin in TB – Austin Bradford Hill credited with establishing RCTs as quoted in the BMJ ‘need for adequately controlled clinical trials’ • RCTs now recognised as the standard approach for determining therapeutic safety and efficacy of new medicinal products RCTs & Phase III Clinical Trials
• By 2004 Cochrane Library contained over 150,000 RCTs • Plus procedures & guidelines around the conduct and reporting of RCTs have been developed and refined • Example – CONSORT Statement for reporting RCTs – 1996, 2001 & 2010 • ClinicalTrials.gov database website (Est 1997) currently sites 21,921 Phase III trials that are actively recruiting. With total number of Phase III studies listed at 43,458. • Over past 70 years – RCTs have reshaped medical knowledge and clinical practice supporting the Evidence Base Medicine approach led by the ‘systematic reviews of RCTs’ (Sackett’s Hierarchy of Evidence) Why have Phase III Trials become so well established? • Prior to the introduction of RCTs the evaluation of therapeutic agents was done using case reports, case series, public demonstrations, testimonials, clinical reasoning and occasional clinical trials. • During the first half of the 20th Century much more rigor was being applied to clinical research methodology with the aim of reducing bias • However, when RCTs first introduced – there were concerns about the ethics of withholding potential new treatments from the control group. • During the 1950’s there was a push for RCT’S to assess new pharmaceutical products e.g. for antibiotics, anti-hypertensives & anti-psychotics. • Editorial in NEJM 1956 - “Physicians should be particularly careful in accepting drugs purely on the basis of the manufacturer’s evidence or on the basis of testimonials provided to the manufacturer. They should demand clear, unbiased, well studied and adequately controlled evidence produced and interpreted by reliable observers.” • At that time most RCTs were being done in academic settings. Pharma companies were reluctant to devote time and resources to RCTs – mainly relied on testimonials and case reports to support their claims. Why have Phase III Trials become so well established?
• Came to a head with the thalidomide disaster– US government enacted the Kefauver-Harris Amendment to the Food & Drug Act in 1962 mandating that new drugs be proven efficacious in ‘adequate and well- controlled investigations’ • By 1970, the FDA interpreted the amendments as requiring RCTs for the approval of all new medicines – hence Phase III trials came about . • Rest of the Regulatory world followed suit – now in the Medicine Regulations worldwide. Medicines Regulations and Phase III Trials • Regulators collaborated to establish international standards for clinical research – ICH* - further embedded RCTs and hence Phase III Trials as the ‘Gold Standard’
• ICH E8 - GENERAL CONSIDERATIONS FOR CLINICAL TRIALS • ‘Trials should have an adequate control group’. • ‘In conducting a controlled trial, randomised allocation is the preferred means of assuring comparability of test groups and minimising the possibility of selection bias.’ • ICH E9 - STATISTICAL PRINCIPLES FOR CLINICAL TRIALS • ‘The most important design techniques for avoiding bias in clinical trials are blinding and randomisation, and these should be normal features of most controlled clinical trials intended to be included in a marketing application’.
• These requirements are still very much in place and the regulators try to get sponsors to adhere to them – Requirement for ‘two confirmatory well-controlled randomised clinical studies’ is the regulators mantra.
*The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Key features of Phase III Trials and their design
• Key aim of the design of a Phase III Trial is to reduce bias • Key element of design is the randomisation to experimental treatment or control (Std Care or placebo etc) • Enables patient to have same chance of receiving the experimental treatment or control • Should be conducted in a blinded fashion if possible. • All patients are exposed to an ‘intervention’ • Groups followed up for outcome of the ‘intervention’ i.e. the endpoints • Seeks to prove a hypothesis (or more accurately disprove a null-hypothesis) What’s achieved from a Phase III Trial
• Examines the effect of the intervention (drug/vaccine etc) on a sample of the population with the disease of interest • Randomisation is the best way that we can make a comparison of the new treatment with previous treatment regimens/no treatment • All other factors/characteristics about the patients should be the same • Based on outcome and evidence – intervention may then be recommended for use in larger population with the disease – external validity • In addition - Phase III trials should be capable of eliminating ineffective, unnecessary and potentially harmful therapies Phase III Clinical Trials, what are they good for? Phase III Clinical Trials & RCTs – wider utilisation?
• RCTs & Phase III trials are the standard for Pharmaceutical research • Other Clinical Specialties have issues with them: • Psychiatry – use of psychotherapy vs psychotropic medicines – evidence base for psychotropic medicines is disproportionate and more robust – may have contributed to the use of less comprehensive approach to psychiatric care (Deacon BJ;2013 Clin Psycho Rev) • Surgery – RCTs has limitations – patient unique pathology, surgical skills, other factors being equal e.g. anaesthesia, Pre-medication, post-op care etc (Love JW; Drugs & Operations: some important differences. 1975 JAMA) • Cardiology – coronary angioplasty & stents developed not involving RCTs but due to the logic of the approach and the compelling evidence seen on angiography • From recent epidemics – Ebola & Zika outbreaks – showed that older methods such as case series, case reports etc were valuable • New methods of observational research – use of large databases of patients to produce comparative data of various treatment outcomes in routine care Phase III Trials – Chances of a success
12 Phase III Trials – why do they fail?
1. Lack of Efficacy — i.e., failure to meet the primary efficacy endpoint 2. Lack of Safety — i.e., unexpected adverse or serious adverse events 3. Lack of Commercial / financial benefit— i.e., failure to demonstrate value compared to an existing therapy
Tufts Center for the Study of Drug Development (CSDD). Causes of clinical failures vary widely by therapeutic class, phase of study. Tufts CSDD study assessed compounds entering clinical testing in 2000-09. Tufts CSDD Impact Report. 2013;15(5). Phase III Trials – why do they fail? • Oncology Phase III Trials - Why these fail? • Review of 235 published Phase III Trials in Oncology • 62% did not achieve results that meet their defined endpoint • ‘High failure rate due to the actual magnitude of benefit achieved in a clinical trial is nearly always less than what was predicted at the time the trial was designed’ • ‘Investigators consistently make overly-optimistic assumptions regarding treatment benefits when designing their studies’ • Other factors to be considered: • Limited data from early phase trials particularly around duration of response • Use of ‘Stable Disease’ & ‘Clinical Benefit Rate’ show little correlation with later Phase III results • Did not enrol enough patients or were underpowered - 50% of studies did not reach statistical significance – risk of false negative?
• Personal Note – Estimating the size effect of a potential treatment is most difficult to do – results seen in Phase II are usually greater than in Phase III
(Gan HK et al; J Natl Cancer Ins (2012)) Phase III Trials – what are their issues?
• Length of time to run them – e.g. RCT of bare-metal stents vs drug- eluting stents • Not designed to cover the eventual population the treatment is intended for – external validity • Exclusion criteria too restrictive – children and elderly use most medicines • Inclusion criteria not wide enough – co-morbidities, concomitant medication • Not enough attention paid to their design – too much focus on ‘administrative tasks & operational matters’ Phase III Trials – need to change our ways
• Adaptive Clinical Trials • Interim Monitoring – stopping for Superiority or Futility • Combined Phase II/III Trials • Multiple-Arms Trial – with a single control arm • Adaptive Trials with Biomarkers • Basket Trials and Umbrella Trials • Basket Trial – Many diseases (or many cancer types), single subgroup, one drug • Umbrella Trials - One disease (or one cancer type), multiple subgroups (identified by the biomarkers), many drugs • Outcome-Adaptive Randomisation Is there a case to eliminate Phase III Trials?
• Since 1992, the FDA has approved a number of medicines without data from confirmatory clinical trials – part of their Accelerated Approval Process
Sharma, M. R. & Schilsky, R. L. Nat. Rev. Clin. Oncol. 9, 208–214 (2012) Is there a case to eliminate Phase III Trials?
Sharma, M. R. & Schilsky, R. L. Nat. Rev. Clin. Oncol. 9, 208–214 (2012) • Accelerated Access Collaborative (AAC) – NICE • ‘Making the process of getting transformative technologies to patients quicker, cheaper and easier for innovators and the NHS’ • ‘11 AAC rapid uptake products will enable patients with conditions such as cancer, heart disease and multiple sclerosis to access new treatments faster.’ Examples of Current Phase III Trials Assessment of Gene Therapy Effectiveness in Inherited Eye Diseases – Results – Control Group after Cross-Over
Investigational Gene Therapy: Voretigene Neparvovec for Biallelic RPE65 Mutation– Associated Retinal Dystrophy
Mean mobility test change score (primary endpoint) at year 1 and year 2 (mITT population). P=0.004 at 1 year; difference (95% CI) Intervention − Control: 1.6 (0.76, 2.50).
ClinicalTrials.gov Identifier: NCT00999609 Go to
A Study to Evaluate INSTILADRIN® in Patients With High-Grade, Bacillus Calmette-Guerin (BCG) Unresponsive NMIBC
Clinical Study Design Study Type : Interventional (Clinical Trial) Estimated Enrollment : 150 participants Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Phase III, Open Label Study to Evaluate the Safety and Efficacy of INSTILADRIN® (rAd- IFN)/Syn3) Administered Intravesically to Patients With High Grade, BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) Study Start Date : September 2016 Estimated Primary Completion Date : June 2019 Estimated Study Completion Date : June 2022
Primary Endpoint: • To evaluate the complete response rate in patients with Carcinoma in situ (CIS), with or without concomitant high-grade Ta or T1 papillary disease. [ Time Frame: 12 Months ] • Complete response rate will be measured by determining the number of patients without recurrence of high-grade disease using results from urine cytology, cystoscopy, and biopsy of the bladder.
ClinicalTrials.gov Identifier: NCT02773849 Phase III Clinical Trials, what are they good for? • Summary • Phase III Clinical Trials recognised as the standard approach for determining therapeutic safety and efficacy of new medicinal products
However: • They are not perfect in every situation in medicine to determine benefits and risks • Need to change our approach to clinical studies and adapt to meet future needs and developments • Observational research & use of large databases being utilised increasingly • Consider applying adaptive designs more and use of Accelerated Access Review for the right products • Change being driven by new biological and advanced medicinal therapies in development • This is already recognised by the Medicine & Device Regulators • As Personalised and Precision Medicine becomes a reality with a focus on the individual patient – the application of RCTs/Phase III Trials will come under greater scrutiny Boyd Consultants Ltd: Tel: +44(0)1270 270010 Mobile: +44(0)7899 873150 Email: [email protected] Website: www.boydconsultants.com
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