Challenges for trials in the 21st Century by sdfwerte

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									Challenges for trials in the
       21st Century
               Professor Janet Darbyshire
  Director MRC Clinical Trials Unit & Joint Director UKCRN
      UKCRN Annual National Meeting, 21 November 2007
Challenges


• in the design, conduct and analysis of trials

• to trials and trialists in the 21st century
Do we still need randomised
trials?

 increasing options in many chronic diseases such as
   cancer and HIV but cure is rare

 only way to reliably assess moderate effects – and most
  are!

 basis of systematic reviews – only as good as the trials
  on which they are based
Why not use databases?

 databases are not available until the treatment has been
  widely used

 data collection likely to be incomplete

 a good database is as much work as a trial - without
  the benefits of randomisation

 even very large databases are very likely to give the
  wrong answer (but very precisely!)
Challenges in trial design,
conduct and analysis


• Assessing lots of new treatments as rapidly as
  possible

• New drugs for diseases treated by combination
  therapy

• Prevention trials – the most difficult challenge?
Lots of new drugs to test!

• Huge explosion in number of promising new drugs
  for cancer

• In 2005 - agents in development: 1994
   – Pre-clinical: 1288 Phase I : 195
   – Phase II:      389 Phase III: 122

• A significant proportion will be ineffective or toxic
Clinical Trials-traditional
approach
• Phase I - safety and dose finding

• Phase II - single arm, safety and activity, based on
  disease response or progression free survival
  (PFS)

• Phase III - randomised, compare experimental
  treatment to standard treatment based on survival

• Slow and unreliable (many examples in many
  diseases – cancer, cardiovascular disease, …)
Early phase trials
 small trials can only detect common toxicities

 can only provide evidence of activity if the outcome
  occurs rapidly and is common or there is a good
  surrogate marker (rarely true)

 are very likely to miss a moderate effect as only large effects
  will be detected

 need better mechanisms to select which treatments to take
  into a large trial

 need novel designs
Multi-Arm Multi-Stage (MAMS)
trials


• Test many new promising treatments in the same
  timescale

• Discontinue unpromising arms as quickly and
  reliably as possible

• Initiate a randomised comparison as quickly as
  possible
      Traditional Approach      Multiarm, Multistage

           A   B   C                     A   B   C
Phase                    150
II



Phase
III                      1800



         1950 patients               1200 patients
Multi-arm Multi-Stage Trial

                  Progression-free
                                     Survival
                      Survival
        Control       Control        Continue
                        Stop
         Arm 1
                    pfs  control

                      Continue
         Arm 2                       Continue
                    pfs > control

                        Stop
         Arm 3
                    pfs < control
Advantages of MAMS trials


• Questions answered concurrently rather than
  sequentially

• One grant application, one protocol, one ethics
  submission

• No significant time delay between phase II and
  phase III

• Fewer patients
Challenges of MAMS Trials


• Complex to set up - negotiations with many
  companies, many national groups

• Complex for participating physicians and research
  staff

• Complex for patients - slower recruitment - not our
  experience to date
Multi-arm, Multi-stage trials in
ovarian cancer
• In 1999 a number of new and exciting cytotoxics -
  gemcitabine, topotecan, doxorubicin

• Most important outcome measure - overall
  survival but progression-free survival (PFS)
  events occur earlier, often by many years

• Assume that if there is an effect on overall
  survival, an effect on PFS will be seen but an
  effect on PFS does not necessarily mean there
  will be an effect on overall survival
ICON5/GOG 182 - randomisation

                            Reference Doublet
                        I   Paclitaxel
                            Carboplatin


                            Gemcitabine Triplet
                        II Paclitaxel
   Stage III or IV          Gemcitabine
                            Carboplatin

 ovarian or primary         Pegylated Liposomal Doxorubicin Triplet
                            Paclitaxel
                        III Pegylated Liposomal Doxorubicin
peritoneal carcinoma-       Carboplatin

 appropriate surgery        Topotecan Doublet                 Topotecan Doublet
                        IV (Module A)                         (Module B)
                            Topotecan                         Paclitaxel
                            Carboplatin                       Carboplatin

                            Gemcitabine Doublet               Gemcitabine Doublet
                        V (Module A)                          (Module B)
                            Gemcitabine                       Paclitaxel
                            Carboplatin                       Carboplatin
ICON5/GOG182:outcome

• Collaboration between four countries, free drug
  from three companies and review and funding
  from public agencies in UK and USA

• First stage (PFS) planned to recruit some 3000-
  4000 women – approx 4000 were recruited in 3
  years

• Second stage planned to recruit a further 1000
  women – trial not continued into second stage as
  a consequence of the first stage analysis
New drugs for diseases
treated with combination
         therapy
Tuberculosis

• The standard 6-month regimen (EHRZ/HR*) is
  highly effective (95% - 97%) in trials in a wide
  variety of settings

• Can it be bettered – a total of 2600 evaluable
  patients would be required to demonstrate a
  reduction from 5% to 2.5% relapses

• Alternatively can we reduce the duration of
  therapy?
The challenge

• The goal is to reduce treatment duration to 4
  months and preferably less.

• How much are we prepared to pay, if anything,
  for such a reduction?
  – must the new regimen be as good as the
    standard?

  – would we be satisfied with a regimen that
    was almost as good?

  – if so, how good is almost?
     Moxifloxacin (M) in murine studies


                         10
                         9
Log CFU in entire lung




                         8
                         7
                         6                                                  Untreated
                                                                            2RHZ+4RH
                         5
                                                                            2RHZM+4RHM
                         4                                                  2RMZ+4RM
                         3
                         2        2.5 logs

                         1
                         0
                              0     1         2       3       4         5       6

                                         Duration of treatment (mos.)
REMox trial

• The control regimen 2EHRZ/4HR is widely used
  as standard therapy

• In the intervention arms - 2MHRZ/2MHR and
  2EMRZ/2MR
   – M is substituted for E in the intensive phase
     and added to the continuation phase or
   – M is substituted for H throughout
   – the continuation phase is reduced to 2 months
     in both
Outcome of REMox


• REMox can be seen as proof of concept trial -
  can a 4 month regimen in which moxifloxacin is
  substituted for ethambutol or isoniazid give
  acceptably low failure/relapse rates.

• Designed as a non-inferiority trial – challenges in
  the selection of the non-inferiority margin and
  importance of high adherence and follow-up
     Prevention trials –
the most difficult trials of all?




                      HIV VIRUS
Microbicides Development
Programme (MDP)
• 4.3M HIV infections in 2006
• Condoms work but poor uptake
• No vaccine in prospect

Microbicides:
• simple technology which is controlled by women
• active against HIV +/- other sexually transmitted
  infections in vitro
• not yet proven to protect
Challenges of microbicide trials
• No intermediate markers of activity or surrogate markers of
  protection

• Low incidence of HIV infection even in high prevalence
  areas

• Need to encourage condom use

• Adherence to gel

• Understanding of placebo design
 Total number of woman years required in a two
 arm study to demonstrate 40% effectiveness of
intervention by HIV-incidence in control arm (90%
             power, 5% significance)
      25000

      20000

      15000

      10000

       5000

          0
              1    2    3       4          5           6
                            *Incidence per 100 woman-years
MDP Partners

MRC SSHPU
Glasgow                               Nsambya Hospital,
                                      Kampala
York/Hull                             MRC/UVRI,
University                            Masaka/Entebbe, Uganda
York

Oxford University                     AMREF/NIMR/LSHTM
                                      Mwanza, Tanzania
Oxford

Imperial College*                     UTH, Lusaka,
                                      Illovo Sugar, Mazabuka
LSHTM                                 Zambia
MRC CTU*
St George’s
Hospital
                    RHRU
London, UK          Johannesburg,
                                      The Africa Centre
University of       SA
                                      Mtubatuba, SA
Southampton
                      Population
                                      MRC SA
                      Services
Southampton, UK                       Durban, SA
                      International
                      Europe and SA
MDP301 trial design
• Nearly 10,000 women to be enrolled and randomised to
       0.5% PRO2000/5* vaginal gel
       2% PRO2000/5* vaginal gel
       Placebo gel

• Primary endpoints
       HIV infection
       Safety

• 6 Sub-Saharan African sites participating

• Over 7000 women recruited since October 2005
Addressing the challenges
• Sustained release preparations – vaginal rings

• Supervised therapy

• Conduct trials in groups with a high incidence of
  HIV infection

• Short follow up
And when we have an effective
microbicide……
• Can we compare a new product of unknown
  efficacy with one known to provide some
  protection?

• Trials will need to be even bigger to detect a
  benefit compared with an effective product

• Combinations may be the best way forward - but
Regulatory and bureaucratic
          hurdles
EU Clinical Trials Directive
and UK Regulations
• Aims
   – to protect the rights, safety and wellbeing of trial
   participants
   – to simplify and harmonise conditions for
   conducting trials in the EU

   But primarily intended for trials leading to marketing
   authorisation

• Reality
   – still require regulatory and ethical approval in each
   member state
   – differences in implementation of directive across
   Europe
          Trial approval process
                             Peer review of proposal, secure funding




                                                                          Confirm drugs
Produce final protocol                  Identify sponsor(s)
                                                                       manufactured to GMP




                                        Obtain EUDRACT
                                             number




  CTA Submission                        Ethics Submission
                                                                         R&D Submission

                         Maximum
                         of 60 days

                                        Favourable ethics
  MHRA Approval                                                         Host R&D approval
                                             opinion




                                        Trial can start!
International trials –
    rare diseases
Osteosarcoma

• Treatment of osteosarcoma improved little since
  the introduction of chemotherapy 25 years ago
   – ~60% five year survival
   – children & young adults – many years of life lost

• Progress slow, mainly because of time taken to
  recruit to trials

• MRC-led MRC B006 ( EORTC 80932)
  – second largest osteosarcoma trial
  – 504 pts in 9yrs despite 11 countries involved
Global collaboration
• EURAMOS: collaboration of 4 major groups worldwide
   – European Osteosarcoma Intergroup – western
     Europe
   – Cooperative Osteosarcoma Study Group – central
     Europe
   – Scandinavian Sarcoma Group – Scandinavia
   – Children’s Oncology Group – USA + Canada

• Supported as part of ESF Eurocores Programme with
  national and charity funding from North America and
  Europe

• Pegylated interferon supplied by Schering Plough
      EURAMOS 1 Design
                                Biopsy-proven diagnosis of
     Time                        resectable osteosarcoma


                                        REGISTER


                                      MAP (induction)


                                         Surgery


                                  Histological response
                       Poor                                       Good
                                       assessment

                  RANDOMISE
                                                                RANDOMISE



          MAP                 MAPIE
                                                          MAP               MAP-ifn

Pam European Sarcoma Trials
EURAMOS groups + structure
                                   Cooperative Osteosarcoma
       Children’s Oncology Group     Study Group (COSS)
                 (COG)
                                      Austria, Germany,
            USA & Canada             Hungary, Switzerland




        European Osteosarcoma        Scandinavian Sarcoma
           Intergroup (EOI)              Group (SSG)
       Belgium, Netherlands, UK    Denmark, Finland, Iceland,
                                       Norway, Sweden
EURAMOS groups + structure
                                              Cooperative Osteosarcoma
       Children’s Oncology Group                Study Group (COSS)
                 (COG)
                                                  Austria, Germany,
            USA & Canada                         Hungary, Switzerland




                        Coordinating Data Centre:
                         MRC Clinical Trials Unit, UK




        European Osteosarcoma                   Scandinavian Sarcoma
           Intergroup (EOI)                         Group (SSG)
       Belgium, Netherlands, UK               Denmark, Finland, Iceland,
                                                  Norway, Sweden
EURAMOS groups + structure
                                                                                                                   Germany

                                                                    Cooperative Osteosarcoma                       Hungary
     USA                     Children’s Oncology Group                Study Group (COSS)
                                       (COG)
                                                                        Austria, Germany,                      Switzerland
    Canada                         USA & Canada                        Hungary, Switzerland
                                                                                                                   Austria




        Quality of Life Centre:                                                          Intergroup Safety Desk:
              Düsseldorf                      Coordinating Data Centre:                        KKS Münster
                                               MRC Clinical Trials Unit, UK
                Germany                                                                          Germany




      UK                                                                                                           Iceland
                              European Osteosarcoma                   Scandinavian Sarcoma
   Belgium                       Intergroup (EOI)                         Group (SSG)                              Denmark
                              Belgium, Netherlands, UK              Denmark, Finland, Iceland,
  Netherlands                                                           Norway, Sweden                             Finland

                                                                                                                   Norway

                                                                                                                   Sweden



                                          EURAMOS Central Account
EURAMOS groups + structure
Schering Plough (USA)

                                                                                                                          Germany

                                                                           Cooperative Osteosarcoma                       Hungary
            USA                     Children’s Oncology Group                Study Group (COSS)
                                              (COG)
                                                                               Austria, Germany,                      Switzerland
           Canada                         USA & Canada                        Hungary, Switzerland
                                                                                                                          Austria




               Quality of Life Centre:                                                          Intergroup Safety Desk:
                     Düsseldorf                      Coordinating Data Centre:                        KKS Münster
                                                      MRC Clinical Trials Unit, UK
                       Germany                                                                          Germany




             UK                                                                                                           Iceland
                                     European Osteosarcoma                   Scandinavian Sarcoma
           Belgium                      Intergroup (EOI)                         Group (SSG)                              Denmark
                                     Belgium, Netherlands, UK              Denmark, Finland, Iceland,
         Netherlands                                                           Norway, Sweden                             Finland

                                                                                                                          Norway

                                                                                                                          Sweden



                                                 EURAMOS Central Account


                                                                                                        Schering Plough (EU)
Sponsorship and agreements

• Intergroups as collaborations
   – No legal existence

• Planned for Sponsor in each country
  – Legal entity in place

• Choose one Sponsor in Europe and one in North
  America

• Complex series of agreements
Major agreements & contracts


                                                               4
                               MRC                                                             COG
                          (European Sponsor)                                            (North American Sponsor)




                               2                                                                      3
   1                                            Schering Plough
                                               (Integrated Therapeutics Group Inc)




   All European countries
 + safety desk + QoL centre
       (EURAMOS framework agreement)




                                                                                         European Trial
                                                                                     Framework Agreement
Progress

  Despite this apparent complexity:

• 13 countries have recruited

• 3 countries ready to recruit

• 2 countries expected to be ready soon

• 3 new countries interested in taking part

• Goal – register 1400 and randomise 1260
  patients over 4 years
Resource challenges

• financial
  – costs of regulatory requirements e.g. fees for
    Clinical Trial Authorisation (CTA) and
    inspections
  – costs of increased trial monitoring

• human
  – shortage of experienced trialists and core
    support for clinical trials units
  – lack of career structure for clinicians,
    statisticians and trial managers
How can UKCRC, UKCRN and
NIHR help?
• Provide NHS infrastructure and R&D management
  support

• “Bust bureaucracy” – research passports, central sign
  off, regulatory advice service, integrated application
  process

• Address career structures for all professional groups

• Review capacity to provide expertise in design,
  conduct and analysis of clinical trials and other well
  designed studies following on from UKCRC Clinical
A key challenge:
    Effective
 involvement of
patients and the
     public
Involvement of patients and
the public
• At all stages of the trial process from design
  through recruitment to dissemination of results

• Increase public understanding of trials – from
  schools to patients and the public
Challenges in involving patients
and the public
• Identifying individuals

• Supporting them to play a full role in committees
  and other activities

• Involving them in research priority setting

• Engaging the research community
The final challenge:
Getting results into
Dissemination of results
• Clinicians and participants involved in the trials

• All clinicians and patient groups

• Oral and written scientific presentations

• Press releases and media briefings

• Guideline development groups

• Commissioners and providers of health care
  The
future?
             Whole System


                       Network
                    Infrastructure
                      in the NHS
INDUSTRY
Industry
FUNDERS

Funders                                Academic
                                        Funders
                  Patients
           Portfolio-
                             Clinical Trials
            Clinical
                                 Units/
            Studies
                                 RDUs
            Groups

								
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