Elements of a Research Protocol Elsa  du  Bruyn  (MB  ChB)  

CIDRI-­‐Africa  19  August  2017  

Research  Methods  Workshop  

Definition: clinical research protocol

• Document  describing  “the  objecIve(s),  design,  methodology,  staIsIcal  consideraIons,  and  organizaIon  of  a  trial…[and]  usually  also  gives  the  background  and  raIonale  for  the  trial”  

•  In  short:  the  study  plan  

Interna'onal  Conference  on  Harmonisa'on  of  Technical  Requirements  for  Pharmaceu'cals  for  Human  Use  (ICH)  E6  Good  Clinical  Prac'ce:  Consolidated  Guidance,  1996  

Clinical  protocol  

ObjecIve(s)  

design  

methodology  

staIsIcs  

organizaIon  

RaIonale  &  background  

Like cooking?

Who reads the protocol?

• Collaborators  •  Supervisors  •  InsItuIonal  Review  Boards  •  Safety  commiVee  •  Ethics  CommiVee  •  Sponsor/Funder  •  Study  staff  responsible  for  conduct  of  the  study  

Image:  hVp://www.interdech.com/blog/escribiendo-­‐relatos-­‐breves-­‐b40.html  

Things to decide on before you write

Research  quesIon?  

Best  study  design  to  answer  

research  quesIon?  

Assemble  building  blocks  of  Research  Plan  

Assemble building blocks of research plan by asking the right questions • Answer  all  the  W  quesIons:  • Who  are  the  stakeholders?  Who  is  the  study  populaIon?  • What  methods  will  be  used  to  answer  the  research  quesIon?  • Where  will  the  recruitment  and  study  invesIgaIons  take  place?  • When/over  what  period  of  Ime  will  it  take  place?  •  Then  get  to  the  H  quesIon  –  HOW?  

Image:  hVps://community.uservoice.com/blog/customer-­‐interview-­‐quesIons/  

Are there any tools available to use whilst planning to write your protocol? • PICOT  format  • P  –  populaIon  •  I  –  intervenIon  • C  –  comparison  • O  –  outcome(s)  •  T  –  Ime  

AssociaIon  between  framing  of  the  research  quesIon  using  the  PICOT  format  and  reporIng  quality  of  randomized  controlled  trials.  Rios  LP  et  al.  BMC  Med  Res  Methodol.  2010  Feb  5;10:11  

Are there any tools available to use whilst planning to write your protocol? • Make  use  of  templates  •  IntervenIonal  vs  observaIonal  studies  • High-­‐risk  vs  low  risk  •  Funder  or  insItuIonal  requirement?  E.g.  NIH  studies  may  require  specific  format  

-­‐  hVps://www.niaid.nih.gov/.../dmid-­‐intervenIonal-­‐protocol-­‐template-­‐and-­‐working-­‐shell  

-­‐  hVp://www.who.int/rpc/research_ethics/format_rp/en/  

-­‐  hVp://www.crc.uct.ac.za/crc/services-­‐faciliIes/study-­‐design-­‐and-­‐protocol-­‐development  

Overview of the key elements of a research protocol (ICH E6) •  General  InformaIon    •  Background  InformaIon    •  Trial  ObjecIves  and  Purpose    •  Trial  Design    •  SelecIon  and  Withdrawal  of  Subjects    

•  Treatment  of  Subjects    •  Assessment  of  Efficacy    •  Assessment  of  Safety    •  StaIsIcs  

•  Direct  Access  to  Source  Data/Documents    

•  Quality  Control  and  Quality  Assurance    

•  Ethics  •  Data  Handling  and  Record  Keeping    •  Financing  and  Insurance    •  PublicaIon  Policy    •  Supplements  

General Information

• Cover  page  •  Index,  list  of  abbreviaIons  •  InvesIgators,  sponsors  and  monitors  list  (Itle,  contact  details,  role  in  study)  

Cover page

Summary page

Background info & scientific rationale •  Statement  that  trial/study  will  be  conducted  in  compliance  with  protocol,  GCP  and  the  applicable  regulatory  requirement(s)  

Background info & scientific rationale

•  Summary  (no  more  than  300  words):  have  a  clear  purpose!  • Background:  review  key,  relevant  findings  from  literature  • Ra9onale:  provide  sound  jusIficaIon  for  conducIng  your  study  •  Trial/study  objec9ves  and  purpose  • Risks  and  benefits  

Image:  hVp://evueu.adtddns.asia/purpose-­‐statement-­‐template  

Trial/study design – the HOW

• Primary  and  secondary  endpoints  •  Specific  study  design  (schemaIc/diagram)    • Measures  to  minimize  bias  (e.g.  blinding;  randomizaIon)  • DuraIon  of  study  parIcipaIon  &  follow  up  • When  to  stop  

Image:  hVps://community.mims.com/general/11377/the-­‐importance-­‐of-­‐blinding-­‐in-­‐randomized-­‐control-­‐trial  

Example of cohort study schematic

Image:  hVp://www2.myoops.org/cocw/tuos/courses/1/content/193106.htm  

Example of case control study schematic

Image:  hVp://ocw.tuos.edu/Content/1/CourseHome/193106  

Selection & withdrawal of subjects – the WHO •  Inclusion  criteria  •  Exclusion  criteria  • Withdrawal  criteria  

Image:  hVp://www.youreventmentor.co.uk/event-­‐management-­‐Ips/event-­‐planning-­‐checklist/  

Treatment of subjects

• Dose  and  route  of  admin,  treatment  period  • Allowed  con-­‐meds  • Measures  of  compliance  

Image:  hVp://www.skincancerclinic.net.au/treatment/medical-­‐treatment/  

Assessment of Efficacy

•  Efficacy  parameters  • Methods  and  Iming  for  assessing,  recording,  and  analysing  of  efficacy  parameters  

Safety

•  Specify  safety  parameters  relevant  to  study  • How  will  they  be  measured,  recorded  analysed?  • ReporIng  (incl.  Iming)  of  AE  •  Type  and  duraIon  of  follow-­‐up  post  AE  

Image:  hVp://www.istockphoto.com/za/photos/safety?excludenudity=true&sort=mostpopular&mediatype=photography&phrase=safety  

Statistics

•  Sample  size  consideraIons,  power  calculaIon  and  jusIficaIon  •  Level  of  significance  •  StaIsIcal  methods  •  Interim  analysis?  (Iming)  • Criteria  for  terminaIon  of  trial  • Procedure  for  accounIng  for  missing,  unused,  and  spurious  data  

Image:  hVp://libguides.lehman.edu/staIsIcs-­‐and-­‐data  

Ethics, data handling and record keeping & insurance •  Ethical  considera9ons  relevant  to  study/trial  • How  long  will  data  be  stored?    • What  measures  taken  to  ensure  security  of  the  records?  • Any  insItuIon  based  insurance  for  research  parIcipants?  

Image:  hVp://www.officedepot.com/a/browse/storage-­‐cabinets/N=5+533602/  

Publication policy and supplements

• PublicaIon  policy:  internaIonal  peer  reviewed  journals,  open  access?  •  Supplements:  study  schedule  if  not  already  elaborated  upon,  study  schedule  schemaIcs  

Study schedule schematics example

hVp://www.nuventra.com/phase-­‐1-­‐clinical-­‐pk-­‐study-­‐Ime-­‐events-­‐table/  

Tips •  Living  document  –  may  have  to  amend  • Be  clear  and  concise  –  avoid  too  much  unnecessary  detail  • Have  focused,  well  defined  outcomes,  avoid  trying  to  do  it  all  and  focus  on  a  number  of  well  considered,  defined  key  quesIons  

• Get  help  from  a  sta9s9cian  early  in  the  planning  phases  •  Eligibility  criteria:  inclusion  criteria  are  there  to  define  your  study  populaIon,  exclusion  criteria  have  the  purpose  to  further  refine  the  study  populaIon  (relevant  contra-­‐indicaIons).  Avoid  re-­‐addressing  the  same  criteria  in  both.  KEEP  IT  SIMPLE!  

•  Safety  repor9ng:  define  what  AEs  will  be  reported,  clearly  define  what  is  expected  in  your  paIent  populaIon    

Why worry about writing a good protocol?

•  Show  collaborators  and  funders  that  you  are  organised  and  ready    • Regulatory  approvals  will  go  much  quicker  with  clear,  concise  protocol  =  save  Ime  

• Remember  the  chefs  who  have  to  read  your  recipe…  

Any questions?

Thank  you  for  your  aVenIon