Writing Clinical Research SOP's

Writing SOPs:

Writing SOPs Dr. Amit Bhatt Dean & CEO

Basic Principle in CR…..:

Basic Principle in CR….. Write down what you do, do what is written down!

What we will discuss today…:

What we will discuss today… Background What is an SOP? Why an SOP? Importance of SOPs What should an SOP contain? Writing SOPs: Intro Writing SOPs: General Tips How to write a SOP? Stopping Problem!! Who writes an SOP? What format should be used? Before & After Writing……. What should SOP cover? Step-by-step Approach

Background :

Background Performing CTs is a complicated business Bound by regulations & GCP, with the overriding concern of protecting safety and welfare of study subjects Sites must follow each protocol exactly & meet other sponsor demands Best way to ensure that all these conditions are met is formulate and follow standard operating procedures (SOPs)

What is an SOP?:

What is an SOP? An ESSENTIAL Document The who, what, when, how, and why of clinical research operations Ensures consistency, compliance, and accountability of personnel Organizations without clinic-specific SOPs run a high risk of GCP non-compliance and poor productivity

What is an SOP?:

What is an SOP? Critical tools in successful business operations for all those involved in doing CTs, investigative sites sponsors IRBs SOPs are critical to compliance and high performance standards

What is an SOP?:

What is an SOP? ICH-GCP guidelines defines SOPs “Detailed, written instructions to achieve uniformity of performance of a specific function” Just that ….. The “procedures” & processes that you use and “operate” under that have been “standardized” to ensure that you do them the same way each time

Why SOPs?:

Why SOPs? Performing CR is a COMPLICATED business It is bound by regulations and GCP overriding concern of protecting safety and welfare of study subjects Sites must follow each protocol exactly + meet other sponsor demands Best ways- formulate and follow SOPs They are essential for standardizing processes, for ensuring regulatory & organizational policy requirements r met for training new personnel for managing workload

Why SOPs?:

Why SOPs? Because study protocol is usually a brief document…… it can give details of how each procedure is to be done, who will do it etc. Provide a historical record of steps in the how, why and when Serve as a training tool for teaching users

Importance of SOPs:

Importance of SOPs Every good quality system is based on its Standard Operating Procedures (SOPs) SOPs are necessary for a clinical research organization pharmaceutical company a sponsor a contract research organization an investigator site an ethics Committee or any other party involved in CR To achieve maximum safety and efficiency of the performed TASKS

Importance of SOPs:

Importance of SOPs Audits have shown sponsor/CRO files are missing important info in several areas with respect to sponsor/CRO training no monitor CVs (75% of 226 sites) no evidence of training in SOPs (57%) No evidence of training in the therapeutic area (53%) no evidence of training in GCP (36%) and no evidence of adequate experience

Importance of SOPs:

Importance of SOPs During of selection of CROs First thing done Look for SOPs quality of SOPs compliance with SOPs other QA systems (e.g. internal auditing, proficiency testing), determine exactly which SOPs (i.e. sponsor or CRO) will be used

What should an SOP contain?:

What should an SOP contain? Two parts 1 st part: Outline or summary – includes description of the aim or purpose scope when it should be reviewed and known risks associated with the task in question Contd…

What should an SOP contain?:

What should an SOP contain? 2 nd part Accurate step-by-step description of how the task will be carried out Who is responsible for each step

Writing SOPs: Intro :

Writing SOPs: Intro Writing SOPs is not an easy process Very time-consuming Involves analysis of your processes pays big dividends when complete

Writing SOPs: General Tips :

Writing SOPs: General Tips A formal document -describes procedures that will be followed to accomplish various tasks Style of the text should be clear, concise, brief and specific to the subject Should be written to provide instructions for completion of certain procedures Mustn’t be ambiguous or confusing Statements concerning procedures to be followed should be made categorical use of words - 'must' and 'will' e.g. 'the following procedure must/will be performed'

Writing SOPs: General Tips:

Writing SOPs: General Tips Important to use words - “will” or “shall” to describe procedural steps Best to avoid words such as “should,” “could,” and “may.” Why? These words convey a since of option SOPs are not optional

Writing SOPs: General Tips :

Writing SOPs: General Tips The word 'may' is to be used only when the conditions are stated e.g. 'the investigator may enter a patient into the study without patient consent only in an emergency and when the patient is unconscious'

How to write? Stopping problem!! :

How to write? Stopping problem!! Most writers - no problem getting started Sometimes follow thro’ needs more info Most difficult thing for most –”to stop” Start at the beginning Follow the task through to the end Then stop Sounds easy Avoid long, complex sentences & paragraphs- make SOP difficult to follow

Avoid Stopping problem!!:

Avoid Stopping problem!! Begin by identifying the purpose of your SOP’s will help to focus your energy set limitations on the necessary content Create an outline of what is actually done on a day-to-day basis Develop the skeleton i.e. the structure of the SOPs important to design your SOPs to achieve specific results

Designing :

Designing Some design options: Simple steps Hierarchical steps Graphic procedures

Who writes?:

Who writes? Sound, hands on experience and knowledge of the tasks Take input from a no. of number greatly enhance usefulness of the procedures Writing SOPs doesn't require a degree in ‘alchemy’ Most important things author of a SOP can bring to word processor common sense logic

Who writes?:

Who writes? Must convey a clear instruction Not only must the user understand the instruction must also be prepared to carry it out The logical step is to let the user, as far as possible, write the SOP, in collaboration with the Trial Manager / Investigator or CRA Brings in familiarity, ownership and prevent awakwardness An improved sense of responsibility for obligation to use and comply with the SOP

What format should be used?:

What format should be used? "Just spill your guts to your computer and don't worry about the format" Format can always be added later If there is a fool proof template that can be given - might help ease some of anxiety of novice author

Format…example :

Format…example Table of contents 1 Purpose.................................................................................................2 2 Scope ................................................................................................. 2 3 Abbreviations .......................................................................................2 4 Definitions.............................................................................................3 5 Responsibilities.................................................................................... 5 6 Procedure............................................................................................ 6 6.1 Clinical Trials, phase I-III ................................................................. 6 6.2 Adverse Events Reported Spontaneously on Marketed Products7 6.3 Post-Marketing Studies ................................................................... 9 6.4 Named Patient Supplies.................................................................. 9 7 References.......................................................................................... Annexures/ Appendices/ Attachments: Forms / checklists Change log

What format should be used?:

What format should be used? Easier to edit SOPs with default formatting rather than a doc that has many extra tabs and returns added in an attempt to emulate accepted format Many new authors - involved in correct formatting - content suffers Don't rely on spell check to find all misspelled words If you use "fur" instead of "for," spell check will blithely accept it Use grammar check with care- not find all goofy little grammar faux pas that can occur when normal people put word to page If a word is changed using the Replace command, be sure to individually approve each replace. Universal replacement is quick and easy - sometimes too easy - and produces fodder for News

Before & After Writing…….:

Before & After Writing……. Identify need for new SOP Gather Input for SOP Create SOP Review and Approve SOP Provide training on SOP and distribute SOP to relevant audience Revision and Deviations of SOPs Quality Assurance Glossary

What should SOP cover?:

What should SOP cover? The no. of SOPs The arrangement of material in SOPs The level of detail in the SOPs Depend upon entirely on the organization and its related role in CT e.g., the SOPs at the sponsor’s site will be different than those at the Trial Site requirement and role of the staff members executing their work Brief outline which in general all the SOPs must cover- · A descriptive title and indication of the SOP’s position in the total collection. · Date when the SOP became operative · The edition number and a statement that this edition replaces an earlier edition from an earlier date · The exact distribution of SOPs · The signature of the person responsible for writing the SOP · The signature of the person responsible for authorising the SOP · In some contexts the purpose of the SOP

What should SOP cover?:

What should SOP cover? Title sufficient information about the contents placed prominently on page to allow the user to identify find it easily Distribution list directs - to place where it will be used distributed at all related places of its function strict check should be kept on nos. of SOPs issued and distributed at each working area

What should SOP cover?:

What should SOP cover? Singatures Signature of the person responsible for writing - shows that - SOP is complete & correct Should an auditor or for that matter any one else have a query about the content of SOP, this would be the person in contact Signature of the person responsible for authorizing - shows that SOP is operative

Step-by-Step Approach :

Step-by-Step Approach 8 steps Mapping the SOP Use of language and Scripting the SOP Editorial responsibilities of SOPs Authorizing the SOPs Distributing and Archiving the SOPs Training of the SOPs Alteration in SOPs Review of the SOPs

Step-by-step approach:

Step-by-step approach Step 1 - Mapping SOPs Process mapping – laying out all the steps in a currently used process analyzing -with goal of making it more efficient and easier to follow Involves taking each step in process & “mapping” it into a process chart All people - involved in doing task should be involved in mapping it into a process chart - free and open discussion. Often discovered during this process - involved people do not do things same way & have very different ideas about how current process works and how it should be done in the future SOPs cover all aspects of a CT protocol preparation ethical approval assessing and monitoring trial sites safety data reporting checking data integrity clinical report writing database preparation validating computer systems all the records are generally created electronically FDA’s Draft Guideline - ‘Computerized System used in Clinical Trials’

Step-by-step approach:

Step-by-step approach SOPs do not have to “fit into a box”. Formats can vary. Presentation techniques such as flow charts, diagrams, narratives, tables and bulleted lists should be considered in addition to the traditional text and paragraph formats. Presentation might vary, and should address conditions pertinent to the individual environment. Procedures should be presented in a format that will work for the institution and address specific needs in various ways. The goal is to have an easily understood procedure that the Clinical Research Staff will clearly understand and utilize.

Step-by-step approach:

Step-by-step approach Step 2 - Use of Language & Scripting the SOP written in the language which is understandable by the staff or people dealing with it If for regulatory purposes or for foreign auditors language has to be in a foreign language, an authorized translation of the SOP in the local language which is understandable by its users must be readily available at the working area Authorities, clients & colleagues must be prepared to accept translations- after all- not primary target must communicate their message effectively -must be crystal clear on who is to do what. almost seems too obvious to write, but many SOPs are difficult to read.

Step-by-step approach:

Step-by-step approach The rule of thumb for writing instructions in SOPs is these- Use short active sentences Use simple words & terms where possible Write sentences as instructions:’ do this, do that’ Write instructions in right order-so operator knows when to do appropriate task Separate instructions from gen info ,either typographically or by putting gen info in a foot note Limit amount of info per page-max 10 different actions Use diagrams wherever appropriate Give sources and references at the end

Step-by-step approach:

Step-by-step approach Step 3 - Editorial Responsibilities of SOPs It is possible for each dept or section to write, authorize &produce SOP’s in isolation. For company or sponsor----advantageous to give someone editorial responsibilities Management decides whether or not to edit SOP’s. Suitable editors might be an interdepartmental GCP committee or some of the QAU (Quality Assurance Unit) personnel Their duties would include checking a new SOP for- Style and format The edition number Consistency of content in context with relevant SOPs from other departments Compliance with policy, ICH GCP and other regulatory requirements

Step-by-step approach:

Step-by-step approach Step 4 - Authorizing the SOPs No SOP is a SOP without proper authorization Purpose is to decide on an appropriate method for a given procedure, standardize the performance of the procedure & communicate these decisions to everyone involved Most effective authorization is done by someone with organizational influence, specialist insight and knowledge of ICH GCP Rational approach - let management, in its policy, mandate use & production of SOPs Same policy -can delegate responsibility for authorization to person in charge of each specialist area defined as ‘management ’in this special context Departmental SOPs then specify which named individuals are empowered to authorize SOP’s in their area

Step-by-step approach:

Step-by-step approach Step 5 - Distributing & Archiving the SOPs Each dept or for that matter section (e .g sponsor ’site or Trial site) administers its own collection of SOPs & must identify (by the management) who is responsible for their distribution and withdrawal Responsibility for typing and copying of SOPs will depend on capacity in different depts When requisite no. of SOPs have been produced, before distribution, they should be stamped ‘DO NOT COPY’ and ‘CONTROLLED COPY’ with coloured stamp, or some other technique to distinguish between the original from photocopied versions. original SOP should be kept by QA or a responsible management representative in a secure place Historical or expired SOPs whose new versions have been issued - properly archived with ‘ARCHIVED’ stamp on original SOP Should be kept in a designated place with controlled entry called ‘Archives’ can be retrieved from the ‘Archives’ for the purpose of reference or audit whenever reqd with a proper documentation and the SOPs should be re-archived after the job is finished. A management designated person called ‘Archivist’ should be responsible for managing archives All photocopies of expired SOP - destroyed immediately after its new version comes in effect to reduce confusion for staff in working by existence of 2 different methods floating simultaneously

Step-by-step approach:

Step-by-step approach Step 6 - Training of the SOPs Training on SOPs is often last thing that people think about once SOP is written When SOP goes into effect there is often a great sense of relief frequently case that staff does not receive adequate training on the SOPs-purpose of SOPs - remains unfulfilled QA/ Monitors / CR Managers & management should see to it that there is continuous training of SOPs among staff trainings should be documented properly and all records - training log must be maintained in the staff training record effective date - must be 2-3 days after it is authorized Give sufficient time for staff to read & understand the SOP before it is actually implemented in system. effective date should be clearly specified - so that staff is aware of it Also staff training on FDA’s 21 CFR Part 11 and related guidelines on electronic records should be undertaken Formal and continuous training sessions should be taken by the QAU, CRA and CR Managers increase SOP awareness among staff and also continuous review will help in amending SOP, if reqd

Step-by-step approach:

Step-by-step approach Step 7 - Alterations in SOPs When a mistake in an SOP is found, it is tempting to alter the text by hand especially tempting when the SOP is newly issued or if the change is only in the distribution list Such alterations are dangerous as no one knows whether comments appear in all SOPs of that edition how long they have existed there whether anyone has modified their working routine as a result, or whether data has been compromised Detection of such actions must prompt inquiry- if alteration is necessary- will need to update electronic SOPs- must be a secured system of change control and rights to modify SOPs should be properly reflected in audit trail procedure of updating a SOP must reflect in the appropriate SOP both electronically and manually (if practiced)

Step-by-step approach:

Step-by-step approach Step 8 - Reviews of SOPs should be regularly reviewed and updated to ensure that they encourage efficient working practices that comply with the ever increasing requirements, improvements and government regulatory framework that have to operate within Prudent for management to introduce a scheme for automatic review - date of next review should be reflected so that everybody is aware of next review date and are ready with their suggestions and improvements If no changes are necessary this decision should be recorded but still version no. should be changed to reflect that review did happen

Parties in a Clinical Trial:

Parties in a Clinical Trial Sponsor Investigator Patient Regulatory Authorities Ethics Committee Clinical Trial

The End………:

The End……… Thanks for the Attention……. Pl feel free to discuss or ask questions

Site SOPs:

Site SOPs Ensure that site has consistent processes that meet or exceed regulatory & GCP standards all employees are familiar with processes processes are reviewed & updated on a regular basis Having and adhering to good SOPs helps to ensure audits by sponsors or by the FDA do not result in detrimental findings may also afford the site some legal protection conduct clinical research and to assure compliance with the current regulations.

How to write?:

How to write? Use short, clear, & concise words and phrases to convey clear and concise concepts in short paras Writing SOPs is a form of technical writing Remember: once a word or phrase is used to describe something, that same word or phrase should be used thro’ out SOP will help keep user focused & prevent confusion If using jargon, abbreviations, or initials, explain, spell in full, or cite the full title or name at the first use

How to write?:

How to write? The use of references in SOPs is a common practice Putting Ref Sec (listing all the references in one place) at the beginning alerts the user that there might be other doc needed to correctly follow SOP Citing other docs is easy and saves some writing overdoing ref citations - nightmare for user best case user will ignore looking at ref worst case, user could ruin a day's (or more) work

Steps in writing …. Simplified :

Steps in writing …. Simplified Write a first draft Don’t forget to distribute for internal review Any necessary modifications to procedures can be at this time Also aid in creating a sense of ownership of document & encourage all concerned to follow SOP Final version of the SOPs should then be distributed for external review and tested in practice

Steps in writing…. Simplified:

Steps in writing…. Simplified The SOPs must then be signed for approval and posted All concerned should be trained on the SOPs Don’t forget to document the training Review SOPs either annually or as needed Amended SOPs will have to be distributed to the users and old versions destroyed Archival copies should be maintained Copies of current SOPs should be available in all areas and at each work site where procedures are to be performed