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Protocol prohibited medications in clinical trials
- 1. Protocol Prohibited Medications in Clinical trials( How to identify from DM Perspective) 2017 WHO Drug User Group Meeting- BANGALORE Rajeswari Gopinathan
- 2. – Information provided in this presentation does not contain any proprietary information; views expressed are those of the speaker and should not be considered official guidance. outlined are not organization perspective
- 3. I WILL SPEAK ABOUT…. Concomitant Medication in clinical trials What is Protocol Prohibited list of Medications How to identify it with coded data Use of SDG Challenges
- 4. Con-meds may interact with the study medication (thus leading to faulty conclusions regarding safety and efficacy) Drug effectiveness: Concomitant medications may also indicate a patient condition (like hypertension) which potentially affects the pharmacokinetics of the study drug. The Issues to be considered for contraindication, for inclusion on label or for further investigation in later stage studies Allowed drugs/Prohibited drugs: typically part of a clinical study’s inclusion and exclusion criteria.
- 5. A protocol prescribes the procedures to be followed during the study to ensure that the data that are being collected are a good representation of the effect that the Investigational Medicinal Product (IMP) has. Therefore the protocol also describes pretrial and concomitant medications whose use is prohibited because they are known to interfere with the IMP or have an effect similar to that as expected from the IMP. Those Medications are so called Excluded/Prohibited medications for that trial. PROHIBITED MEDICATIONS FALL INTO THREE TYPES: Drugs that interact with the study drug. Drugs that diminish liver or kidney function, or otherwise raise pharmacokinetic or safety issues. Drugs that produce confounding effects, such as masking or enhancing the intended benefits or potential side effects of the study drug.
- 6. CONCOMITANT INTERVENTIONS- PROTOCOL TEMPLATE Note: Prohibited medications descriptions in protocol will have list of medications, route and also time period of use. Instructions like discontinue them for at least how many number of days, Specific washout requirements etc.. Other instructions like Subjects who have previously received XXXXX therapy for any reason are excluded.
- 7. SOME METHODS TO IDENTIFY Computer-Assisted Prescribing Programmed Pre selection Concomitant Medication Monitoring System Decision support system Drug interaction alerting system CliniSafe Coding Input
- 8. PROGRAMMED PRE SELECTION Sponsor will send the list of Prohibited Medications. Coding of medications(Preferred term/ATC) SDG for reference Programmed Pre-selection Listing preparation Medical expert review/Manual selection from sponsor side Documentation of selected medications
- 9. SCENARIOS OF PROHIBITED DRUGS Specific drug names sent/Preferred term available in WHO DD Categories of excluded medication that has corresponding SDG Categories of excluded medication that can be linked to an ATC code Categories /drugs names that are not available in the dictionary Provide PT/code Provide the SDG Provide the ATC code corresponding SDG or ATC code not available/ Contact Sponsor Medical expert
- 10. PROHIBITED MEDICATION LIST- (SAMPLE)
- 11. PROVIDING THE PREFERRED TERM
- 12. WHAT IS SDG An SDG is any grouping of medicines having one or several properties in common
- 13. USES OF SDG
- 14. USES OF SDG
- 15. SDG USER GUIDE
- 16. SDGs 2016
- 17. SDG SUB GROUPS
- 18. SAS PROGRAMMING BASED ON PROVIDED PREFERRED TERMS
- 19. LISTING OUTPUT
- 20. ANALYSIS POPULATION MEETING Sponsor/medical monitor, biostatistician & PK pharamacokineticist at a minimum will determine what protocol deviations may impact the final analysis Analysis population meeting. Analysis Population Template
- 21. CHALLENGES Off label use Human error (coding decision went wrong)
Editor's Notes
- What is this prohibited list of medications.
- this is one of the protocol template the section saying about Cond med Interventions, usually says about allowed medications optionally required medications & finally protocol prohibited /excluded /restricted medications. Sponsor has ultimate responsibility in ensuring the safety, welfare of subjects & its regulatory requirement as well, ie why Protocol will have the schedule of activities when CM review will start They will analyze and see why it was used and if there is any specific ingredients or dose to be accepted then they would be fine, else discussion will go on with Investigator to analyze why it was used and still it is enrolled/dosed, then depending on the analysis subject will be either terminated or continued (depends on sponsor & medication) Complexity is more than 7000 official licensed generic ingredients & along with added difficulties posed by trade names, non unique names and multi ingredient preparations. Consolidating & summarizing is tedious. common method of summarizing concomitant medication data is mapping the verbatim terms using a thesaurus such as WhoDrug
- Electronic case report form (“eCRF” or “EDC”) systems could catch prohibited medications in an automated and semi-timely manner, but, remarkably, do not include this feature. These computer assisted method is Internet-based system that study coordinators, site monitors, and eCRF systems could use to check conmeds quickly and reliably.It is unreasonable to expect study personnel to reliably handle long, complicated or ambiguous lists of prohibited drugs. Given the risks to subject safety and scientific validity, minimizing the chance of human error with computerized decision support makes sense. Computer-Assisted Prescribing:Two types of computer-based systems are widely used to help physicians prescribe correct medications. Decision-support systems guide the physician through the prescribing process with a series of questions, such as potential medication conflicts. Drug interaction alerting systems just focus on notifying the physician or pharmacist of potential medication conflicts. These databases have rules to identify drugs of a particular chemical group (e.g., phenothiazine anti psychotics), therapeutic use (e.g., anti-Parkinson’s agents), or pharmacological characteristics (e.g., CYP2C19 inhibitors). These databases can support complex requirements for concomitant medications in clinical trial patients using the available drug decision support technology for drug interactions. A Concomitant Medication Monitoring System A new web-based system, CliniSafe™, enables study personnel to check conmeds in rea1 time. The study coordinator, for example, logs into the system for the study and enters subject’s medications to be checked. CliniSafe then informs the coordinator if there is a problem and which study drug rule would be violated, e.g., “Amiodarone is a moderate CYP4502D6 inhibitor and cannot be taken within 28 days of visit 1.” CliniSafe provides centralized concomitant drug checking, ensuring that even complex d rules are applied with a standardized approach. The system can be configured for use in multiple localities and languages. Reports can be generated for safety monitoring. Databases of patient drugs can be screened to enhance subject recruitment. CliniSafe c also be integrated into eCRF systems, although the results would not be as timely. Medications entered once can be saved to speed up future review or subsequent study visits. Multiple drugs can be checked in a single query. CliniSafe checks conmeds against rules created exclusively for the study and is configure for simultaneous use on multiple drug databases, such as the UK dmd, the WHO Drug Dictionary, the FDA approved list of drug products, or the CliniSafe Drug Index. These comprehensive databases are constantly updated. It takes approximately one minute for a coordinator to check five medications offering considerable time savings in relation to reviewing paper protocol and paper formularies. Drug Checking Wizard is what your Investigators see, and everything here is translated. A simple interface helps the Investigator select all of the drugs that the subject is taking. Once the subject has been added, their medications are recorded to be viewed later, or retrieved again at a later appointment. The Wizard then displays the Results - which clearly indicates which medications are safe to take for the Clinical Trial, and more importantly, which medications are not.
- a budget method for the Identification from DM perspective
- The coded data forms one of the key components of the tables and reports required for regulatory submission These are 4 scenarios of prohibited drugs:Preferred terms that are available in the WHO dictionary -- provide the PT and code
- In protocol annexure has this list
- In a typical study, the coordinator screens potential subjects against the list of prohibited (i.e., restricted) medications in the protocol’s eligibility Requirements. Later, if the person enrolls in the study, the coordinator checks for problems with any new medications. The investigator presumably reviews the coordinator’s work. The site monitor verifies that the coordinator did not miss any prohibited medications. After data lock, the scientists and biostatisticians review the data to catch any remaining problems. The list of prohibited medications is complete and unambiguous. The coordinator or site monitor correctly identifies prohibited medications from the list. It then lists them in the eligibility criteria. Potential problems with the list include the following: Study personnel may be familiar with a generic or a trade name, but not the other(s). A prohibited drug may be an ingredient in a combination drug. If a class of drugs, e.g., opiates or nonsteroidal anti-inflammatories, is listed instead of the individual drugs, study personnel may not be aware that a specific drug is in the prohibited class. This problem is more severe if a group of medications is prohibited based on its pharmacological properties or metabolic characteristics. The restrictions may be complicated, e.g., against the combined use of more than one hypertensive drug from a class. There may be unacceptable dosages of otherwise acceptable drugs. Any ambiguity requires interpretation by the study coordinator or investigator. Some therapeutic areas (e.g., neurology) have exceptionally lengthy and complex exclusion criteria. Drug names may vary by country. There may be too many drugs on the list for the study coordinator and site monitor to remember or scan reliably. A list organized alphabetically or by class may be unintuitive for some people. Drugs may need to be added to or removed from the list during the course of the study.
- short checklist for how to use the SDGs: • What is the purpose of creating a list of medicines? • Compare your purpose with the definition of the SDG you think is relevant. Are the inclusion/exclusion criteria relevant to you? • Is there a risk that the SDG contains substances that are not relevant to you, or that something is missing? • Read the description of the subgroups. • Are you interested in any particular subgroup, or the complete SDG? • Read the description of the scope, broad and narrow. • Decide on which scope is relevant to you. • Do you wish to include single substances, or combinations and trade names as well? • Are you interested in all combinations where at least one ingredient is within the scope of the SDG? – Then select the whole SDG. • Are you interested in single substances only? – You should select the entries with ‘number of ingredients = 1’. • Are you interested in umbrella entries (drug classes used when no substance or trade name is known)? – select the entries with ‘number of ingredients = 0’. • Review the SDG; make sure that the substances and classes seem correct for your intended use. Before you implement the list you should decide if you want to use the SDG as it is or if you want to modify it. • The drug codes in the list are the preferred name entries. The first six characters in the code are common to all products that contain a particular active ingredient or unique combination of ingredients. Identify the drug codes in the SDG. The list of drug codes can be used either as a checklist or be implemented in your coding or analysis software.
- We can use the SDG listing for times when they are not able to give us a comprehensive list of drug names but do have a specific classification that they are looking for. For example, if they are looking for Antihypertensives or Antineoplastic agents >250 subgroups
- The narrow scope generally represents the well-known substances with an established use and known chemical properties. The broad scope generally represents medicines with similar effects or other properties that might be helpful in a broader analysis, for eg CYP3A all entries has only narrow scope here in screenshot, if you take antineoplastic This SDG includes substances classified with ATC L, L01, L02, and L03 with antineoplastic properties. Additionally, substances classified with ATC L03AA ‘Colony stimulating factors’, V03AF ‘Detoxifying agents for antineoplastic treatment’ and A04A ‘Antiemetics and antinauseants’ are included. These medications do not have antineoplastic properties; however, they are frequently administered as part of an antineoplastic regimen, and are considered a standard adjuvant for the majority of these regimens. This SDG excludes substances classified with ATC L04 ‘Immunosuppressants’.
- Sort out variables name u want to include in the listings/output from which datasets/table A( Alias Name) is dataset name JOIN is SAS statement, RANDNUM is a condition statement to join PT name & other table, end QUIT Flag: Yes or No anything description to identify , if the condition what evert you give to identify is satisfying it will not flag , any deviation from that it will flag, you can see the output in next slide We can also customize this listing if they want to see the time period
- The medications used in a study need to be judged by a medical expert, to see whether any of these medications are in violation. In this process amongst others the route of administration, the dosage and the time period of usage are taken into account. Fortunately, the programmer can help to make the identification of violating medications more efficient, by creating clever review listings: limited to the medications that are at least a possible violation. Also, a division into separate logical listings will help the reviewer. With minor additional programming effort the identified violating medications can also be indicated in listings, and thus provide for a more complete study documentation.
- Medication-related exclusion criteria are among the most common barriers to enrollment in clinical trials. A systematic review of randomized controlled trials identified 54.1% of trials to have at least one medication-related exclusion criterion. The identical terms and the consistent classification of the term allow the analysis to draw valid statistical conclusions pertaining to the subject’s experience. The coding process can therefore affect the statistical interpretation of the adverse events or medications in which the subject is taking during the clinical trial. Protocol violations" may occur, such as when the patients do not receive the full intervention or the correct intervention or a few ineligible patients are randomly allocated in error. Despite the fact that the most clinical trials are carefully planned, many problems can occur during the conduct of the study, the analysis may bias the trial results
- Some medications may be used off-label, i.e. for an indication that is not officially accepted. Such medications may perhaps not have an ATC code that matches with the indication, and thus may not be selected as a potentially violating medication, even though reviewer might find it violating. Fortunately, during the ongoing data review, the consistency between medications and adverse events is checked, so such off-label use of medications should be detected there. If reviewer finds such a medication to be a violation then, with some additional program code, the appropriate medication class flag can be set. Sometimes medications may be added to the clinical database even after the reviewer has completed his identification of violating medications. By electronically comparing the dataset and/or review listing at database lock against those that were reviewed we can detect whether the review needs to be repeated.