The Chemotherapy and Pharmacy Advisory Service

The Chemotherapy and Pharmacy Advisory Service

Guidance on the drug-related content of clinical trial protocols

This guidance has been produced to help investigators with the pharmaceutical content of trial protocols.

The guide is made up of seven sections:

1.  Trial procedures

2.  Treatment of patients

3.  Trials drugs

4.  Glossary of formulae

5.  Manipulation of IMPs in pharmacy

6.  Labelling of IMPs

7.  National Patient Safety Agency (NPSA) information

Guidance updated by:
Group: / Chemotherapy and Pharmacy Advisory Service (CPAS) on behalf of the National Institute for Health Research, Clinical Research Network:cancer
Name: / Sally Harvey / Role: / CPAS Pharmacy Advisor
Signature: / / Date: / 09 December 2015
Guidance authorised by:
Name: / Jonathan Gower / Role: / Assistant Specialty Cluster Lead (Cancer, Surgery and Oral & Dental Health)
Signature: / / Date: / 10 December 2015

1. Trial procedures

1.1 Randomisation

Give details of the randomisation procedure/method. Describe how patients will be allocated to trial treatments/groups. For example,

·  Telephone randomisation with fax/email confirmation. If this is the case, include the telephone number and the ‘opening hours’ for randomisation.

·  Faxed randomisation with fax/email confirmation. If this is the case, include the fax number and the ‘opening hours’ for randomisation.

·  Remote randomisation process (IXRS). If this is the case, include reference to training manual, location and site staff access to remote system. Give details of the randomisation procedure.

State who will receive new patient/randomisation alerts (preferably to include pharmacy), together with research nurse and/or investigator. Describe how these alerts will be received.

Studies that involve a trial-specific procedure prior to randomisation must include a registration phase prior to randomisation. Describe the procedure for registration and how it relates to subsequent randomisation e.g.

·  After randomisation, if a patient is eligible for randomisation do they get allocated a randomisation number to be used in conjunction with the registration number?

·  Who will be informed of the patient registration and how?

1.2 Study Unblinding Procedure/Code-breaks

If the trial is single or double-blind give details of who is responsible for unblinding a subject/patient in an emergency. Include full details of the procedure to be followed and by who. If an automated IXRS system is used give details of who and how sites will have access to the unblinding facility e.g. investigator/pharmacy. Bear in mind that an out of hours, an ‘on call pharmacist’ without specialist knowledge of clinical trials may be involved. Include details of any documentation which must be completed at the time of unblinding and by who.

2. Treatment of patients

2.1 Introduction

·  Clearly list all supplies to be used in the study which are IMPs or nIMPs.

·  Add information on supply of drugs e.g. normal hospital stock, sponsor supplied.

·  Drugs status – licensed product or whether being used within license or not.

·  Give general information about treatment i.e. patients will be randomised between: <CONTROL TREATMENT> and <EXPERIMENTAL TREATMENT> (consider giving information in a diagram/flow chart that is easy to follow).

·  List all treatment arms available for randomisation.

·  If study is Phase I/II include sufficient information on starting doses, dose level and cohorts to be explored.

2.2 Treatment schedule

Give details of drugs (using generic/approved/international non-proprietary names – not brand names - unless specifically listed under brand names as IMPs in the CTA).

·  Route of administration.

·  Order of administration (if important) i.e. paclitaxel before carboplatin, temozolomide 1 hour before radiotherapy.

·  Doses (including maximum doses, number of doses/cycle).

·  Can doses be split over two days if all of the treatment cannot be completed in one day e.g. trastuzumab/pertuzumab.

·  Intrathecal doses – can some flexibility be built into monthly dosing e.g.+/- 3 days.

·  Infusion times (if applicable).

For clarity, this information should be detailed in a table or diagram which is easy for sites to follow.

2.3 Duration of Treatment

Give details of the number of cycles/duration of treatment.

Examples:

·  Patients should receive <X> cycles of chemotherapy. Include frequency and length of cycle, (number of days/weeks), maximum number of cycles.

·  Treatment should be given continuously until disease progression or up to 2 years.

·  Treatment should continue for <X> cycles unless there is evidence of disease progression, unacceptable toxicity or at the patient’s request.

·  Additional cycles may be given at the discretion of the investigator.

2.4 Drug administration

Give information on drug administration including:

·  Any special precautions that need to be taken when administering the drug as outpatient/inpatient.

For studies with oral drugs the following information should be included (if relevant):

·  Starting dose (dose increments/adjustments/frequency).

·  Information on what to do if a patient misses a dose.

·  Information on what to do if a patient vomits a dose.

·  Information on what to do if a patient has swallowing difficulties.

·  Whether drugs should be taken before/with/after food, with what quantity of water (fruit juice).

·  Whether drugs should be swallowed whole (do not chew, crush, dissolve) or (can be chewed, crushed, dissolved).

·  Whether to be taken at approximately the same time each day.

·  Whether to be taken when patient in an upright position.

·  Dose made up of X> amount of tablets/capsules (from more than one container).

·  Patient information e.g. steroid treatment card.

·  Pregnancy prevention programmes

Please Note: relevant and detailed dosing information must be included for all other drug routes used e.g. intravenous, subcutaneous, inhaled or powder for reconstitution for oral administration.

If applicable give detailed information on how to deal with hypersensitivities or state if local policy can be followed.

·  Indicate if/what patient monitoring is required after drug administration.

·  Any specific treatments for extravasation following intravenous administration.

Examples:

·  Patients will be instructed to take <DRUG> once daily preferably in the morning with up to 200ml of water at least one hour before or two hours after food. Patients should take the tablets at approximately the same time each day.

·  Take <DRUG> capsules on an empty stomach.

·  Missed doses will not be made up. The next dose must be taken as scheduled.

·  If a patient misses a dose, the dose should be taken later provided the patient remembers within 12 hours. If the patient does not remember within 12 hours, the missed dose should be omitted. Doses should NOT be doubled to make up for missed doses. [Suitable for once a day dosing].

·  If a patient vomits after taking a dose, the dose should only be replaced if the vomited tablets/capsules can actually be seen and counted.

2.5 Dose modification

It may be necessary to separate instructions against specific toxicity e.g. haematological or nausea and vomiting or other reasons for dose modifications.

For treatment administered as cycles give details of:

·  Which tests e.g. FBC, U&E, proteinuria are required prior to each cycle/day of treatment and when they must be performed e.g. on day 1 (or within 3 working days).

Please Note: units of measurement e.g. ANC to be consistent throughout document

For treatment given continuously, give details of:

·  Blood results etc required prior to first day of treatment.

·  How often treatment should be reviewed, quantities to be supplied during therapy and which tests (if any), are required prior to re-supply of drug.

Add details to clearly show:

·  Dose escalations at start of therapy and procedure/criteria for increasing doses.

·  Dose reductions for individual drugs, permitted dose levels and dose to be administered for X> number of days.

·  Interruption and permanent discontinuation for toxicities/adverse events. State whether dose escalation is allowed or not allowed.

·  State whether dose re-escalation is allowed or not.

·  If the phrase ‘when resolved’ is used, define “resolved” e.g. to ≤ grade 1, to baseline.

·  Provide information on expected side-effects and the management of these. Reference can be made to the SmPC.

·  If more than one experimental drug is being given, explain whether a patient can stop one drug due to toxicity and continue on another or whether both must be stopped.

2.6 Compliance (see also 3.7 Drug returns from patients)

Give any procedures for measuring patient compliance e.g. questionnaires, counting drugs (returned at each visit) and if reasons for dose delays, reductions or omissions require documenting by research nurse in CRF.

Examples:

·  Patients should be asked to bring completed diary cards or other records and all their unused/remaining trial medicines (empty, open or unopened) with them to each clinic visit.

·  Patients will be instructed to keep a record of compliance with treatment, by means of a “patient diary” that will be provided to them.

2.7 Support medication

It is preferable to allow sites to follow their own local policies with regard to support medication. If it is acceptable for sites to follow their local policies please add a statement to confirm this. Some sites may require guidance if unfamiliar with drugs being used. With this in mind it is often helpful for sites to be given a suggested regimen for support medication. If this is done it should be clearly stated that the regimen is suggested rather than mandated.

If local policies are not allowed please add specific details for sites to follow. Consider adding information on:

·  Anti-emetics, pre-medication, hydration schedules, calcium folinate rescue, urine alkalinisation, mesna, G-CSF, antibiotics/antifungals, anti-diarrhoeals.

·  Thromboprophylaxis for central lines, drugs for tumour lysis, drugs for mouth care.

Add information on whether any support medications will be provided free of charge by the sponsor e.g. G-CSF or at a reduced cost.

Examples:

·  Local anti-emetic policy may be followed.

·  All patients should be pre-medicated with oral corticosteroids for <X> days starting 24 hours prior to <DRUG> administration.

·  A suggested hydration schedule for <DRUG> is given in table <X>, local practice may be followed.

·  All patients should receive prophylaxis against pneumocystis jirovecii pneumonia (PJP) with co-trimoxazole 960mg orally bd Monday/Wednesday/Friday. Patients who are allergic to co-trimoxazole should receive an alternative. PJP prophylaxis should continue throughout treatment and for at least 2 months after the last course of treatment.

·  Tumour lysis prophylaxis, suggest Allopurinol 300mg od or follow local policy.

·  All blood products should be irradiated for patients in both arms of the trial.

·  The use of erythropoietin for the treatment of anaemia is not permitted.

·  The use of G-CSF is at the clinician’s discretion.

2.8 Concomitant medication

Describe any restrictions concerning concomitant medications. Include:

·  Treatments for other conditions.

·  Details of cautions and contra-indications where appropriate.

·  List of drugs either permitted or not permitted.

·  Information on how long a patient must have been taken off previous treatment before starting trial treatment if appropriate.

·  Clear instructions around wash out times from previous medication.

·  Clear instructions around tapering of corticosteroid therapy, if appropriate.

·  Whether surgery is allowed whilst on study drug.

·  Whether radiotherapy is allowed whilst on study drug.

Examples:

·  Concomitant medication may be given as medically indicated. Details of the concomitant medication given must be recorded in the Case Report Form.

·  Radiotherapy may be given concomitantly for the control of bone pain or as indicated, however these irradiated lesions will not be evaluable for response.

·  The patients must not receive other anti-cancer therapy or investigational drugs whilst on study or within <X> days of starting or stopping treatment.

·  Systemic corticosteroids are not permitted except for the treatment of anaphylactic-like reactions.

2.9 Drug interactions / potential drug interactions

It is acceptable to refer to the current SmPC or Investigator Brochure regarding drug-food interactions. However, where you require the investigator to act in a particular manner, not listed in the SmPC, in response to a drug-food interaction it is advisable to list the known or potential clinically significant drug interactions (including drug–food interactions) with follow-up instructions.

Examples:

·  There is a potential interaction between <DRUG> and warfarin. Patients have experienced elevated INRs and bleeding with this combination of drugs. Patients on warfarin and <DRUG> should have more frequent INR/PT determinations.

·  <DRUG> should NOT be taken with grapefruit or grapefruit juice.

2.10 Actual versus ideal body weight (See Section 4 for formulae)

State whether actual or ideal body weight should be used in calculations. If ideal body weight is to be used give the formula. If applicable, include information on compensating for missing limbs/ascites.

Example:

·  The dose of <DRUG> will be calculated for each patient based on actual body weight.

2.11 Calculating and recalculating BSA/doses (See section 4 for formula).

State method of calculating BSA e.g. Dubois and Dubois or refer to local policy or CCLG table, ‘Estimation for BSA in infants and children’, for paediatrics.

State whether BSA/doses should be recalculated at each cycle or only under certain conditions. Give any conditions such as ≥ 10% change and state what is compulsory and what is at clinician’s discretion.

There is an increasing use of computer prescribing systems for chemotherapy, eg: ChemoCare. For sites using these systems it is usual practice to recalculate at each cycle.

Example:

The patient’s weight at baseline will be used to determine the dose of <DRUG> for the duration of the study. If a patient’s weight changes by ≥10% during the course of the study, the dose of <DRUG> should be recalculated. If a patient’s weight changes by <10% the dose may be adjusted according to local policy/clinician’s discretion, but this is not an absolute requirement.

2.12 Carboplatin dosing

For carboplatin dosing using the Calvert formula; give the formula, the starting AUC and state which method of estimating GFR should be used (EDTA/DTPA, calculated creatinine clearance, measured creatinine clearance). If a calculated method is to be used, state which method of calculation e.g. Cockcroft and Gault, Wright and give the formula. If local policy may be followed state this.