Checklist to select contract Research Organization for early phase Bioavailability/Bioequivalence Clinical Studies in Healthy Adult Human Volunteers

 

Sharad Desai1, Nilesh Patel2*

1Ph.D Research Scholar, Ganpat University, Ganpat Vidyanagar-384012, Mehsana, Gujarat, India.

2Associate Professor and Head, Department of Pharmacology, Shree S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Ganpat Vidyanagar-384012, Mehsana, Gujarat, India.

*Corresponding Author E-mail: sharadarva@gmail.com, nileshcology127@gmail.com

 

ABSTRACT:

Nowadays health agencies of regulated markets are becoming stringent regarding the bio-studies. So clinical/contract research organization (CRO) need to be selected carefully after their detailed assessment. As per requirement of bio-study CRO should be assessed with the study specific checklist of questions before awarding the bio-study. Questions related to various services of study like: Clinic phase, analytical phase, Pharmacokinetic and statistical phase, ethics approval, QA/QC, record handing etc. and related to CRO capabilities are discussed here with their relevance to conclude the abilities of CRO for successful execution of bio-study. Hence, this paper focuses all possible questions which need to be assessed before selection of CRO mainly for Bioavailability/Bioequivalence (BABE) study in healthy adult volunteers. Properly selected CRO will help for smooth execution of study and quality report and subsequently, hassle-free approval of dossier submitted to regulatory agency.

 

KEYWORDS: Questionnaire, CRO, Clinical Research, Healthy, BABE study.

 

 


INTRODUCTION:

Two third of the pharmaceutical companies who have not capabilities (in term of infrastructure and/or competitive employees) to conduct the clinical research, are contracting the organization who are providing the clinical research work and such organization is known as Clinical/contract research organization (CRO) 1. Such research work is being done for development of new therapy or generic drugs2, replacement of expensive medicine. This trend is increasing day-on-day by outsourcing the work to full service CRO as stated by Michael Hennig et al 3.

 

It is pharmaceutical companies’ (Sponsor) responsibility to select the proper CRO, who is expert in this by following Good Clinical Practise4 and all norms of regulatory agencies. Many observations are issued to Sponsors, which were related to investigators and CROs in past. As per regulatory agency, CRO should be assessed by Sponsor before contracting it 5. Also, Sponsors are evaluating the CRO so their research work cannot be at risk in which too much expenses and efforts were involved. But, this selection process is always frightening job as wrong decision will put all investment at risk. Also some time the tie-up gets ended due to poor services or outcome from vendor selected by other partner. So before their strategic partnering, sponsor must have to decide that which part of service and type of services will be out sourced. Sponsors should be mainly concerned about the total experience, relevant experience for same projects, financial stability, employees’ experience, project cost, timeline adherence, infrastructure, mission and vision, quality and service 6, 7. Due to many drugs in pipeline and its larger investment, sponsors are focusing on the cost of project as main factor for selection but, the questions which are drafted in next section with their rationale must be considered before selecting the CRO. It will be easily to judge the right partner based on CRO’s response to Request for Information (RFI). The questions stated here are in form of short sentence to cover the all main aspects in limited space. So it can be modified in form of sentence and included in RFI as per type of project/evaluation requirement.

 

Questions to be assessed and its rationale:

Below are the information/questions for which responses can be obtained either in Yes/No or with description/details as per need and requirement to evaluate CRO. The questions and its rationale provided here are based on literature search, guideline/ requirements of various health/drug regulatory agency, rich experience and observation of authors during their professional career.

 

1. Company overview:

Questions: Current (historical, if changed) name, History and Description of organization. Year of foundation. HO and All sites address with contact person name with designation, department, email ID, Phone #, Mobile # and Fax #. Web address (site wise, if any). Ownership: Private or public. Parent company details, in case of subsidiary. Plan to expand in next 5 years. Organogram. Financial stability. Management of cash flow. Total revenue. Disaster Recovery and Business Continuity Plans. Policies on ethics standards and business conduct principles. Contact person for: Contingency planning, Legal Documents/ Contracts and Invoices and Payment. Procedure and verification (mail/telephonic) for change in bank account details.

 

Rationale:

Full company details with historical name helps to identify the background of company. Name of parent company and other site helps to Sponsor to check its past experience with those companies. Financial stability helps to know capability of CRO to manage the project or company in case of unavoidable situation or temporary shutdown (like COVID-19 pandemic). Process to verification of change of bank details helps to keep away the phishing problem for both Sponsor and CRO.

 

2. Inspection:

Questions: Procedure and Requirement of local health regulatory to conduct the study and centre with approval timeline. List of all (active and expired) Licenses, certifications, registrations, approval and accreditations including GCP, GLP, NABL and CAP, premises use, local sanitary, environmental agency and Fire department license with validity, if any. All facilities’ FEI # and DUNS #. Details of all past regulatory inspections with reason for inspection its reports/EIR, responses. Past inspections’ are closed or not, provide detail and reason for of open inspections. Details of receipt of Untitled Letter, Warning Letter, Field Alerts, Seizures, Detentions, Injunctions, and Debarments from any regulatory (US, EMA, MHRA etc.) with its copy, product name, date of action and current status. Details of past inspection of same sponsor like reason, audit report, response and closer, if any.

 

Rationale:

It is always important to know the requirement of local regulatory as different country has different laws, requirement and timeline and it’s always necessary to follow to avoid rejection of any trial. Always check the past inspection details and its status as based on that sponsor can conclude about past credit and working pattern and misconduct of CRO. From these try to find out the root cause and its relation and future impact to planned projects. It is also import to know the validity of all license and approval along with plan of renewal of which are about to expiry and during tenure of projects.

 

3. Experience:

Questions: Year of first executed study. Outsourced Phase and contracted site/vendor. Total % of work for generic BE studies. Other services % wise at CRO. Type of study can be conducted: Fast/ Fed/ Sprinkle-fast/ Steady-state/ multiple-dose/ SAD (Single Ascending Dose)/ MAD (Multiple Ascending Dose)/ dose-dumping/ etc. How Fed and dose dumping studies are done. Number of studies submitted and approved by regulatory with molecule name and file number also provide pending approval, if any. Turnaround time for project completion. Average per Volunteer per study cost (USD). Number of simultaneous studies can be run by clinical and bio-analytical site at a time. Policy/Procedure to meets contracted timelines of sponsor. List of pharmaceutical customers (attach list, if required). List any alliances/partnership/ contract with third party organizations. CRO’s Project Management process and structure, include name of management tools/software being used. Per volunteer only clinic phase cost. Number of studies ongoing at Clinical site and analytical site. Amounts spend per volunteer. Number of studies (Pilot and Pivotal) conducted till and in last 12 months. Number of sponsor visited till and in last 12 months. Average number of samples processed/month. Per sample analysis cost. Availability of confidentiality policy. Availability of enough full proof security and stringent access control for the scientific data. Procedure to take written permission from the sponsor prior to publication of information/data. Flexibility and requirement of CRO for pre-qualification audit and study monitoring, also on short notice. Provision to inform to Sponsor about regulatory inspection of study. Any past experience to work with same sponsor, if yes then share the details. Lead time to start the study. Average time for completion. Penalty for termination or postponement of study. Primary language is being used for documentation and report, apart from primary language, in which other languages report can be provided. Provision to provide an interim progress report upon request requested. Frequency of assessment of customer satisfaction.

 

Rationale:

It is necessary to ask to CRO for its experience for typical study and based on that expertise and trust of other Sponsors for typical study can be concluded. Information of passing/regulatory approval ratio suggests the success of CRO. Take the detail of number projects done till and in last year to know the existing market credit. Asking of about general cost helps to decide the average market rates. Normally English is used worldwide for documentation but confirm it at initial level to avoid end time surprise. There any many possibilities for delay in IPs and due that project may get postponed or cancelled and that attract the postponement or cancellation so it is advisable to get the idea of said charges before project award. All information related to project is sole property of Sponsor so CRO cannot publish it without permission of Sponsor hence, always inform CRO, that publication can be done based on Sponsor approval only. Check with CRO for confidentially policy as there are chances of leakage of information of/from one sponsor to other Sponsor. Check the process of intimation of any regulatory inspection so Sponsor will be aware about inspection of their projects. Lastly, take rough idea of lead time to start the project and capacity to run the maximum number of studies at a time, this can help to plan in advance and how many studies to be awarded as sponsor are not giving all projects to one CRO to dilute the risk and meet the expected timeline.

 

4. Infrastructure:

Questions: Plan to change the location. Facility/premise is self-owned/ rented/ leased. Total area, area of major departments and lay-out of each site. Enough provision for: lighting, ventilation, security at important areas, receptionist at entrance, door alarms, first aid box and personnel protective equipment (like safety goggles, safety gloves, mask, lab coats, foot and head covers). Enough provision and frequency for Pest control, Facility cleaning, sanitization. Availability of changing and rest rooms for employees. CCTV places and duration to store recording. Way to prevent any offsite trips for smoking or other reasons. Visitor access control: (a) in-out sign book (b) visitor badges (c) permitted area for visitor (d) control entry of any unauthorized personnel (e) monitoring of visitors to prevent passage of non-permitted materials to the study volunteers. Premises has: (a) appropriate hygienic conditions (b) clean vicinities (c) protection against the entry of insects or other pests (d) no source of environmental pollution and contamination (e) Floors, Walls and Ceiling in good condition and suitable for the activities (f) Hepa filter at clinical unit and pharmacy (g) air condition and/or heating system (h) separate bins for disposing normal waste and sharps (i) wash basin at required places (j) fire alarms, sprinkle system and Smoke detectors at ceiling. Floors have: (a) warning signs: always wash hands after toilet use (b) emergency Contacts number are displayed in major department (c) adequate safety exit and emergency evacuation plan (d) safety slogans and displayed directions prominently (e) fire extinguishers at proper places in facility (f) appropriately marked emergency exits. Toilets are: (a) separate for volunteer, staff, visitor, male, female and transgender (b) equipped with hot water, cold water, soaps, towels (paper) and air driers.

 

Rationale:

Infrastructure should be safest for all employee and volunteers. Always check the availability of CCTV camera and process to keep the record of in-out of employees, visitors and volunteers so that in future sponsor can verify the traffic of any person. It is mandatory to check the availability of safety equipment and emergency exit with marks and emergency contact number. There should be enough safety slogan and warning signs. Toilet and urinals of employee should not be accessible to volunteers so they cannot present water for urine sample analysis collected from employees’ washroom while water supply of their washroom is blocked during screening, check in and check out. Plan to shift the location is important to know as shifting may affect the volunteers’ flow and validity of regulatory authority. Ceilings, walls and floors should be intact so volunteer cannot hide anything once they are in.

 

5. Human Resources:

Questions: Total employees: XX (Full-time XX, part-time XX and temporary XX). Department wise employee #. Operation hours. Number and time of Shifts. Work days. Holiday and shutdown schedule. Current turnover rate of employees, formula to calculate and most affected areas. Medical check-up and vaccination program for employees with frequency. Present workload. Procedure to maintain employee’s personal qualification records, training, experience, CVs and Job description. Details of employee hierarchy and designation. System in place for personnel to report any safety concerns or incidents.

 

Rationale:

Based on information of employees, conclusion can be drawn for experience of staff. Working hour and workload aids to predict the quality output of work. Operation hour, working days/week, holiday and shutdown calendar helps to plan the visit and to contact for the project status. Also check the job profile are clearly defined or not for all department. As per the international standard, employee health and personal safety is important so this is also important point of evaluation.

 

6. Employee Training:

Questions: Training management system of organization. SOP followed for training. Mode of training: Consultants or in-house. Decision criteria and decision maker for training of employee. Training schedule for key person. Training system: online or paper based. Frequency of training. Procedure to evaluate the training. Procedure and place to store training records. Frequency of GCP/GLP training and list the departments participating. When and Which employees are eligible for On-the-job training: Full-time/ part-time/temporary. What is the difference in training of Full-time/ part-time/ temporary employee?

 

Rationale:

Well experienced and trained person can handle the any deviation by adhering the regulatory guidance. Training also helps to improve/update technical know-how. Frequency, method of training and trainer are important factors as outside trainer doesn’t know the real day to day problem happening for project, taking care of same and forecasting of impact on other projected/activities. Also online training system is advisable for easy tracking of the result and consolidated training report.

 

7. Emergency Handling:

Questions: Availability of proper size elevators to carry stretchers. Distance of elevators from clinical unit. Availability of well-equipped Ambulance. Availability of Defibrillator Oxygen Mask and Ambu bags, Laryngoscope, ECG Machines, Intubation tube with cuffs in good condition in ICU. Are Principal Investigator and staff qualified for resuscitation and emergency care? ACLS certified? Policy to check expiry date and frequency of replacements Emergency Medicines. Frequency and policy to check working condition of ICU instrument and ambulance and its accessories. List number and location of crash carts. Number of Intensive Care Units with bed. ICU access: controlled or open. Rational arrangement of equipment/instruments in ICU. Name, location, agreement and distance of nearest contracted general hospital with details of emergency room and all facilities to deal emergency. Process to conduct mock drill for handling of medical emergencies.

 

Rationale:

As investigational products are being tested in human, all due resources should be available to handle any emergency situation without compromise any activities. Delay in few second can cause serious adverse event/fatality. So it is always necessary to check the availability of ICU and its essential accessories in line with international standard to give the utmost care of volunteer. Frequency to check the working condition of equipment and Mock drill has equal importance. In short, ICU and emergency services should be easily accessible. Doors of ICU should not be controlled access as it delay the medical care till get accessed.

 

8. QA/QC/SoPs:

Questions: QA/QC: Name of responsible person for Quality Assurance (QA). Provide documented Quality Policy or Manual and organogram of QA. Is the QA unit (QAU) independent? To whom it report? Describe the QAU and its functions. Quality Control (QC) procedures for raw data and report review. Describe reporting of audit findings. Procedure to document corrective actions. Process for follow-up QA audits. Process for deviation reporting and evaluation before concluding the study. Availability of QA statement in final report. Enlist the vendors. List of vendors with whom agreement is not available with reason for so. Procedure for selection, qualification and management of vendors for sub-contracting and/or out sourcing done by CRO. Responsibility of validity of data from the sub-contracted/out sourced vendor done by CRO. Availability of written internal audit program. Describe briefly about the various audits (study and non-study like System and surprise audits) audits performed by QA. Provision to check the data and calculations by second person and its countersigned, define area where it is not followed. Written instructions for no overwrites, white-outs or pencil entries of official records and do sign and date for each entry. SoPs: List of all SoPs. Availability of current SoPs in operational area/equipment to access by all employees. Control and management system of SoPs. Frequency of SoPs revision. Maintenance of historical file of SoPs. Provision to archive outdated SoPs archived for future reference. How SoPs are periodically reviewed, updated and training is performed after update. Availability of document control procedures for SOPs, Test Methods, Protocols, and Forms. Facility has SoP for: (a) writing, handling and updating SoPs (b) handling deviations (c) requesting, conducting and reporting investigations (d) corrective action and preventative action (CAPA) (e) important activities mainly like emergency care, delegation to staff, reporting of adverse event, reporting serious adverse event, reporting pregnancy and its follow up procedure, maintaining confidentiality of volunteers, reporting Protocol Deviations, Change Control, and receiving, handling and storing of controlled substance.

 

Rationale:

Overall success of any projects and subsequently CRO is based on how well defined QA system implemented and followed. Any QAU should be independent8 and report to only management so their decision cannot be influenced by the any department being QA’ed. Take through idea of review process by QC and QA with % of data audited by each department before final release of data. How vendors are selected by QA is also important along with kind of services and its agreement furthermore, CRO should has option to have another qualified vendor which can be used in case of temporary/sudden shutdown of regular vendor. Focus on how audit plan is prepared, followed and reported for audit of study or non-study. Sponsor is responsible for monitoring of any project not CRO as CRO is responsible for only QA/QC measures not for monitoring. How correction is done and recorded has much importance as mistake can happen but regulatory always seeks how it is identified and corrected without tampering the data? List of many essential SoPs is mentioned here for reference but two things are important: how past obsoleted/outdated/superseded SoPs are archived for future reference and SoPs to maintain all SoPs.

 

9. Ethics Committee (EC):

Questions: Enlist separately IEC and IRB with registration details with local regulatory body. Number of visits made by EC during past 3 years. Provide working SoPs, member name with qualification of ethical Committee. Duration for which records are retained by EC. Frequency to convene of EC. Composition of EC according to GCP and at least includes a social worker, non-scientific member and both sexes. Audit requirement and schedule of local regulatory agency for EC with details of last audit and its finding. Provide copy of general EC approved consent forms. Number of protocols reviewed v/s approved v/s rejected by IEC/IRB till. EC has procedure/ SoP: (a) for protocol review before meeting and/or before approval (b) to record the suggested changes in the minutes (c) maintain log books for meeting and circulating the minutes (d) to circulate minutes to members (including absent) (e) to provide responsibilities and duties to each member individually and collectively (f) to review informed Consent of the volunteers (g) to review advertising and volunteer compensation (h) to specify presence of minimum members and specific member present for meeting (i) for calling EC meeting (j) for expedited review and approval of protocols or protocol modifications/amendments (k) to specify qualification and experience of members (l) for constitution of an ethical Committee (m) to co-opt additional members if so, provide criteria for co-opting. CRO: (a) keeps copies or communications or reports shared with EC in trial master file (b) communicates the clinical update, adverse events, study close out report, pregnancy and discontinued trial to EC (c) inform about outsourced activities during study and audit report of agencies.

 

Rationale:

One of the major responsibility of EC to ensure that participants are given enough information related trial or not 9. All rules to be followed by EC is defined by the international and local regulatory so first make sure it is followed or not by Ethics committee with whom CRO is working. It is essential to check the number of years for which EC retains the data so in case CRO closes the operation then EC should have data to present. Do through evaluation of process for reporting of discontinued trial, Adverse Event, Serious Adverse Event and Pregnancy as EC are the responsible body for Clinical study after respective local health regulatory as Pharmacovigilance activity helps to establish safety of drug 10, 11, 12. If CRO is working with few EC then it’s very good as chances of approval of rejected protocol from another EC is minimized and hence, always take the details of projects rejected by EC. In order to plan the projects very well, take the overview of expedite protocol approval process and its timeline as many time sponsor changes the design and need EC approval for minor amendments on urgent basis for the BABE planned in nearest future.

 

10. Clinical Site:

Questions: Availability of: sufficient # of Emergency exits with clear mark, panic or emergency button at each bed, monochromatic lights for light sensitive drug, central clocks in all study rooms linked to a master clock, facilities and separate area for leisure or recreation activities, kitchen and meal area for standardized meals, meal preparation site: on site or off site, registered dietician for meal planning, pathological laboratory: on site or off site, if off site provide vendor details, sample collection, sample processing, ambulatory collection and change room with locker for volunteers. Provide: (a) SoP for collection of samples, processing, storing and transferring to analytical facility (b) SoP for recruitment, screening and enrolment of the volunteers (c) general protocol template which mainly includes volunteer recruitment, study design, drug administration, laboratory test, exclusion/inclusion criteria, sample collection, sample processing and analysis (d) procedure for reviewing and communicating findings that could adversely affect the safety of volunteers and study outcome (e) procedure for labelling of vacutainer used during clinic phase (f) site wise bed capacity including ICU beds. Type of bed: single or bunk (g) number volunteers enrolled in the past 12 months and largest number of volunteers enrolled in one study and its groups (h) modes of recruitment for volunteers for volunteers outside of site database: Advertising xx%, Referrals xx%, other mode xx% (i) no. of volunteers in volunteer database. Male: xx, Female: xx, Postmenopausal Female: xx, Elder: xx (j) active enrolling number of studies clinical research coordinators typically manage (k) fed study high fat – high calorie breakfast menu (l) number of sub investigators/nurses will participate in a study (m) Adverse Event (AE) and Serious Adverse Event (SAE) management along with personal involves in evaluating the relationship to drug (n) process for checking, recording and reporting SAE and AE to health authorities, EC and sponsor in timely manner. AE coding system. (o) the additional approvals or review needed from regulatory authority, if any (p) procedure to ensure the study compliance with the protocol (q) procedure to keep records for all adverse events (r) volunteer data base and biometric systems used (s) name of screening and end study test with validity of screened volunteer (xx days) with practice of screening; General or study specific (t) biggest volunteer compliance problem (u) number of volunteers screened for routine study with 24 volunteers (v) the languages in which informed consent is taken (w) experience with special populations like postmenopausal female and elder volunteers and if any other (x) system for follow up of withdrawn and dropped out volunteers along with dropout rate in two, three and four period study. CRO has: (a) procedure for volunteers check-in and check-out (b) insurance for study volunteer with type and sum assured (c) facility of overnight stay of volunteers (d) no open windows, thus not allowing unauthorized food, drugs, etc. into clinic rooms (e) adequate design and size of clinical unit to perform the clinical study and study documentation? Provide a facility diagram (f) deviation controlling system. If yes, provide system that followed (g) procedure to take information consent process before the clinical study and provision to take witness signature on Inform consent sheet. If so, provide the Informed Consent Form template (h) logbooks for registering the volunteers’ in and out each time during screening, study and ambulatory (i) procedure to inform volunteers about study, purpose of the study and details of drug including its known adverse reactions (j) dedicated area for recruitment, counselling, screening, dosing, Phlebotomy, sample separation/ processing/ storage, recreation, dinning and physician which are segregated from the clinical ward (k) procedure for handling of screening failures and Inclusion of impartial witness as per GCP (l) procedure to provided personal hygiene kit to volunteer (m) procedure of inventory of items brought by volunteers to study (n) procedure of cleaning of beds and change of linens. Provision to avoid cross participation. Checking of volunteer identity by passport, driving license or any other Government ID. How to ensure that volunteers are not allowed to leave till check-out once inside. Centralized records for outlier, withdrawn and dropped out volunteers including its reason. Dropped ceilings are sealed or monitored to prevent storage of non-permitted materials. Number of studies have been delayed due to under enrolment or started with less volunteers.

 

Rationale:

This is one of the areas which need much attention as carelessness in clinic activities puts volunteer or study at risk so all safety measures are needed along with focused provision panic button at bed. Nowadays, many studies needs planned diet to control the PK behaviour of drug so CRO with onsite meal preparation having fulltime registered dietician needs to be preferred first. CRO with onsite laboratory is desirable as laboratory test results can be impacted because of time in transportation and logistics. By asking protocol template, sponsor can check the standard procedure followed by CRO and what is requirement of sponsor’s QA and Pharmacovigilance team. Also it will help to check the CRO’s routine tests for screening and end study and from that Sponsor can anticipate the tests which will have additional cost. Furthermore, content of fed menu can be reviewed as per the study/regulatory requirement. It is always insisted that CRO has all lower beds so volunteer safety can be ensured for the drugs which has mainly cardiac or psychiatric effect. If CRO is doing the general screening than CRO faces less problem for volunteer recruitment as they need to search the volunteer which are fit for study specific criteria as normal parameters are already screened but it has one disadvantage, screening validity period is more to save the cost so check the duration, which is normally 21 days. To avoid false enrolment always check CRO is following biometric (finger and/or Iris) scan or not. Screening duration can be judged by asking the ratio of fit to screened volunteers, normal ratio is 33% so lesser ratio suggest the longer screening duration. Screening efficiency can be concluded based on number of large volunteer studies with least groups. Sponsor can save the money by planning type of insurance and amount sum insured based on the insurance available at CRO so deep dive in this is very much important. Also insurance copy should be checked for some loopholes like coverage for injury related to procedure, coverage for pre-study activity, approval process in case of change of treatment13. Centralized record of dropped out, withdrawn and outlier volunteer helps to identify the past behaviour of the volunteer and based on that suitability of study can be concluded. To avoid future problems by local healthy regulatory it is important to know the requirement of documentation, timeline and approval from it. This also helps to Sponsor to plan project timeline and necessary documents like stability data, CoA, rational for study etc.

 

11. Pharmacy:

Questions: Provide the floor plan, equipment and degree/ license/ CVs of pharmacist. System/ process/ SoPs/ criteria for receipt, acceptance, handling, tracking, dispensing, storing (after dispensing till dosing and after study completion) and retention of study investigational Products (IPs) from sponsor. Procedure for temperature/ humidity monitoring of instrument in pharmacy area. SoP stating destruction process of IPs and its documentation with location: at site or outside. Availability of DEA/Controlled Substance license handling. Capacity and provision to handle Controlled and radioactive substance. If yes, provide details. Does IP need to clear customs? If yes then please provide brief procedure, required documents, charges and duration. Provision of controlled access of pharmacy and fire and water preventive measures. Pharmacy location: on site or off site, provide all details.

 

Rationale:

Always Pharmacy is remained interested area for the auditors of regulatory authority. So all said criteria should be evaluated carefully. Areas of main focus are SoPs for said activities, procedure/documentation to access the pharmacy and stored IPs. Always check approvals and feasibility to handle the controlled/radioactive substance. It is advisable to get the idea for IP shipment procedure, custom requirement and custom duty so Sponsor has not end time surprise related to cost and transit time. During award of project, cost and free storage duration of IPs is neglected but it is advisable to negotiate it at the initial level as after completion of study, charges may be higher to store further as per duration stated by respective regulatory agency and consequently it affects the budge of other future projects when invoiced are being received.

 

12. Bio-Analytical Site:

Questions: Provide: (a) organogram of lab (b) numbers of analyst and operator (c) list of Assay with their status like under development, under validation or planned (d) number of methods validated per year with average time for each MD/MV (e) distance between each clinical unit and analytical laboratory (f) charge associated with the method development (g) number of instruments (e.g. LC-MS/MS, HPLC, ICP etc.) being used in analysis with its make and model (h) written procedure describing laboratory documentation practices (i) SoPs for acceptance/rejection of a run set during the analysis (j) SoP for selection and acceptance of repeat analysis and re-integration of chromatograms (k) free storage duration of biological fluid after analysis and charges post that (l) Policies and processes in place for scheduling of work. How does this differ for method development versus production work? Define/ Describe: (a) the method validation procedure along experiments which are performed during validation (b) procurement procedure of blank plasma (c) Procedure for Working / Reference standards procurement, store, tracking, handling and disposition with proper record (d) procedure for Working / Reference standards procurement, store, tracking, handling and disposition with proper record (e) procedure for cleaning and labelling of laboratory glassware (f) handling of missing samples (g) procedure for bio analytical concentration data transfer to pharmacokinetics/statistics department (h) storage and handling of biological samples in freezers (i) selection of sample for ‘Incurred Sample Reanalysis’ (ISR) and its passing criteria (j) sample tracking systems used for sample handling during storage and analysis (k) procedure for preparation and handling of laboratory reagents/chemicals. Does it have ‘use before’ date? (l) Sample shipment process from clinic site to analytical laboratory. Does laboratory data includes: (a) Sample identification and description? (b) Start date of testing? (c) Test method used? (d) Standard and sample preparation? (e) Reagent and solution preparation including all weights, lot number, and expiration dates? (f) Equipment ID and calibration dates? (g) Chromatograms and printouts labelled for traceability? (h) Equipment use parameters? (i) Calculations? Results? (j) Analyst signature and date? (k) Second person checked by signature and date? How: (a) temperature maintain during transit of samples? (b) Samples are shipped: own facility or vendor? If vendor then share the agreement (c) laboratory deviations or investigations documented? (d) Integration of chromatograms is performed. Does CRO has: (a) procedures for the acceptance or rejection of standards? Please specify (b) written re-test procedure? (c) audit trail of instruments used in analytical facility? (d) laboratory facilities of adequate design and size to prevent contamination and or mix up of samples, reagents and laboratory equipment during storage and use? Provide facility diagram (e) adequate facilities for examining (specifically chemical and microbiological) water quality specified for sample and reagent preparation? What is the duration for examining the water quality? (f) written procedures for operation of laboratory equipment? Confirm availability of oven, fume hood, nitrogen evaporator, positive pressure solid phase extraction, eye washer, safety shower, analytical balance, micro balance, refrigerators, PH-meter, water purification system, refrigerated centrifuges, digital synchronized clock, thermo hygrometers, pipettes, LC-MS/MS and deep (ultra-low temperature) freezers for long storage of biological matrices. Specify which is not available. Controlled access areas separated for activities like: weighing, sample processing unit for light sensitive drug, sample processing unit with normal light, sample processing unit for temperature sensitive drug, cold storage room, chemical storage with fume hood, bio-waste storage and separate space for LC-MS/MS along with defined documentation area. Specify which is not available. System to accept the samples from third party clinic during working and non-working hours/days. Grade of Working / reference standards are used for analysis and MD/MV: USP, Commercial or any other, specify.

 

Rationale:

Bio analytical outsourcing often provides sponsors with more flexibility, global reach and less investment in personnel and capital infrastructure. It is important to fully understand what present and future needs are or will be in order to find a complementary partner for outsourcing bio analytical services. Outsourcing of bio analytical services may be done strategically or tactically and depends on business, financial and technical factors. Depending upon the specific type of project and compound, commercial bio analytical laboratories can often quickly develop and validate scientifically robust methods, then smoothly integrate those methods into sample analysis. Finding a laboratory with the breadth and depth to match the various talent, expertise, capacity and speed requirements of a drug development program can be a daunting challenge. So it should be evaluated carefully and relevance some important point is stated in next lines. Checking of method available at CRO can helps to select the products from basket to work and can reduce the project cost. Development cost helps to plan budget as some CRO charge for it and some not as its cost is half of total analytical cost of routine study. Timeline of development help to decide the length of project as it is major contributor. Always check all routine experiments are covered as per regulatory requirement or not. Also seek the process of repeat and re-test run, incurred analysis with its passing criteria as these are the weakest point of CRO and big opportunity of regulatory to give the observations. Sometime sponsor only outsource the analytical to CRO so for such cases it is important to know the process and time of sample receipt as excursion in temperature may adversely affect the outcome of BABE study. Capacity lab in term of machine and # of sample analysed can help to decide the type and number of projects to be given ant CRO at a time. Ask for tracking, follow up and CAPA of laboratory Error. Vocabulary may sound similar, meanings from organization to organization often differ, so expectations and terminology should be well defined in order to maximize efficiencies and effectiveness of study. The right combination of capacity, experience, quality, performance, communication and other attributes must be carefully assessed for "ease of use" in the evaluation of a contract laboratory. Each drug development program has its own unique requirements and those requirements change as the stages of development unfold. Identifying a laboratory with too narrow a match with one drug or stage of development will likely produce inefficiency later in the program as those needs change. Conversely, identifying a laboratory with a broader range of capabilities may provide a less effective match with the needs of "today."

 

13. Pharmacokinetic and Statistical analysis:

Questions: Name of Responsible Person, experience and qualification. Describe the Statistical analysis process. Preparation of Statistical Analysis Plan (SAP). Describe briefly about the randomization, pharmacokinetic analysis and statistical analysis procedures. Process for generating the randomization schedule. Statistical program is checked by independent statistician? Does Biostatistician verify the data prior to calculation through software? Does the facility have procedures for the determination of study volunteer outliers? Please describe briefly. Procedure to conclude and investigate that the analytical sample are inter changed along with criteria to include /exclude in statistical calculations. Enlist professional software and statistical programs used for randomization and statistical and pharmacokinetics calculations and are validated according to CFR Part 11 14 requirement (Copy of the validation report can be asked in the future)? Do you validate the statistical programs and pK analysis program in-house? How are formal reviews of documents recorded? Describe the database lock process. Capabilities for CDSIC (Clinical Data Interchange Standards Consortium) deliverables: In house or outsourced? Provide the timeline, cost and list of dataset to be provided. Format and guideline followed for final study report preparation. Report is prepared by: respective department or centralized. Report/medical writers are native-English speakers? Who provide Debarment/GCP/GLP compliance certificate in the final report? Final report shared to sponsor as: hard copy, computer disk, fax, soft copy, modem or other. Provision of written procedure for stating; how corrections of documentation errors, omissions and other inconsistencies found in the final report are to be made and documented.

 

Rationale:

Details regarding experience and qualification of concern person helps to evaluate the study requirement/bio-waiver as per biopharmaceutical classification system (BCS) 15, 16 and in vivo in vitro data correlation mainly for small companies or new start up when expert staff is not available. Outliers are the game changer for any study so it is necessary to take the information on process of same. Volunteer will be outlier due to abnormal concentration and this happens due to genetically altered metabolism or error at the time of conduct hence, check the procedure for investigation and its inclusion/exclusion from statistical analysis. From concentration graph it is easy to identify the interchanged blood samples so take insight of process at the time of RFI. Since December-2016, USFDA started to ask the CDISC data set for pivotal study, so confirm the feasibility, timeline and cost of same by CRO in-house team only as further logistic handling with third party can be reduced and sponsor can get ready to submit single dossier. Also confirm, the number of data set/domain/program files will be provided as per the regulatory requirement or not. To check the language and format of report as per the regulatory guideline is also important along with number of free draft revision. Confirm the feasibility to address the concern and to provide the report for other than intended region as some time sponsor’s business development team plans to launch the successful product in another region and need some modification or additional document as per regulatory requirement of another region. Check the length of duration (after report) for which CRO will address queries from intended region as well as another region as sometime late submission is done by sponsor to another region and CRO raises the hand to address the query at that time due to long gap. Amendment of report is required some time based on retrospective evaluation of data by sponsor or comments of regulatory authority so evaluate the practice.

 

14. Bio-Waste:

Questions: System for disposal of waste/unused biological specimen. Adequate gowning and protective wears used while handling biological samples. Do have experience of any worst situation regarding disposal of waste/unused biological specimen? If yes, how it was handled? Provide supporting evidence if have. Record keeping procedure of such incidence.

 

Rationale:

It is responsibility of every human being to take care of environment. Some CRO of underdeveloped countries are not following the rules of bio-waste and this malpractice affects the environment and drags the life of others in danger. Asking about past disaster give the idea about level of negligence.

 

15. Instruments:

Questions: Frequency of instruments calibration. Calibration done by: Third-Party or In-house, if third party then provide service provider and list out sourced services. Provision and requirement of cross-validation of instrument. Provision of acceptance limits for calibration. Availability and procedure to generate IQ, OQ, PQ protocols for instruments. Provision to mention name or number of equipment used for methods, charts, chromatograms, etc. Written instructions for performing testing on each instruments or general for same type of instrument/model that specifies methods, operating parameters and acceptance specifications. Availability of usage logbooks for each instrument. Calibration sticker on every equipment with due date. Provision to keep sticker like: “under maintenance”, “not in use”, “under calibration”, “out of order”. Master calibration records. Enlist place (pharmacy etc.) and instruments (refrigerator, freezer etc.) where temperature control is needed along with: (a) mode to set point for alarm in case of temperature excursion (b) number and place of available devises with its specialty, validation frequency and reliability of results (c) recording and correction of excursed temperature. List of equipment area wise (with supplier name and model no. if applicable) and their validation status. Number of refrigerators with temperature at each site.

 

Rationale:

Focus on the calibration ‘done by’ is most important as some temporary vendor do calibration but, they are not working for long duration and not available when regulatory come to inspect. Cross validation process helps to know the usage of any machine during break down. Process to keep said sticker helps to avoid the usage of machines by mistake and generation of wrong results. Always give the emphasis on instruments which are involved to store the temperature sensitive items along with process to monitor and record the temperature excursion. During onsite inspection, check the availability of operating instruction of all important machines.

 

16. Information and communication Technology:

Questions: Name of operating system, anti-virus, application, and other software utilities in use. Main servers and other electronic data systems are secure, environmentally controlled (Temp/humidity) and with access log. Availability of uninterrupted power supply. Number of emergency generators. Provision of security system (with password controls etc.) to protect data from tampering and alteration for all computer systems. If passwords are used as a security measure, are there provisions for periodic changing of passwords with someone in upper management having a list of all passwords in case of an emergency? Back-up (so that duplicate copy of each file can be retrieved and verified with master file) and disaster recovery procedures. Procedure and frequency for validation for computer systems involved in storing, analysing, calculating, modelling and/or transmitting clinical, analytical, PK, report and other data. System(s) are validated or not, if yes then results are documented and available for audit. Are the interfaces between systems validated? Systems are in compliance with FDA requirements on electronic systems/records (21 CFR Part 11). Log maintained for system and program changes for all computer systems. Provision to remove the immediate access of system for person who leave the company/department or loses authority. Using electronic signatures or not. Facility of automatic electronic data systems (EDS) to gather clinical (e.g., case report forms, adverse experiences, concomitant medications) and analytical data (e.g., analytical worksheets, peak heights, peak area of chromatograms), store, analyse and/or calculate and transmit. If no automatic EDS then manual data entry is done in EDS? How manually entered data are verified for security, traceability and accuracy or data integrity? Double data entry is done or not. How data will be transferred to sponsor: transformed or original or both? Written procedure to correct documentation errors, omissions and other inconsistencies found during online data collection in EDS. List of Software and their validation status.

 

Rationale:

Data tempering is not possible without loose computer security. So all stated security measures (log, validation, access, password strength, and password change process) are important to maintain to avoid data tempering and are 21 CFR Part 11 compliant. To handle emergency situation or avoid data theft, there should be a defined process for the computer access of any person who is absent, left the organization or loses authority by higher management of CRO. Make sure CRO has additional place where back up is stored apart from main site so data are available at additional site in case of disaster at main site. EDS are widely used by well advanced CRO to expedite and smoothen the processes but it should be with tight security, traceability (audit trail) and accuracy. Due to cost, limitation of infrastructure and competency of staff, some CROs are not using the EDS so in this case it is necessary to know the process of data entry from hard copy to software as there are many chances or error during such transcribing.

 

17. Data Archival:

Questions: Facilities for temporary storage of records till study completes. Permanent retention policy of records after completion of study. Archival facility: in house or third party. Access and admittance to archive facilities is secured and documented. Dedicated person for archiving. Procedures and availabilities of inventory (log) for retaining, retrieval and disposal of documents. Procedure for temporary removal and return of documents. Protection from loss or damage by: Fire, Flood, Break-in (theft) and Vermin. Disaster recovery procedure. Method to store the records: hard or soft copy. Free storage duration and its start time with charges. Process after completion of free storage period: documents will be discarded or returned, if return then charges. Procedure and duration to store the data in soft copy once destructed/returned. Method of electronic data archive.

 

Rationale:

Normally, this requirement is not focused at initial level. But keep in mind, proper availability of records is most essential when any query is received and need retrospective evaluation for verification. So verification of necessary SoPs, process to access the Archival facility and its entry in log book is important. Take the visit of archival facility to check how it is protected from Fire, Flood, Break-in (theft) and Vermin. Always insist CRO to keep the data at in-house archival so records are not impacted by third party agency. During award of project, cost and free storage duration of records is neglected but it is advisable to negotiate it at the initial level as after completion of study, charges may be higher to store further as per duration stated by respective regulatory agency and consequently it affects the budge of other future projects when invoiced are being received. In case any records are destroyed due to some valid reasons then keep soft copy with sponsor as well as ask the CRO to it for as long as possible.

 

18. Declaration/Information:

Instructions: Any other point willing to share. Fill this questionnaire electronically or hand written to evaluate your company’s quality, integrity and ability to fulfil our requirements. For any clarification, contact to Mr. /Ms. XXX YYY at xxxyyy@abc.com or Mobile +00 0000000000 of ZZZ department of abc company. Please return the completed, signed and stamped questionnaire immediately/by DD/MM/YYYY with supporting document at above contact. Do not leave any response blank; instead write “N/A or NA” signifies that the response is ‘not applicable’ or ‘not available’ respectively. Please provide: Normal lab ranges for all clinical laboratories parameters, Site Master File, Company Profile, Site Quality Overview/Quality manual, Safety manual, financial strength certificate or equivalent site related documents etc.

 

Rationale:

At the end of questionnaire, keep the instruction, details of contract person of sponsor and required documents by default. This information helps CRO how to fill it and who will be to contacted as some time few copied questions are not relevant to scope of work. It is always better to differentiate the meaning of NA (i.e. Not applicable or Not available) to avoid ambiguity at the time of reviewing answer. It is worth to mention the timeline based on depth of information requested to return the RFI for better planning of CRO as well as Sponsor.


 

Table-1: Template for Request for Information from CRO

Date:

CRO Name and Address:

Sponsor Name and Address:

Questions

Yes

No

NA

Remark/ Response- by CRO

^^ Observations/ Recommendations- by Sponsor

Q-1

 

 

 

Site-1:

Site-2:

 

Q-2

 

 

 

Site-1:

Site-2:

 

CRO confirms that enclosed information is correct and relevant to the product(s) in scope.

Quality Assurance Head or representative of CRO who have completed the questionnaire.

Name and Designation:

 

Signature and Date:

 

Site Operations Lead Representative of CRO.

Name and Designation:

 

Signature and Date:

 

Sponsor confirms that provided information is satisfactory / not satisfactory and qualifies / disqualifies the CRO.

Name and Designation of Representative of Sponsor:

 

Signature and Date:

 

^^ Here sponsor can add the various other columns like status (open/close), timeline to finish open questions and reference of regulatory guidance for observation/ recommendations.

 


CONCLUSION:

Sponsor may select the relevant questions as per the scope of services and will send to different vendors and then responses will be evaluated and weighted appropriately. Detail format is provided in Table-01 for reference. During evaluation, enough time will be taken to decide the vendor based on business requirements and quality expectations, which highly valued in early phase study17. It is always necessary that followed process should be unbiased to vendor. Based on capabilities and responses concluded, CRO can be decided as per scope of services. Text of responses can help to judge the flexibility of CRO as per sponsors’ requirements. Assignment of activities to CRO is double edge sward: properly selected CRO can reduce the burden of monitoring and coordinating 18 of the awarded project at site but, assignment doesn’t mean that work is completed as if any problem arise then sponsor must has to deal it without jeopardize the research. Furthermore, make sure it should be re-evaluated periodically to know the changes in experience, capabilities and infrastructure of CRO. Such RFI also gives the details of CRO about its working with similar products and clients, which is one of important requirement 19. Main thing to focus is what activities are subcontracted and its impact can be assessed as per need. Employee details, expertise and service will let to judge the quality and timeline of work to be done at CRO. Financial details/requirement helps to decide the financial stability of CRO and based on that budget planning can be done by Sponsor. Conclusion can be done that up to what level CRO has resources and sponsor can rely on it. Challenges can be find out based on information and its regulatory risks can be anticipated. Always focus on the transparency and commitment in answers of CRO during evaluation of RFI. CRO reliability must be evaluated based on answer received from the questions related to reputation, track records, key employee, organizational structure and contingencies plan. Sometime tactful probing to CRO to their answer helps to judge their tendency/flexibility in case of change in plan/scope. Workload and dedication of CRO is also important factor to achieve the goal of Sponsor. Finally best suited CRO will be invited to defend the requirement and criteria for productive, successful and long lasting relationship with quality output.

 

Rationale given here are only for points which need more attention but, can be criticized at individual level and as per the need of project and organization. Also, questions mentioned here are as per the requirement of current guidelines and may be edited as per prevailing guidelines of regulatory agency at the time of RFI. Also the questions may be modified with ‘who’, ’why’, ’where’, ’whom’, ’when’, ‘how’ etc. to get detail insight of mentioned questions.

 

Also, some questions can be extracted for project monitoring visits. Furthermore, questions stated in sections like, experience, Employee Training and infrastructure can be drawn for detail insight of any other department involved in execution of clinical, bio-analytical and statistical analysis.

 

These facts can improve the steepest learning curve for those who (mainly small and virtual pharmaceutical companies) are new to this field and struggling to select the right vendor.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this work.

 

REFERENCES:

1.        Dennis Salotti. Industry Report on Outsourcing Spend, Models, and Measures. Applied Clinical Trials. 2019; 28: 10-16.

2.        R. K. Verma. Generic Medicines: Core Issues and Legal Mechanism. International Journal of Reviews and Research in Social Sciences. 2019; 7 (2): 405-414. doi: 10.5958/2454-2687.2019.00033.9

3.        Michael Hennig, Ferdinand Hundt, Susanne Busta, Stefan Mikus, Per-Holger Sanden, Andrea Sörgel et al. Current practice and perspectives in CRO oversight based on a survey performed among members of the German Association of Research-Based Pharmaceutical Companies (vfa). GMS German Medical Science. 2017; 15: 1-15. doi: 10.3205/000243

4.        Lovely Joylen Castelino, Anoop Narayanan V, Swapnil Dylan Fernandes, Pankaj Kumar, Sandeep D S. Good Clinical Practices: An Indian Perspective. Research J. Pharm. and Tech. 2018; 11 (7): 3209-3215. doi: 10.5958/0974-360X.2018.00590.5

5.        Anonymous. E6 (R2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1). Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration. 2018.

6.        Eric Langer. Survey Examines Trends in the Outsourcing Relationship. BioPharm International. 2011, [cited 2021 Apr 26]; 24 (10). Available on: http://www.biopharminternational.com/ survey-examines-trends-outsourcing-relationship

7.        2014 Annual Outsourcing Survey. Contract Pharma. 2014, [cited 2021 May 02]. Available on: https://www.contractpharma.com/ contents/view_outsourcing-survey/2014-05-11/2014-annual-outsourcing-survey/

8.        Patil SM, Sapkale GN, Kumbhar PB and Maske AP. Quality Assurance in Clinical Trial. Research J. Pharmacology and Pharmacodynamics. 2010; 2 (1): 01-04.

9.        Muniyandi S. Bio Ethics in Research. International Journal of Advances in Nursing Management. 2017; 5 (4): 351-353. doi: 10.5958/2454-2652.2017.00074.9

10.      Ragul Viknesh V, Saranya P. Pharmacovigilance - An Overview in a Pharmacist Perspective. Research J. Pharm. and Tech. 2020; 13 (8): 3941-3946. doi: 10.5958/0974-360X.2020.00697.6

11.      Shraddha Anil Naik. Review on Pharmacovigilance. Asian Journal of Pharmaceutical Research. 2020; 10 (2): 123-128. doi: 10.5958/2231-5691.2020.00024.6

12.      Manohar D. Kengar, Kiran K. Patole, Akshay K. Ade, Sumesh M. Kumbhar, Chetan D. Patil, Ashutosh R. Ganjave. Introduction to Pharmacovigilance and Monitoring. Asian Journal of Pharmaceutical Research. 2019; 9 (2): 116-122. doi: 10.5958/2231-5691.2019.00019.4

13.      Thakur Abhimanyu, Kondru Sushmita, Kamilya Shruti, Kumar Amit, Goldar Epshita. Assessment of Prevailing Insurance Policies and Regulations in Context of Clinical Research Industry. Asian J. Pharm. Res. 2015; 5 (2): 114-117. doi: 10.5958/2231-5691.2015.00017.9

14.      Anonymous. Guidance for Industry Part 11, Electronic Records; Electronic Signatures — Scope and Application. Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration. 2008.

15.      Swati Saxena, Sarang Jain. A Review on Biopharmaceutical Classification System. Asian Journal of Pharmacy and Technology. 2019; 9 (4): 267-270. doi: 10.5958/2231-5713.2019.00044.8

16.      SV Deshmane, PP Chinchole, RM Gaurkhede, MA Channawar and AV Chandewar. The Biopharmaceutics Classification System: A Review. Research J. Pharm. and Tech. 2009; 2 (1): 8-11. doi:

17.      Tilde Dombernowsky, Merete Haedersdal, Ulrik Lassen, Simon Francis Thomsen. Criteria for site selection in industry- sponsored clinical trials: a survey among decision-makers in biopharmaceutical companies and clinical research organizations. Trials. 2019; 20: 2-12. doi:10.1186/s13063-019-3790-9

18.      Michael Strauss, Jeanne Novak. Selection and oversight of domestic and international CMOs. BioProcess International. 2009; 24-31.

19.      Harold E. Glass, Daniel P. Beaudry. Key factors in CRO selection. Applied Clinical Trials. 2008, [cited 2021 Jun 01]. Available on: http://www.appliedclinicaltrialsonline.com/key-factors-cro-selection-0

 

Received on 02.06.2021         Modified on 29.06.2021

Accepted on 19.07.2021     ©AandV Publications All right reserved

Res. J. Pharmacology and Pharmacodynamics.2021;13(4):131-142.

DOI: 10.52711/2321-5836.2021.00026